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Sample records for 5-grass-pollen sublingual immunotherapy

  1. Adherence to Sublingual Immunotherapy.

    PubMed

    Incorvaia, Cristoforo; Mauro, Marina; Leo, Gualtiero; Ridolo, Erminia

    2016-02-01

    Adherence is a major issue in any medical treatment. Allergen immunotherapy (AIT) is particularly affected by a poor adherence because a flawed application prevents the immunological effects that underlie the clinical outcome of the treatment. Sublingual immunotherapy (SLIT) was introduced in the 1990s, and the early studies suggested that adherence and compliance to such a route of administration was better than the traditional subcutaneous route. However, the recent data from manufacturers revealed that only 13% of patients treated with SLIT reach the recommended 3-year duration. Therefore, improved adherence to SLIT is an unmet need that may be achieved by various approaches. The utility of patient education and accurate monitoring during the treatment was demonstrated by specific studies, while the success of technology-based tools, including online platforms, social media, e-mail, and a short message service by phone, is currently considered to improve the adherence. This goal is of pivotal importance to fulfill the object of SLIT that is to modify the natural history of allergy, ensuring a long-lasting clinical benefit, and a consequent pharmaco-economic advantage, when patients complete at least a 3-year course of treatment. PMID:26758865

  2. The future of sublingual immunotherapy.

    PubMed

    Marcucci, F; Duse, M; Frati, F; Incorvaia, C; Marseglia, G L; La Rosa, M

    2009-01-01

    Sublingual immunotherapy (SLIT) is currently the most prescribed form of allergen immunotherapy in many European countries. Its use has been accepted in the international consensus publications, and recently also the scepticism of USA scientists is attenuated. Still, this treatment may be improved, and the possible developments consist of modification of the materials, use of adjuvants and use of recombinant allergens. Moreover, new applications of SLIT, such as food allergy, seem promising. Concerning materials, the future form of SLIT is likely to be represented by tablets, which were already tested for efficacy and safety with grass pollen extracts, and are likely to increase the convenience for the patient by the use of no-updosing schedule. Adjuvants fitting with the characteristics of SLIT seem to be CpG oligodeoxynucleotides (CpG), able to interact with the Toll-like receptor 9 (TLR9) whose activation induces a Th1-like pattern of cytokine release, combination of 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3-Dex), and Lactobacillus plantarum. The approach with recombinant allergens, named component-resolved diagnosis, offers the possibility to tailor immunotherapy, which was found to be effective in two randomized trials of subcutaneous SIT (16-17), while studies with SLIT are not yet available. Regarding food allergy, an important controlled study demonstrated that SLIT with hazelnut is able to increase patients tolerance over possible reactions from inadvertent assumption of the culprit food, and warrants for further trials with other foods. PMID:19944008

  3. Sublingual immunotherapy: a comprehensive review.

    PubMed

    Cox, Linda S; Larenas Linnemann, Désirée; Nolte, Hendrik; Weldon, David; Finegold, Ira; Nelson, Harold S

    2006-05-01

    Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is viewed with increasing interest by allergists in the United States. To address this interest, a Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology's Immunotherapy and Allergy Diagnostic Committees reviewed the available literature on SLIT and prepared this report. The task force concluded that despite clear evidence that SLIT is an effective treatment, many questions remained unanswered, including effective dose, treatment schedules, and overall duration of treatment. Until these have been determined, an assessment of the cost/benefit ratio of the treatment cannot be made. SLIT does appear to be associated with few serious side effects, but it has not been administered in high-risk asthmatic patients, nor in the studies reviewed has it been administered as a mixture of non-cross-reacting allergens. Furthermore, there is currently no allergy extract approved for this use in the United States, nor is there a Current Procedural Terminology code for billing purposes. All of these factors should be given careful consideration by anyone contemplating initiating SLIT treatment for their allergic patients. PMID:16675328

  4. Mechanisms of Aeroallergen Immunotherapy: Subcutaneous Immunotherapy and Sublingual Immunotherapy.

    PubMed

    Ozdemir, Cevdet; Kucuksezer, Umut Can; Akdis, Mübeccel; Akdis, Cezmi A

    2016-02-01

    Allergen immunotherapy (AIT) is an effective way to treat allergic disorders, targeting the underlying mechanisms and altering the disease course by inducing a long-lasting clinical and immune tolerance to allergens. Although sublingual and subcutaneous routes are used in daily practice, many novel ways to decrease side effects and duration and increase efficacy have been pursued. Further studies are needed to develop biomarkers for the identification of AIT responder patients and also to use the developed knowledge in allergy prevention studies. Future directions in AIT include treatments for autoimmune diseases, chronic infections, organ transplantation, and breaking immune tolerance to cancer cells.

  5. Sublingual immunotherapy: World Allergy Organization position paper 2013 update

    PubMed Central

    2014-01-01

    We have prepared this document, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update”, according to the evidence-based criteria, revising and updating chapters of the originally published paper, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2009”, available at http://www.waojournal.org. Namely, these comprise: “Mechanisms of sublingual immunotherapy;” “Clinical efficacy of sublingual immunotherapy” – reporting all the data of all controlled trials published after 2009; “Safety of sublingual immunotherapy” – with the recently published Grading System for adverse reactions; “Impact of sublingual immunotherapy on the natural history of respiratory allergy” – with the relevant evidences published since 2009; “Efficacy of SLIT in children” – with detailed analysis of all the studies; “Definition of SLIT patient selection” – reporting the criteria for eligibility to sublingual immunotherapy; “The future of immunotherapy in the community care setting”; “Methodology of clinical trials according to the current scientific and regulatory standards”; and “Guideline development: from evidence-based medicine to patients' views” – including the evolution of the methods to make clinical recommendations. Additionally, we have added new chapters to cover a few emerging crucial topics: “Practical aspects of schedules and dosages and counseling for adherence” – which is crucial in clinical practice for all treatments; “Perspectives and new approaches” – including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, “Raising public awareness about sublingual immunotherapy”, as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail. PMID:24679069

  6. Onset of oral allergic syndrome during birch sublingual immunotherapy.

    PubMed

    Ciprandi, G

    2012-08-01

    Pollen allergy may be frequently associated with oral allergy to fruits and/or vegetables (the so called oral allergic syndrome). Some studies reported a possible positive effect exerted by allergen-specific immunotherapy on OAS course, while others did not. A case of OAS case onset after starting sublingual immunotherapy is reported.

  7. Sublingual Immunotherapy: A Useful Tool for the Allergist in Private Practice

    PubMed Central

    2016-01-01

    This is a review of the author's experience with Sublingual Immunotherapy in a private office setting. Sublingual Immunotherapy should be considered by any allergy practitioner as a useful tool. Sublingual Immunotherapy is safe while at the same time it is effective. It enables the practitioner to treat asthmatics and young children without the concerns implicit with allergy injections. PMID:27340673

  8. Five-grass-pollen sublingual immunotherapy tablet for the treatment of grass-pollen-induced allergic rhinoconjunctivitis: 5 years of experience.

    PubMed

    Didier, Alain; Wahn, Ulrich; Horak, Friedrich; Cox, Linda S

    2014-10-01

    Oralair(®) (OA) (Stallergenes, Antony, France) is a unique pre- and co-seasonal 5-grass-pollen sublingual immunotherapy tablet launched in 2008, and now approved in 31 countries worldwide for the treatment of grass-pollen allergic rhinitis and rhinoconjunctivitis. OA is the first oral treatment with a consistent, well-balanced allergen extract that mimics natural exposure and sensitization. A wealth of data exists from over 5 years of clinical and real-world experience demonstrating the efficacy and safety of OA for grass-pollen-allergy treatment. OA is highly effective from the first pollen season in all patient subgroups, including children and those with comorbid mild asthma, irrespective of sensitization status and symptom severity. OA also has sustained long-term benefits for symptom control and quality of life. This article provides an overview of the pharmacodynamics and pharmacology of OA; its efficacy, safety, tolerability and cost-effectiveness for the treatment of allergic rhinitis and rhinoconjunctivitis and its role in clinical practice.

  9. Dropouts in sublingual allergen immunotherapy trials - a systematic review.

    PubMed

    Makatsori, M; Scadding, G W; Lombardo, C; Bisoffi, G; Ridolo, E; Durham, S R; Senna, G

    2014-05-01

    Participant dropouts can reduce the power of allergen immunotherapy clinical trials. Evaluation of the dropout rate and reasons for dropout are important not only in the planning of clinical studies but are also relevant for adherence to immunotherapy in daily clinical practice. A systematic review was carried out in order to establish the overall dropout rate among published double-blind, placebo-controlled randomized clinical trials of sublingual immunotherapy for respiratory allergic diseases. Dropouts were analysed in regards to allergen, formulation, treatment schedule, participant age, study size, number of centres and type of allergic disease. Relative dropout rates in placebo and active groups as well as reasons for dropout were also assessed. A total of 81 studies, comprising 9998 patients, were included. Dropout rates in sublingual immunotherapy controlled studies do not appear to be a major problem with a composite dropout percentage of 14% (95% CI:11.9-16). Furthermore, they are not different for active compared to placebo-treated participants. This lends support to the positive clinical outcomes seen in meta-analyses of these trials. PMID:24673502

  10. Sublingual immunotherapy for allergic rhinitis: where are we now?

    PubMed

    Incorvaia, Cristoforo; Mauro, Marina; Ridolo, Erminia

    2015-01-01

    Sublingual immunotherapy (SLIT) was introduced in the 1980s as a safer option to subcutaneous immunotherapy and in the latest decade achieved significant advances. Its efficacy in allergic rhinitis is supported by a number of meta-analyses. The development of SLIT preparations in tablets to fulfill the requirements of regulatory agencies for quality of allergen extracts made available optimal products for grass-pollen-induced allergic rhinitis. Preparations of other allergens based on the same production methods are currently in progress. A notable outcome of SLIT, that is shared with subcutaneous immunotherapy, is the evident cost-effectiveness, showing significant cost savings as early as 3 months from starting the treatment, that become as high as 80% compared with drug treatment in the ensuing years.

  11. [Sublingual immunotherapy in children. Immunotherapy Committee of the Spanish Society for Clinical Immunology and Pediatric Allergology].

    PubMed

    Lleonart, R; Muñoz, F; Eseverri, J L; Martínez-Cañabate, A; Tabar, A I; Pedemonte, C

    2003-01-01

    Sublingual immunotherapy is currently attracting growing interest because of its ease of administration and, according to previous studies, its infrequent and mild adverse effects. However, at least in children, the efficacy of this therapy has not been completely demonstrated. In addition, the mechanisms of action remain to be elucidated since few studies have been published and the results have been contradictory and sometimes inconclusive. For this reason, we performed a literature review through the MEDLINE database, selecting double-blind studies carried out in children. Only 10 studies meeting these requirements were retrieved. All the studies were performed by European researchers and nine were published in European journals. Efficacy was evaluated by clinical parameters and by reduction in medication use. The results on efficacy are not homogeneous, although most support the utility of this route of administration. Moreover, reports of allergens other than those used in these studies dust mites and grass pollens are lacking. In conclusion, further studies evaluating the efficacy of this therapy in children are required. Among the general population, if the efficacy of sublingual immunotherapy in the treatment of sensitization to hymenoptera venoms were demonstrated, as has been the case with subcutaneous immunotherapy, the utility of this route of administration would be definitively confirmed. Finally, sublingual immunotherapy could be used in children who have shown systemic reactions to subcutaneous immunotherapy or who refuse to undergo injections.

  12. Selection of patients for sublingual versus subcutaneous immunotherapy.

    PubMed

    Larenas Linnemann, Désirée E S; Blaiss, Michael S

    2014-01-01

    Allergen immunotherapy is the sole treatment for IgE-mediated allergic diseases directed at the underlying mechanism. The two widely accepted administration routes are sublingual (SLIT) and subcutaneous (SCIT). We reviewed how patients should best be selected for immunotherapy and how the optimal administration route can be defined. Before deciding SCIT or SLIT, appropriate selection of patients for allergen immunotherapy (AIT) is mandatory. To be eligible for AIT, subjects must have a clear medical history of allergic disease, with exacerbation of symptoms on exposure to one or more allergens and a corresponding positive skin or in vitro test. Then the route of administration should be based on: published evidence of clinical and immunologic efficacy (which varies per allergic disease and per allergen); mono- or multi-allergen immunotherapy, for SLIT multi-allergen immunotherapy was not effective; safety: adverse events with SLIT are more frequent, but less severe; and, costs and patient preferences, closely related to adherence issues. All these are discussed in the article.

  13. Sublingual immunotherapy for pediatric allergic rhinitis: The clinical evidence.

    PubMed

    Poddighe, Dimitri; Licari, Amelia; Caimmi, Silvia; Marseglia, Gian Luigi

    2016-02-01

    Allergic rhinitis is estimated to affect 10%-20% of pediatric population and it is caused by the IgE-sensitization to environmental allergens, most importantly grass pollens and house dust mites. Allergic rhinitis can influence patient's daily activity severely and may precede the development of asthma, especially if it is not diagnosed and treated correctly. In addition to subcutaneous immunotherapy, sublingual immunotherapy (SLIT) represents the only treatment being potentially able to cure allergic respiratory diseases, by modulating the immune system activity. This review clearly summarizes and analyzes the available randomized, double-blinded, placebo-controlled trials, which aimed at evaluating the effectiveness and the safety of grass pollen and house dust mite SLIT for the specific treatment of pediatric allergic rhinitis. Our analysis demonstrates the good evidence supporting the efficacy of SLIT for allergic rhinitis to grass pollens in children, whereas trials regarding pediatric allergic rhinitis to house dust mites present lower quality, although several studies supported its usefulness. PMID:26862501

  14. Adherence issues related to sublingual immunotherapy as perceived by allergists

    PubMed Central

    Scurati, Silvia; Frati, Franco; Passalacqua, Gianni; Puccinelli, Paola; Hilaire, Cecile; Incorvaia, Cristoforo

    2010-01-01

    Objectives: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence. Methods: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10. Results: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists. Conclusion: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers. PMID:20622914

  15. The special challenge of nonadherence with sublingual immunotherapy.

    PubMed

    Bender, Bruce G; Oppenheimer, John

    2014-01-01

    Patient nonadherence is a problem that impacts all chronic illness treatments. To determine the degree of nonadherence and its impact on treatment effect in sublingual immunotherapy (SLIT), we conducted a systematic review of published research that assessed adherence or tested interventions to improve SLIT adherence. Adherence to SLIT is similar to other long-term therapies. Across studies, 55% to 82% of patients abandoned SLIT before completing the recommended course of therapy. Only 1 study attempted to test an educational intervention to improve SLIT adherence. Composite evidence indicates that 3 to 5 years of sustained SLIT is required for full long-term benefits, but fewer than half of the patients on SLIT persist to that point. Surprisingly little research has addressed the consequence of partial adherence, including implication to its cost-benefit profile or strategies to improve adherence. Lessons from research into treatments of other chronic health conditions suggest several adherence interventions that may be applied to SLIT, including strategic use of communication and education tools, incorporation of standardized follow-up visits, and employment of telecommunication technologies.

  16. Importance of Quality of Life for Adherence to Sublingual Immunotherapy

    PubMed Central

    Eberle, Peter

    2016-01-01

    Background. Nonperception of efficacy ranks among the most commonly cited causes for nonadherence to sublingual immunotherapy (SLIT). Quality of life (QoL) in patients is a determining factor influencing adherence. We investigated QoL and adherence separately in SLIT patients at one pediatric practice in Germany. Methods. We conducted a noninterventional, cross-sectional, retrospective, quality-of-life survey among pediatric patients treated with SLIT. QoL was assessed using the generic SF-12 health survey in German. The items contained in the SF-12 health survey are weighted, added up, and converted to obtain a physical component score (PCS) and a mental component score (MCS). Each component score ranges from 0 to 100; the higher the score, the better the QoL perceived. Results. 201 surveyed patients who had undergone SLIT showed PCS-12 of 49.3 (± 7.0) and MCS-12 of 52.6 (± 7.2). These figures correlate strongly with those reported for the German general population (n = 2453): PCS-12 of 49.6 (± 8.7) and MCS-12 of 52.3 (± 8.0). 70.2% (73) of 104 patients were adherent at this practice. Conclusions. QoL in the SLIT patients surveyed here appears as good as that of the general population. Adherence to SLIT at this practice was remarkably better than that reported elsewhere. PMID:27504453

  17. Rare adverse events due to house dust mite sublingual immunotherapy in pediatric practice: two case reports.

    PubMed

    Galip, Nilufer; Bahceciler, Nerin

    2015-01-01

    Sublingual route, a noninjective way of allergen administration appears to be associated with a lower incidence of severe systemic reactions compared with the subcutaneous route. Local adverse reactions are reported which resolve spontaneously within a few days without need for discontinuation of treatment. Hereby, we report two pediatric cases, one with persistent asthma and the other one with persistent allergic rhinitis. Both were treated by house dust mite sublingual immunotherapy, one of whom developed severe wheezing (grade 2 systemic reaction based on World Allergy Organization subcutaneous systemic reaction grading system) and the other intractable vomiting (grade 3 local reaction based on World Allergy Organization sublingual immunotherapy local adverse events grading system) at the end of the build-up phase which repeated on re-administration of the same dose. Both of those two cases completed their 3-year immunotherapy successfully by patient-based adjustment of the highest tolerated dose of the maintenance.

  18. Influence of sublingual immunotherapy on the expression of Mac-1 integrin in neutrophils from asthmatic children.

    PubMed

    Ciepiela, Olga; Zawadzka-Krajewska, Anna; Kotula, Iwona; Pyrzak, Beata; Demkow, Urszula

    2013-01-01

    Asthma can be effectively treated with sublingual immunotherapy. The influence of -sublingual immunotherapy on the function of granulocytes in asthmatic patients is largely unknown. Mac-1 integrin is a transmembrane protein containing α (CD11b) and β (CD18) chains. High expression of the complex is found on the surface of neutrophils, NK cells, and macrophages. CD11b/CD18 may bind to CD23, ICAM-1, ICAM-2, and ICAM-4. It plays a crucial role in diapedesis of neutrophils. The aim of the present study was to assess Mac-1 expression on neutrophils from asthmatic children before and after sublingual immunotherapy. Twenty five children aged of 8.1 ± 3.1 suffering from atopic asthma and allergic rhinitis, shortlisted for specific immunotherapy, served as the study group. Fifteen healthy individuals, aged 9.8 ± 3.4, served as a control group. The assessment of CD11b and CD18 expression on cells from peripheral blood was performed with a flow cytometer. The tests were performed before and after 12 months of sublingual immunotherapy. In the asthmatic children, 98.08 (90.79-99.12)% of Mac-1 positive neutrophils were detected. The group was divided into two subgroups: of more than 98% and less than 95% of neutrophils with CD11b/CD18 expression in the sample. After immunotherapy, the percentage of Mac-1 positive granulocytes increased to 99.60 (99.29-99.68)%, p = 0.01. In the control group, 90.56 (87.08-88.86)% granulocytes were Mac-1 positive, p = 0.002. We conclude that sublingual immunotherapy strongly influences the function of the immunological system, including Mac-1 expression on neutrophils.

  19. Adverse reactions and tolerability of high-dose sublingual allergen immunotherapy

    PubMed Central

    Moral, Angel; Moreno, Victoria; Girón, Francisco; El-Qutob, David; Moure, José D; Alcántara, Manuel; Padial, Antonia; Oehling, Alberto G; Millán, Carmen; de la Torre, Fernando

    2016-01-01

    Background Sublingual allergen immunotherapy is an effective treatment against allergic respiratory disease. Many studies have shown the safety of this type of therapy, although the factors that might affect the tolerability of high-dose sublingual immunotherapy have not been well established. The aim of this study was to determine the factors that affect the tolerability of sublingual allergen immunotherapy. Patients and methods A total of 183 subjects aged ≥5 years, diagnosed with allergic rhinitis with/without mild to moderate asthma due to sensitization to grass, olive pollen, or mites, were included in this open, retrospective, multicentric, noninterventional study. Sublingual immunotherapy was administered for at least 3 months. Results The most frequent adverse reaction was oral pruritus (13.7% of the patients). Most of the reactions were local (84.7%) and immediate (93.5%) and occurred during the initiation phase (60.6%). All reactions were mild to moderate in severity. No serious adverse reactions were registered. When comparing factors with potential influence on the occurrence of adverse reactions, the results between the groups of subjects with and without adverse reactions showed no statistically significant differences in sex (P=0.6417), age (P=0.1801), years since the disease was first diagnosed (P=0.3800), treatment composition (P=0.6946), polysensitization (P=0.1730), or clinical diagnosis (P=0.3354). However, it was found that treatment duration had a statistically significant influence (3 months, >3 months: P=0.0442) and the presence of asthma was close to statistical significance (P=0.0847). Conclusion In our study, treatment duration is significantly associated with the occurrence of adverse reactions after the administration of high doses of sublingual allergen immunotherapy. PMID:27418842

  20. Sublingual Immunotherapy as an Alternative to Induce Protection Against Acute Respiratory Infections

    PubMed Central

    Muñoz-Wolf, Natalia; Rial, Analía; Saavedra, José M.; Chabalgoity, José A.

    2014-01-01

    Sublingual route has been widely used to deliver small molecules into the bloodstream and to modulate the immune response at different sites. It has been shown to effectively induce humoral and cellular responses at systemic and mucosal sites, namely the lungs and urogenital tract. Sublingual vaccination can promote protection against infections at the lower and upper respiratory tract; it can also promote tolerance to allergens and ameliorate asthma symptoms. Modulation of lung’s immune response by sublingual immunotherapy (SLIT) is safer than direct administration of formulations by intranasal route because it does not require delivery of potentially harmful molecules directly into the airways. In contrast to intranasal delivery, side effects involving brain toxicity or facial paralysis are not promoted by SLIT. The immune mechanisms underlying SLIT remain elusive and its use for the treatment of acute lung infections has not yet been explored. Thus, development of appropriate animal models of SLIT is needed to further explore its potential advantages. This work shows how to perform sublingual administration of therapeutic agents in mice to evaluate their ability to protect against acute pneumococcal pneumonia. Technical aspects of mouse handling during sublingual inoculation, precise identification of sublingual mucosa, draining lymph nodes and isolation of tissues, bronchoalveolar lavage and lungs are illustrated. Protocols for single cell suspension preparation for FACS analysis are described in detail. Other downstream applications for the analysis of the immune response are discussed. Technical aspects of the preparation of Streptococcus pneumoniae inoculum and intranasal challenge of mice are also explained. SLIT is a simple technique that allows screening of candidate molecules to modulate lungs’ immune response. Parameters affecting the success of SLIT are related to molecular size, susceptibility to degradation and stability of highly concentrated

  1. Sublingual immunotherapy as an alternative to induce protection against acute respiratory infections.

    PubMed

    Muñoz-Wolf, Natalia; Rial, Analía; Saavedra, José M; Chabalgoity, José A

    2014-01-01

    Sublingual route has been widely used to deliver small molecules into the bloodstream and to modulate the immune response at different sites. It has been shown to effectively induce humoral and cellular responses at systemic and mucosal sites, namely the lungs and urogenital tract. Sublingual vaccination can promote protection against infections at the lower and upper respiratory tract; it can also promote tolerance to allergens and ameliorate asthma symptoms. Modulation of lung's immune response by sublingual immunotherapy (SLIT) is safer than direct administration of formulations by intranasal route because it does not require delivery of potentially harmful molecules directly into the airways. In contrast to intranasal delivery, side effects involving brain toxicity or facial paralysis are not promoted by SLIT. The immune mechanisms underlying SLIT remain elusive and its use for the treatment of acute lung infections has not yet been explored. Thus, development of appropriate animal models of SLIT is needed to further explore its potential advantages. This work shows how to perform sublingual administration of therapeutic agents in mice to evaluate their ability to protect against acute pneumococcal pneumonia. Technical aspects of mouse handling during sublingual inoculation, precise identification of sublingual mucosa, draining lymph nodes and isolation of tissues, bronchoalveolar lavage and lungs are illustrated. Protocols for single cell suspension preparation for FACS analysis are described in detail. Other downstream applications for the analysis of the immune response are discussed. Technical aspects of the preparation of Streptococcus pneumoniae inoculum and intranasal challenge of mice are also explained. SLIT is a simple technique that allows screening of candidate molecules to modulate lungs' immune response. Parameters affecting the success of SLIT are related to molecular size, susceptibility to degradation and stability of highly concentrated

  2. An extract of Timothy-grass pollen used as sublingual immunotherapy for summer hay fever.

    PubMed

    Kay, A B

    2007-12-01

    Grazax is a lyophilisate of an extract of Timothy-grass pollen (Phleum pratense) administered by the sublingual route to induce desensitization (or hyposensitization) to grass pollen in subjects with hay fever. Since allergen avoidance measures are limited in hay fever sufferers, present treatment, at least in the United Kingdom, is almost always by symptomatic medication. The effectiveness of symptomatic treatment in hay fever is variable and depends on patient compliance and the judicious prescribing of antihistamines and anti-inflammatory preparations either alone or in combination. Desensitization (hyposensitization or specific immunotherapy) by subcutaneous injection has been shown to be very efficacious and is used for patients who do not adequately respond to drug treatment. A rare side effect of desensitizing injections is anaphylaxis, and so use is limited to specialized centers. For these reasons there has been considerable interest in specific immunotherapy by the sublingual route. Grazax has recently been approved in the United Kingdom. It is commenced at least four months prior to the expected start of the grass pollen season and in line with injection immunotherapy treatment will be recommended for a period of three years with annual reviews to assess patient outcomes. Grazax grass allergen tablets are well tolerated in patients with grass pollen allergy with most adverse events being mild local reactions. There have been no instances of anaphylaxis. In randomized double-blind placebo controlled trials Grazax reduces symptoms and medication scores in adults with hay fever. The long-term effects of Grazax are currently being investigated.

  3. Sublingual immunotherapy (SLIT)--indications, mechanism, and efficacy: Position paper prepared by the Section of Immunotherapy, Polish Society of Allergy.

    PubMed

    Jutel, Marek; Bartkowiak-Emeryk, Małgorzata; Bręborowicz, Anna; Cichocka-Jarosz, Ewa; Emeryk, Andrzej; Gawlik, Radosław; Gonerko, Paweł; Rogala, Barbara; Nowak-Węgrzyn, Anna; Samoliński, Bolesław

    2016-01-01

    SLIT (sublingual immunotherapy,) induces allergen-specific immune tolerance by sublingual administration of a gradually increasing dose of an allergen. The mechanism of SLIT is comparable to those during SCIT (subcutaneous immunotherapy), with the exception of local oral dendritic cells, pre-programmed to elicit tolerance. In the SLIT dose, to achieve the same efficacy as in SCIT, it should be 50-100 times higher with better safety profile. The highest quality evidence supporting the efficacy of SLIT lasting 1-3 years has been provided by the large scale double-blind, placebo-controlled (DBPC) trials for grass pollen extracts, both in children and adults with allergic rhinitis. Current indications for SLIT are allergic rhinitis (and conjunctivitis) in both children and adults sensitized to pollen allergens (trees, grass, Parietaria), house dust mites (Dermatophagoides pteronyssinus, Dermatophagoides farinae), cat fur, as well as mild to moderate controlled atopic asthma in children sensitized to house dust mites. There are positive findings for both asthma and new sensitization prevention. Severe adverse events, including anaphylaxis, are very rare, and no fatalities have been reported. Local adverse reactions develop in up to 70 - 80% of patients. Risk factors for SLIT adverse events have not been clearly identified. Risk factors of non-adherence to treatment might be dependent on the patient, disease treatment, physician-patient relationship, and variables in the health care system organization. PMID:27012173

  4. Adverse Events During Immunotherapy Against Grass Pollen-Induced Allergic Rhinitis - Differences Between Subcutaneous and Sublingual Treatment.

    PubMed

    Aasbjerg, Kristian; Dalhoff, Kim Peder; Backer, Vibeke

    2015-08-01

    Allergic rhinitis (AR) triggered by grass pollen is a common disease, affecting millions of people worldwide. Treatment consists of symptom-alleviating drugs, such as topical corticosteroids or antihistamines. Another option is potentially curative immunotherapy, currently available as sublingual and subcutaneous treatment. We investigated the potential differences in the prevalence and severity of adverse events related to subcutaneous and sublingual immunotherapy (SLIT) against grass pollen-induced AR. A thorough literature search was performed with PubMed and EMBASE. The findings were compared with the available summaries of product characteristics (SPC) and with commercial pharmacology databases (Micromedex). The majority of available safety data originate from registered products of standardized allergens. A surprisingly large percentage of drugs, especially those used in the United States, have no systematically collected safety data. No sufficiently powered randomized trials comparing sublingual and subcutaneous immunotherapy (SCIT) were available, but general safety assessments indicate that sublingual tablet treatment is safer than subcutaneous treatment. Not all commonly used immunotherapy drugs are officially registered, and not all have systematically collected safety data. This is especially true for older drugs used in the United States. In contrast, newer drugs that have undergone extensive clinical testing have better documentation, but unified collection of safety data is still lacking. Considering the evidence available, most drugs elicit similar side effects from the same organ systems, and symptoms from the sublingual drug classes are probably less severe. However, a head-to-head comparison of safety and efficacy is lacking.

  5. Safety evaluation of standardized allergen extract of Japanese cedar pollen for sublingual immunotherapy.

    PubMed

    Mitobe, Yuko; Yokomoto, Yasuki; Ohashi-Doi, Katsuyo

    2015-04-01

    Japanese cedar (JC) pollinosis is caused by Japanese cedar pollen (JCP) and most common seasonal allergic disease in Japan. Subcutaneous immunotherapy (SCIT) with allergen extract of JCP (JCP-allergen extract) is well established for JC pollinosis treatment with improvement of symptoms. However, major drawbacks for SCIT are repeated painful injections, frequent hospital visits and anaphylactic risk. Currently, sublingual immunotherapy (SLIT) has received much attention as an advanced alternative application with lower incidence of systemic reactions because the liquid or tablet form of allergen is placed under the tongue. The aim of this study was safety evaluation of standardized JCP-allergen extract currently developed for SLIT in JC pollinosis. JCP-allergen extract showed no potential genotoxicity. No systemic effects were observed in rats administered JCP-allergen extract orally for 26 weeks followed by 4-week recovery period. Mild local reactions such as hyperplasia and increased globule leukocytes resulting from vehicle (glycerin)-induced irritation were observed in stomach. No-observed-adverse-effect level was greater than 10,000 JAU/kg/day for systemic toxicity, equivalent to 300-fold the human dose. No local irritation was found in rabbits oral mucosae by 7-day sublingual administration. These results demonstrate the safe profile of standardized JCP-allergen extract, suggesting it is suitable for SLIT in JC pollinosis.

  6. Efficacy of Sublingual Immunotherapy with Dermatophagoides farinae Extract in Monosensitized and Polysensitized Patients with Allergic Rhinitis: Clinical Observation and Analysis

    PubMed Central

    Xu, Chen-Xia; Zhang, Miao-Lian; Li, Bi-Zhou; He, Ying; Zou, Ze-Hong; Wu, Qiu-Rong; Tao, Ai-Lin; Lai, He; Sun, Jin-Lu

    2015-01-01

    Aim. To investigate differences in the efficacy of sublingual immunotherapy with Dermatophagoides farinae drops in monosensitized and polysensitized allergic rhinitis patients. Methods. The patients enrolled in the study were treated for more than one year by sublingual immunotherapy (SLIT) using Dermatophagoides farinae drops and were divided into a monosensitized group (n = 20) and a polysensitized group (n = 30). Total nasal symptom scores of patients before and after SLIT were analyzed to evaluate the curative effect. The phylogenetic tree of dust mite allergens as well as other allergens that were tested by skin prick test was constructed to help the analysis. Results. There was no significant difference in the efficacy of SLIT between dust mite monosensitized and polysensitized patients. Conclusions. Both dust mite monosensitized and polysensitized patients could be cured by SLIT using Dermatophagoides farinae drops. This study provides a reference for the selection of allergens to be used in immunotherapy for polysensitized AR patients. PMID:26000283

  7. Oral and sublingual peanut immunotherapy is not ready for general use.

    PubMed

    Greenhawt, Matthew J

    2013-01-01

    Food oral immunotherapy (OIT) is an investigational peanut allergy treatment aimed to achieve specific oral tolerance induction. Allergic children are given titrated oral (or sublingual) doses of their allergen on a daily basis, unlike in subcutaneous immunotherapy (SCIT). OIT is theorized to cause a shift from a Th2 to a Th1 regulatory environment, reflected by increases in food-specific IgG4/IgE, and the production of FoxP3. Peanut OIT holds special promise because peanut allergy has an unfavorable natural history and is rarely outgrown. A high percentage of the participants experience symptoms during peanut OIT, including anaphylaxis, warranting epinephrine and/or discontinuation of therapy. This is a concerning fact given that the studies have mostly targeted only older children, with less historical reactivity for enrollment. The handful of peanut OIT studies have shown that some participants can be desensitized to peanut, but none have shown that long-term tolerance can be reestablished. Factors predictive of which patients are most likely to succeed and become desensitized through OIT are unknown. Some private practices have begun offering peanut OIT as a therapy. Such practice is potentially dangerous given the safety and efficacy of OIT in randomized controlled clinical trials is still not well established. Therefore, until further investigation emerges that conclusively demonstrates OIT is safe, intermediate and long-term outcomes are better established, the number of participants that experience symptoms is reduced, and proof of concept established in patients of all ages, (irrespective of past reaction severity), OIT is not ready for use in the general allergy practice.

  8. Randomized, double-blind, placebo-controled clinical trial of sublingual immunotherapy in natural rubber latex allergic patients

    PubMed Central

    2011-01-01

    Background Natural rubber latex allergy is a common and unsolved health problem. Since the avoidance of exposure is very difficult, immunotherapy is strongly recommended, but before its use in patients, it is essential to prove the efficacy and safety of extracts. The aim of the present randomised, double-blind, placebo-controlled clinical trial was to assess the efficacy and tolerability of latex sublingual immunotherapy in adult patients undergoing permanent latex avoidance. Methods Twenty-eight adult latex-allergic patients (5 males and 23 females), with mean age of 39 years (range 24-57) were randomized to receive a commercial latex-sublingual immunotherapy or placebo during one year, followed by another year of open, active therapy. The following outcomes were measured at baseline and at the end of first and second year of follow-up: skin prick test, gloves-use score, conjunctival challenge test, total and specific IgE, basophil activation test, and adverse reactions monitoring. Results No significant difference in any of the efficacy in vivo variables was observed between active and placebo groups at the end of the placebo-controlled phase, nor when each group was compared with their baseline values at the end of the two year-study. An improvement in the average percentage of basophils activated was observed. During the induction phase, 4 reactions in the active group and 5 in the placebo group were recorded. During the maintenance phase, two patients dropped out due to pruritus and to acute dermatitis respectively. Conclusion Further studies are needed to evaluate latex-sublingual immunotherapy, since efficacy could not be demonstrated in adult patients with avoidance of the allergen. Trial registration number ACTRN12611000543987 PMID:21827704

  9. Sublingual immunotherapy for peanut allergy: Long-term follow-up of a randomized multicenter trial

    PubMed Central

    Burks, A. Wesley; Wood, Robert A.; Jones, Stacie M.; Sicherer, Scott H.; Fleischer, David M.; Scurlock, Amy M.; Vickery, Brian P.; Liu, Andrew H.; Henning, Alice K.; Lindblad, Robert; Dawson, Peter; Plaut, Marshall; Sampson, Hugh A.

    2015-01-01

    Background We previously reported initial results of the first multi-center randomized, double blind, placebo controlled clinical trial of peanut sublingual immunotherapy (SLIT), observing a favorable safety profile associated with modest clinical and immunologic effects in the first year. Objective To provide long-term (3-year) clinical and immunologic outcomes for our peanut SLIT trial. Key endpoints: (1) percentage of responders at 2 years (could consume 5g of peanut powder or a 10-fold increase from baseline), 2) percentage reaching desensitization at 3 years, (3) percentage attaining sustained unresponsiveness after 3 years, (4) immunologic endpoints and (5) assessment of safety parameters. Methods Response to treatment was evaluated in 40 subjects aged 12-40 years by performing a 10g peanut powder oral food challenge (OFC) following 2 and 3 years of daily peanut SLIT therapy. At 3 years, SLIT was discontinued for 8 weeks followed by another 10g OFC, and an open feeding of peanut butter to assess sustained unresponsiveness. Results Approximately 98% of the 18,165 doses were tolerated without adverse reactions beyond the oropharynx, with no severe symptoms or uses of epinephrine. A high rate (>50%) discontinued therapy. By study end, 4/37 (10.8%) of SLIT treated participants were fully desensitized to 10g of peanut powder, and all 4 achieved sustained unresponsiveness. Responders at 2 years showed a significant decrease in peanut-specific basophil activation and skin prick test titration compared to non-responders. Conclusions Peanut SLIT induced a modest level of desensitization, decreased immunologic activity over 3 years in responders, and had an excellent long-term safety profile. However, most patients discontinued therapy by the end of year 3, and only 10.8% of subjects achieved sustained unresponsiveness. PMID:25656999

  10. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial

    PubMed Central

    Fleischer, David M.; Burks, A. Wesley; Vickery, Brian P.; Scurlock, Amy M.; Wood, Robert A.; Jones, Stacie M.; Sicherer, Scott H.; Liu, Andrew H.; Stablein, Donald; Henning, Alice K.; Mayer, Lloyd; Lindblad, Robert; Plaut, Marshall; Sampson, Hugh A.

    2012-01-01

    Background There are presently no available therapeutic options for peanut-allergic patients. Objective To investigate the safety, efficacy, and immunologic effects of peanut sublingual immunotherapy (SLIT). Methods After a baseline oral food challenge (OFC) of up to 2g of peanut powder (~50% protein) (median successfully consumed dose [SCD] 46mg), 40 subjects, aged 12–37 (median 15) years, were randomized 1:1 across 5 sites to daily peanut or placebo SLIT. A 5g OFC was performed after 44 weeks followed by unblinding; placebo subjects then crossed over to higher dose peanut SLIT, followed by a subsequent crossover Week 44 5g OFC. Week 44 OFCs from both groups were compared to baseline OFCs; subjects successfully consuming 5g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders. Results After 44 weeks of SLIT, 14/20 (70%) subjects receiving peanut SLIT were responders compared to 3/20 (15%) subjects receiving placebo (p<0.001). In peanut-SLIT responders, median SCD increased from 3.5mg to 496mg. After 68 weeks of SLIT, median SCD significantly increased to 996mg (compared to week 44, p=0.05). The median SCD at the Week 44 crossover OFC was significantly higher than baseline (603mg vs 71mg; p=0.02). 7/16 (44%) crossover subjects were responders; median SCD increased from 21mg to 496mg among responders. Of 10,855 peanut doses through Week 44 OFCs, 63.1% were symptom-free; excluding oral/pharyngeal symptoms, 95.2% were symptom-free. Conclusions Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared to placebo. Longer duration of therapy showed statistically significant increases in the SCD. PMID:23265698

  11. Improvement of shrimp allergy after sublingual immunotherapy for house dust mites: a case report.

    PubMed

    Cortellini, G; Spadolini, I; Santucci, A; Cova, V; Conti, C; Corvetta, A; Passalacqua, G

    2011-10-01

    The appropriateness of house dust mite specific immunotherapy in patients allergic to shrimps still remains unclear We present a clinical case as an immunological model for the strong sensitization to tropomyosin with symptoms of anaphylaxis due to shrimps and coexisting asthma due to house dust mite. The improvement in respiratory symptoms for house dust mite and in the food challenge for shrimps during mite immunotherapy with a known and high dosage of tropomyosin suggests the hypothesis that efficacy of mite immunotherapy in food allergy to tropomyosin may be dose dependent.

  12. Grass pollen sublingual immunotherapy and paediatric allergic rhinitis: A patient-oriented decision.

    PubMed

    Miceli Sopo, Stefano; Battista, Andrea; Greco, Monica; Monaco, Serena

    2016-01-01

    Guidelines and systematic review report that allergen immunotherapy (AIT) is, in general, effective in the treatment of allergic rhinitis. However, experts suggest not generalising the results of different clinical studies: for example, it would not be advisable to translate the results found in an adult population to a paediatric population or the results on the efficacy of AIT against a specific allergen to the AIT against a different allergen. Moreover, according to Evidence Based Medicine (EBM), clinical decisions are individualised and should derive from the "integration of best research evidence with clinical expertise and patient values". Taking into account the high specificity of the AIT and EBM principles, we tried to answer the question on how advisable it is to prescribe the AIT for the management of grass allergic rhinitis in children. To do this, we revised the scientific literature in order to solve a specific case scenario.

  13. Evaluation of stability of allergen extracts for sublingual immunotherapy during transport under unfavourable temperature conditions with an innovative thermal insulating packaging.

    PubMed

    Puccinelli, P; Natoli, V; Dell'albani, I; Scurati, S; Incorvaia, C; Barbieri, S; Masieri, S; Frati, F

    2013-10-01

    Many pharmaceutical and biotechnological products are temperature-sensitive and should normally be kept at a controlled temperature, particularly during transport, in order to prevent the loss of their stability and activity. Therefore, stability studies should be performed for temperature-sensitive products, considering product characteristics, typical environmental conditions, and anticipating environmental extremes that may occur during product transport in a specific country. Staloral products for sublingual immunotherapy are temperature sensitive and are labelled for maintenance under refrigerated conditions (2-8°C). Given the peculiar climatic context of Italy and the great temperature fluctuations that may occur during transport, this study was aimed at evaluating the impact of a new engineered thermal insulating packaging for Staloral. In particular, the purpose was to assess whether the new packaging could create a container condition able to preserve the stability and immunological activity of the product during the transport phase throughout Italy. The results showed that the range of temperatures that can affect the product, in the area surrounding the product packaging, may reach a peak of 63°C during transport under the most unfavourable climatic conditions, i.e. in a non-refrigerated van during the summer season, from the site of production in France to the patient's house in Catania, the city with the highest temperatures in Italy. However, the highest temperature reached inside the vaccine did not exceed 45°C over a period of about 2 h. The ELISA inhibition test on samples subjected to the extreme temperature conditions previously defined (45°C) showed an immunological activity higher than 75% of that initially measured and was comparable to those obtained with samples stored at controlled temperature (5°C). This means that, even in the worst case scenario, the structure of the allergen extracts is not influenced and the vaccine potency is

  14. Peanut immunotherapy

    PubMed Central

    2014-01-01

    Peanut allergy is common and can be a cause of severe, life-threatening reactions. It is rarely outgrown like other food allergies, such as egg and milk. Peanut allergy has a significant effect on the quality of life of sufferers and their families, due to dietary and social restrictions, but mainly stemming from fear of accidental peanut ingestion. The current management consists of strict avoidance, education and provision of emergency medication, but a disease- modifying therapy is needed for peanut allergy. Recent developments involve the use of immunotherapy, which has shown promise as an active form of treatment. Various routes of administration are being investigated, including subcutaneous, oral, sublingual and epicutaneous routes. Other forms of treatment, such as the use of vaccines and anti-IgE molecules, are also under investigation. So far, results from immunotherapy studies have shown good efficacy in achieving desensitisation to peanut with a good safety profile. However, the issue of long-term tolerance has not been fully addressed yet and larger, phase III studies are required to further investigate safety and efficacy. An assessment of cost/benefit ratio is also required prior to implementing this form of treatment. The use of immunotherapy for peanut allergy is not currently recommended for routine clinical use and should not be attempted outside specialist allergy units. PMID:25276342

  15. Fentanyl Sublingual Spray

    MedlinePlus

    ... a solution (liquid) to spray sublingually (under the tongue). It is used as needed to treat breakthrough ... the nozzle into your mouth and under your tongue. Squeeze your fingers and thumb together to spray ...

  16. Lactic acid bacteria as adjuvants for sublingual allergy vaccines.

    PubMed

    Van Overtvelt, Laurence; Moussu, Helene; Horiot, Stéphane; Samson, Sandrine; Lombardi, Vincent; Mascarell, Laurent; van de Moer, Ariane; Bourdet-Sicard, Raphaëlle; Moingeon, Philippe

    2010-04-01

    We compared immunomodulatory properties of 11 strains of lactic acid bacteria as well as their capacity to enhance sublingual immunotherapy efficacy in a murine asthma model. Two types of bacterial strains were identified, including: (i) potent inducers of IL-12p70 and IL-10 in dendritic cells, supporting IFN-gamma and IL-10 production in CD4+ T cells such as Lactobacillus helveticus; (ii) pure Th1 inducers such as L. casei. Sublingual administration in ovalbumin-sensitized mice of L. helveticus, but not L. casei, reduced airways hyperresponsiveness, bronchial inflammation and proliferation of specific T cells in cervical lymph nodes. Thus, probiotics acting as a Th1/possibly Treg, but not Th1 adjuvant, potentiate tolerance induction via the sublingual route.

  17. Allergen-specific immunotherapy.

    PubMed

    Nelson, Harold S; Norman, Philip S

    2014-01-01

    Specific immunotherapy was introduced for the treatment of grass pollen-induced hay fever in 1911. The treatment was soon extended to other pollens as well as perennial allergens, and to the treatment of bronchial asthma. Definitive studies of its efficacy for both rhinitis and asthma came only many decades later. Understanding gradually emerged of the underlying immunologic mechanisms that include the generation of regulatory T lymphocytes, immune deviation from allergen-specific Th2 to Th1 responses, and a shift in allergen-specific antibody production from immunoglobulin (Ig) E to IgG4. Along with understanding of the immune basis came an appreciation that immunotherapy modifies allergic disease expression, producing protection against disease progression and symptomatic improvement that persists for years after the treatment is discontinued. Recent new directions for immunotherapy include sublingual administration of inhalant allergens and use of the oral route to treat food allergy.

  18. Requirements for acquiring a high-quality house dust mite extract for allergen immunotherapy

    PubMed Central

    Frati, Franco; Incorvaia, Cristoforo; David, Marie; Scurati, Silvia; Seta, Simona; Padua, Guglielmo; Cattaneo, Eleonora; Cavaliere, Carlo; Di Rienzo, Alessia; Dell’Albani, Ilaria; Puccinelli, Paola

    2012-01-01

    The house dust mite is a major cause of respiratory allergy worldwide. The management of mite allergy is based on avoidance measures, drug treatment, and allergen immunotherapy, but only allergen immunotherapy is able to modify the natural history of the disease. Injectable subcutaneous immunotherapy was introduced a century ago, while sublingual immunotherapy was proposed in the 1980s and emerged in the ensuing years as an effective and safe option to subcutaneous immunotherapy. However, the quality of the extracts to be used in allergen immunotherapy is crucial for the success of treatment. The mite extract for sublingual immunotherapy known as Staloral 300 was developed to offer optimal characteristics concerning the mite culture medium, standardization, and allergen dose. Double-blind, placebo-controlled trials with Staloral 300 have provided a substantial part of the clinical evidence analyzed in a meta-analysis of the efficacy of allergen immunotherapy in mite-induced rhinitis and asthma. Safety and tolerability are very good, mild local reactions in the mouth being the most common side effect. This makes it feasible to carry out sublingual immunotherapy for the 3–5-year duration needed to achieve long-lasting tolerance to the specific allergen. The performance of Staloral 300 may provide optimal conditions for an effective and safe sublingual immunotherapy in patients with mite-induced respiratory allergy. PMID:22654506

  19. Requirements for acquiring a high-quality house dust mite extract for allergen immunotherapy.

    PubMed

    Frati, Franco; Incorvaia, Cristoforo; David, Marie; Scurati, Silvia; Seta, Simona; Padua, Guglielmo; Cattaneo, Eleonora; Cavaliere, Carlo; Di Rienzo, Alessia; Dell'Albani, Ilaria; Puccinelli, Paola

    2012-01-01

    The house dust mite is a major cause of respiratory allergy worldwide. The management of mite allergy is based on avoidance measures, drug treatment, and allergen immunotherapy, but only allergen immunotherapy is able to modify the natural history of the disease. Injectable subcutaneous immunotherapy was introduced a century ago, while sublingual immunotherapy was proposed in the 1980s and emerged in the ensuing years as an effective and safe option to subcutaneous immunotherapy. However, the quality of the extracts to be used in allergen immunotherapy is crucial for the success of treatment. The mite extract for sublingual immunotherapy known as Staloral 300 was developed to offer optimal characteristics concerning the mite culture medium, standardization, and allergen dose. Double-blind, placebo-controlled trials with Staloral 300 have provided a substantial part of the clinical evidence analyzed in a meta-analysis of the efficacy of allergen immunotherapy in mite-induced rhinitis and asthma. Safety and tolerability are very good, mild local reactions in the mouth being the most common side effect. This makes it feasible to carry out sublingual immunotherapy for the 3-5-year duration needed to achieve long-lasting tolerance to the specific allergen. The performance of Staloral 300 may provide optimal conditions for an effective and safe sublingual immunotherapy in patients with mite-induced respiratory allergy.

  20. Buprenorphine Sublingual and Buccal (opioid dependence)

    MedlinePlus

    ... a sublingual film (Suboxone) to take under the tongue and as a buccal film (Bunavail) to apply ... the sublingual tablets, place the tablets under your tongue until they completely melt. If you are taking ...

  1. Immunotherapy in asthma.

    PubMed

    Warrington, Richard

    2010-09-01

    Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. Chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, as well as variable airflow obstruction within the lung. With time, such airflow obstruction may become permanent due to remodeling. It has been treated for more than 100 years by subcutaneous immunotherapy with allergen extracts but in recent years, other forms and types of immunotherapy have been introduced. Perhaps the most successful of these to date, is sublingual immunotherapy, which has attained significant usage in European countries but has yet to make inroads into clinical practice in North America. Other mechanisms to modify the inflammatory responses of asthma have included immunotherapy with recombinant allergens, the use of allergen peptides targeting antigen-specific T cells and the administration of Toll-like receptor agonists coupled to allergen proteins. As the inflammatory responses in asthma frequently involve IgE, a modified monoclonal antibody to IgE and interfering with its binding to the IgE receptor have gained acceptance for treating severe allergic asthma. Other monoclonal antibodies or recombinant receptor antagonists are being assessed for their ability to block other contributors to the inflammatory response. Finally, attempts have been made to generate autoantibody responses to cytokines implicated in asthma. Most of these therapies aim to modify or inhibit the so-called Th 2 immune response, which is implicated in many forms of asthma, or to inhibit cytokines involved in these responses. However, an added benefit of classical immunotherapy seems to be the ability to prevent the allergic progression to new sensitivities and new forms of allergic disease.

  2. Immunotherapy for food allergies: a myth or a reality?

    PubMed

    Praticò, Andrea D; Leonardi, Salvatore

    2015-01-01

    Food allergy is a worldwide issue, with an estimated prevalence of 2-10%. An effective treatment is not available for people affected and the only management is the avoidance of the allergen. Oral immunotherapy and sublingual immunotherapy have been tested by several authors, in particular for milk, egg and peanuts allergy, with significant results in term of desensitization induction. The achievement of tolerance is by the contrary doubtful, with different results obtained. In this review, we reviewed protocols of oral and sublingual immunotherapy for food allergy published in literature, mainly against milk, egg and peanut. At present, immunotherapy does not represent the gold standard in the treatment of food allergy, even if it can desensitize patients.

  3. New types of immunotherapy in children.

    PubMed

    Rodríguez-Pérez, Noel; Penagos, Martin; Portnoy, Jay M

    2008-11-01

    Injection immunotherapy has been shown to be particularly beneficial in treating allergic rhinitis, mild to moderate asthma, and anaphylaxis caused by bee and wasp venom. It also produces a long-term, antigen-specific, protective immune effect and is the only treatment that offers the possibility of reducing the risk of asthma development in children with allergic rhinitis. Nonetheless, the potentially severe side effects associated with this form of immunotherapy limit its widespread use. Diverse preparations are being developed to increase its safety and improve its efficacy. These include alternative routes of administration, particularly the sublingual route; use of novel adjuvants, such as CpG oligonucleotides and mycobacterial vaccines; and other approaches, such as peptide immunotherapy, recombinant allergens, DNA vaccination, and combined therapy. Some of these immunotherapy forms have been evaluated in children.

  4. A practical view of immunotherapy for food allergy

    PubMed Central

    2016-01-01

    Food allergy is common and sometimes life threatening for Korean children. The current standard treatment of allergen avoidance and self-injectable epinephrine does not change the natural course of food allergy. Recently, oral, sublingual, and epicutaneous immunotherapies have been studied for their effectiveness against food allergy. While various rates of desensitization (36% to 100%) and tolerance (28% to 75%) have been induced by immunotherapies for food allergy, no single established protocol has been shown to be both effective and safe. In some studies, immunologic changes after immunotherapy for food allergy have been revealed. Adverse reactions to these immunotherapies have usually been localized, but severe systemic reactions have been observed in some cases. Although immunotherapy cannot be recommended for routine practice yet, results from recent studies demonstrate that immunotherapies are promising for the treatment of food allergy. PMID:26958062

  5. Sublingual dermoid causing stertor in an infant.

    PubMed

    Naina, P; Syed, Kamran Asif; Koshy, Lisa; Mathews, Suma Susan

    2016-01-01

    Sublingual dermoids are uncommon lesions in the floor of mouth. The most common age of presentation is early adulthood, but presentation in infancy has also been reported. This report highlights the clinical presentation and treatment challenges in infants. An 8-month-old infant presented with inability to close mouth, intermittent stertor and snoring. MRI suggested a sublingual dermoid which was confirmed on histopathology of the surgically enucleated specimen. Sublingual dermoids are uncommon lesions of the floor of mouth. The age of presentation of a sublingual dermoid depends on the initial size of the lesion. Large sublingual dermoids in neonates can present with respiratory embarrassment and need early surgical intervention. Surgical enucleation via an intraoral approach is the treatment of choice with external approach reserved for very large cysts below the mylohyoid. Large sublingual cysts can present with anaesthetic challenges and may need fibreoptic intubation. PMID:27637278

  6. The treatment of sublingual gland tumours.

    PubMed

    Sun, G; Yang, X; Tang, E; Wen, J; Lu, M; Hu, Q

    2010-09-01

    This study assessed the clinical and histological features and therapeutic efficacy of 25 cases of sublingual gland tumours from 1998 to 2008. There were 17 female patients and 8 male, the ratio of females to males was 2.1:1. The mean age was 48.6 years. 4 cases were benign tumours (16%). 21 cases were malignant sublingual gland tumours (84%) and of these, 18 were adenoid cystic carcinoma (86%). Adenoid cystic carcinoma was mainly of the histological type, and the other histological classifications included mucoepidermoid carcinoma, pleomorphic adenoma, myoepithelioma, oncocytoma and polymorphous low-grade adenocarcinoma. Sublingual gland tumours are rare and most are malignant. For malignant sublingual gland tumours, early diagnosis and aggressive surgical treatment, especially for tumours with nerve involvement, is the key to improving prognosis. Free radial forearm flap or pectoralis major myocutaneous flap are appropriate methods for mouth floor reconstruction. For benign sublingual gland tumours, the resection of tumour and sublingual gland is the preferred treatment.

  7. Oral immunotherapy for allergic conjunctivitis.

    PubMed

    Ishida, Waka; Fukuda, Ken; Harada, Yosuke; Yagita, Hideo; Fukushima, Atsuki

    2014-11-01

    Antigen-specific immunotherapy is expected to be a desirable treatment for allergic diseases. Currently, antigen-specific immunotherapy is performed by administering disease-causing antigens subcutaneously or sublingually. These approaches induce long-term remission in patients with allergic rhinitis or asthma. The oral route is an alternative to subcutaneous and sublingual routes, and can also induce long-term remission, a phenomenon known as "oral tolerance." The effectiveness of oral tolerance has been reported in the context of autoimmune diseases, food allergies, asthma, atopic dermatitis, and allergic rhinitis in both human patients and animal models. However, few studies have examined its efficacy in animal models of allergic conjunctivitis. Previously, we showed that ovalbumin feeding suppressed ovalbumin-induced experimental allergic conjunctivitis, indicating the induction of oral tolerance is effective in treating experimental allergic conjunctivitis. In recent years, transgenic rice has been developed that can induce oral tolerance and reduce the severity of anaphylaxis. The major Japanese cedar pollen antigens in transgenic rice, Cryptomeria japonica 1 and C. japonica 2, were deconstructed by molecular shuffling, fragmentation, and changes in the oligomeric structure. Thus, transgenic rice may be an effective treatment for allergic conjunctivitis.

  8. A European perspective on immunotherapy for food allergies.

    PubMed

    Beyer, Kirsten

    2012-05-01

    Food allergies are common, and frequently, the only treatment option is strict avoidance. Unfortunately, many patients accidentally ingest allergenic foods, which can result in severe anaphylactic reactions. Several immunotherapies are being developed for food allergies; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. Oral immunotherapy seems to be the most promising approach based on results from small uncontrolled and controlled studies. However, it is a challenge to compare results among immunotherapy trials because of differences in protocols. Studies conducted thus far have tested the most prevalent food allergens: it is not clear whether their results can be extended to other allergens. Sublingual administration of immunotherapy has shown some efficacy and fewer side effects than oral administration in some trials, yet neither approach can be recommended for routine practice. Controlled studies with larger numbers of subjects are needed to determine short- and long-term efficacy and side effects. In Europe immunotherapy trials for food allergies face many ethical and regulatory issues. Guidelines from the European Medicine Agency on the clinical development of products for specific immunotherapy of allergic diseases do not adequately address immunotherapy for food allergies, especially for therapies that orally administer native food or that include pediatric patients.

  9. New directions in immunotherapy.

    PubMed

    Cox, Linda; Compalati, Enrico; Kundig, Thomas; Larche, Mark

    2013-04-01

    Allergen immunotherapy (AIT) is effective in reducing the clinical symptoms associated with allergic rhinitis, asthma and venom-induced anaphylaxis. Subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with unmodified allergen extracts are the most widely prescribed AIT regimens. The efficacy of these 2 routes appears comparable, but the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time. However, both require that the treatment is taken regularly over several years, e.g., monthly in a supervised medical setting with SCIT and daily at home with SLIT. Despite the difference in treatment settings, poor adherence has been reported with both routes. Emerging evidence suggests that AIT may be effective in other allergic conditions such as atopic dermatitis, venom sting-induced large local reactions, and food allergy. Research with oral immunotherapy (OIT) for food allergies suggest that many patients can be desensitized during treatment, but questions remain about whether this can produce long term tolerance. Further studies are needed to identify appropriate patients and treatment regimens with these conditions. Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified allergens and alternate routes. Intralymphatic (ILIT) has been shown to produce long-lasting clinical benefits after three injections comparable to a 3-year course of SCIT. Epicutaneous (EPIT) has demonstrated promising results for food and inhalant allergies. Vaccine modifications, such as T cell epitopes or the use of viral-like particles as an adjuvant, have been shown to provide sustained clinical benefits after a relatively short course of treatment compared to the currently available AIT treatments, SLIT and SCIT. These newer approaches may increase the utilization and adherence to AIT because the multi-year treatment requirement of currently available AIT is a likely deterrent for

  10. A review of allergoid immunotherapy: is cat allergy a suitable target?

    PubMed

    Nguyen, Nhung T; Raskopf, Esther; Shah-Hosseini, Kija; Zadoyan, Gregor; Mösges, Ralph

    2016-01-01

    To modify the course of allergy, different types of specific allergen immunotherapy have been developed such as sublingual immunotherapy and subcutaneous immunotherapy with native allergens or subcutaneous immunotherapy with polymerized allergoids. However, the optimal specific immunotherapy, especially for cat allergy, remains undetermined. Few studies investigating immunotherapy in cat allergy have been published, and the risk of serious adverse reactions and systemic reactions has often been an important issue. Monomeric allergoids have lower allergenic potential while their immunogenicity remains constant, resulting in excellent safety with notable efficacy. Specific immunotherapy with monomeric allergoids could, therefore, be of high value, especially in cat allergy as well as other types of allergy, and bring relief to a great community of patients.

  11. Basal cell adenoma of the sublingual gland.

    PubMed

    Lin, Hsin-Ching; Chien, Chih-Yen; Huang, Shun-Chen; Su, Chih-Ying

    2003-12-01

    Salivary gland tumors constitute about 3% to 4% of all head and neck neoplasms. Approximately 80% originate in the parotid gland, and they rarely present in the sublingual gland; however, a disproportionately large majority of sublingual gland tumors are malignant. Basal cell adenoma is a benign epithelial salivary gland tumor that appears to have unique histologic characteristics, different from those of mixed tumors, and has a predilection for development in the parotid and minor salivary glands. No case has ever been reported as arising from the sublingual gland in the otolaryngology literature. We report here a case of a middle-aged woman with basal cell adenoma of the sublingual gland. The clinical presentation, pathological features, differential diagnosis, and treatment options for this relatively rare tumor are discussed.

  12. An Examination of Clinical and Immunologic Outcomes in Food Allergen Immunotherapy by Route of Administration.

    PubMed

    Chiang, David; Berin, M Cecilia

    2015-06-01

    Allergen immunotherapy for the treatment of food allergy has been a subject of intensive study within the last 10 years. After an unsuccessful attempt with subcutaneous immunotherapy for peanut allergy, other routes with varying degrees of safety and efficacy have been tested for peanut, milk, and egg allergies. In this review, we summarize the results to date with oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy for the treatment of food allergy. While results of immunotherapy trials are promising, increases in efficacy are commonly associated with an increased side effect profile. There is a need for additional research beginning at the preclinical level to develop safe and effective treatments for food allergy. PMID:26141581

  13. Allergen Immunotherapy.

    PubMed

    Rael, Efren

    2016-09-01

    Allergies affect a large proportion of the population. Allergies can adversely affect productivity, sleep, and quality of life and can lead to life-threatening reactions. Allergies can spread to affect multiple organ systems. Allergen immunotherapy is the only therapy that can change the natural history of allergic disease. PMID:27545737

  14. [Basal cell adenocarcinoma of the sublingual gland].

    PubMed

    Petersen, Stig Krarup; Bjørndal, Kristine; Krogdahl, Annelise; Godballe, Christian

    2010-02-15

    The cause of a swelling in the floor of the mouth will in most cases be benign. For example, a ranula, sialolithiasis and/or infection. Tumors of the sublingual gland are very rare, but 90% are malignant and therefore malignancy should always be excluded in case of an asymptomatic swelling covered by intact mucosa. PMID:20156409

  15. Novel ways for immune intervention in immunotherapy: mucosal allergy vaccines.

    PubMed

    Mascarell, Laurent; Van Overtvelt, Laurence; Moingeon, Philippe

    2006-05-01

    Allergen-specific immunotherapy is currently the only curative treatment for allergy. Subcutaneous immunotherapy (SCIT) has been successfully used to treat patients who are allergic to insect venom, house dust mites, or tree or grass pollens. In the context of potentially severe, albeit infrequent, side effects associated with SCIT, mucosal routes of administration are being investigated to conduct allergenic desensitization. This article reviews recent developments in the field of nasal, oral, and sublingual immunotherapy as they relate to safety, clinical efficacy, and immune mechanisms of action. Implications for the design and development of improved allergy vaccines that could be used through such nonparenteral routes are discussed. Specifically, allergen presentation platforms and adjuvants facilitating the targeting of immune cells at mucosal surfaces to promote tolerance induction are reviewed.

  16. Melanoma immunotherapy.

    PubMed

    Sivendran, Shanthi; Glodny, Bradley; Pan, Michael; Merad, Miriam; Saenger, Yvonne

    2010-01-01

    Melanoma immunotherapy has been an area of intense research for decades, and this work is now yielding more tangible results for patients. Work has focused on 4 main areas: cytokine therapy, administration of immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Cytokine therapy is an established treatment for advanced melanoma, and immune-modulating antibodies have recently emerged as an exciting new area of drug development with efficacy now established in a phase III trial. Adoptive T-cell therapy provides the proof of principle that T cells can attack and eliminate tumors. It has been challenging, however, to adapt this treatment for widespread use. Vaccines have generally yielded poor results, but intratumor pathogen-based strategies have shown encouraging results in recent trials, perhaps due to stronger immune stimulation. A review of the field of melanoma immunotherapy is provided here, with emphasis on those agents that have reached clinical testing. Novel strategies to induce the immune system to attack melanomas are reviewed. In the future, it is envisioned that immunotherapy will have further application in combination with cytotoxic and targeted therapies.

  17. Sublingual Microcirculation in Pulmonary Arterial Hypertension

    PubMed Central

    Dababneh, Luma; Cikach, Frank; Alkukhun, Laith; Dweik, Raed A.

    2014-01-01

    Rationale: Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that leads to failure of the right ventricle and premature death. Objectives: To determine whether the sublingual microcirculation is affected in patients with PAH compared with healthy age- and sex-matched control subjects. Methods: Using the CapiScope Handheld Video Capillaroscope we measured the sublingual microvasculature density, flow index, tortuosity, and curvature. Videos were acquired immediately after right heart catheterization, and determinations were made off-line by investigators blinded to the group assignment or hemodynamics. Measurements and Main Results: In this cross-sectional pilot study, we included 26 patients with PAH (age, mean ± SD, 56.7 ± 10 yr; 77% women) and 14 healthy control subjects (age, 53.1 ± 12 yr; 71% women). Sublingual microvasculature flow index was lower (2 ± 0.66 vs. 2.7 ± 0.37, P < 0.001) with higher heterogeneity index (0.63 ± 0.63 vs. 0.25 ± 0.25, P = 0.04) in patients with PAH than control subjects. Microvasculature density was similar between the groups, but tortuosity was more pronounced in patients than control subjects (tort 0: 45 ± 19 vs. 23.6 ± 12, P = 0.001 and tort 1: 0.2 ± 0.16 vs. 0.06 ± 0.04, P < 0.001). Conclusions: Patients with PAH showed lower sublingual microvasculature flow index and higher tortuosity compared with healthy age- and sex-matched control subjects. Further investigations are needed to assess whether this methodology can provide information on disease prognosis and/or response to therapy in this condition. PMID:24601682

  18. Recombinant Mal d 1 facilitates sublingual challenge tests of birch pollen-allergic patients with apple allergy.

    PubMed

    Kinaciyan, T; Nagl, B; Faustmann, S; Kopp, S; Wolkersdorfer, M; Bohle, B

    2016-02-01

    It is still unclear whether allergen-specific immunotherapy (AIT) with birch pollen improves birch pollen-related food allergy. One reason for this may be the lack of standardized tests to assess clinical reactions to birch pollen-related foods, for example apple. We tested the applicability of recombinant (r) Mal d 1, the Bet v 1-homolog in apple, for oral challenge tests. Increasing concentrations of rMal d 1 in 0.9% NaCl were sublingually administered to 72 birch pollen-allergic patients with apple allergy. The dose of 1.6 μg induced oral allergy syndromes in 26.4%, 3.2 μg in 15.3%, 6.3 μg in 27.8%, 12.5 μg in 8.3%, 25 μg in 11.1%, and 50 μg in 4.2% of the patients. No severe reactions occurred. None of the patients reacted to 0.9% NaCl alone. Sublingual administration of 50 μg of rMal d 1 induced no reactions in three nonallergic individuals. Our approach allows straight forward, dose-defined sublingual challenge tests in a high number of birch pollen-allergic patients that inter alia can be applied to evaluate the therapeutic efficacy of birch pollen AIT on birch pollen-related food allergy.

  19. Sublingual vein extraction algorithm based on hyperspectral tongue imaging technology.

    PubMed

    Li, Qingli; Wang, Yiting; Liu, Hongying; Guan, Yana; Xu, Liang

    2011-04-01

    Among the parts of the human tongue surface, the sublingual vein is one of the most important ones which may have pathological relationship with some diseases. To analyze this information quantitatively, one primitive work is to extract sublingual veins accurately from tongue body. In this paper, a hyperspectral tongue imaging system instead of a digital camera is used to capture sublingual images. A hidden Markov model approach is presented to extract the sublingual veins from the hyperspectral sublingual images. This approach characterizes the spectral correlation and the band-to-band variability using a hidden Markov process, where the model parameters are estimated by the spectra of the pixel vectors forming the observation sequences. The proposed algorithm, the pixel-based sublingual vein segmentation algorithm, and the spectral angle mapper algorithm are tested on a total of 150 scenes of hyperspectral sublingual veins images to evaluate the performance of the new method. The experimental results demonstrate that the proposed algorithm can extract the sublingual veins more accurately than the traditional algorithms and can perform well even in a noisy environment. PMID:21030208

  20. Dysplastic pleomorphic adenoma of the sublingual salivary gland.

    PubMed

    Clark, J; Bailey, B M; Eveson, J W

    1993-12-01

    All tumours of the sublingual gland are rare and paradoxically the large majority are malignant. A case of pleomorphic adenoma in the sublingual gland is described. The tumour showed areas of dysplasia and the difficulties in distinguishing this from benign pleomorphic adenoma or carcinoma in pleomorphic adenoma are considered, and the literature is reviewed.

  1. [The role of immunotherapy in the prevention of allergic diseases].

    PubMed

    Lugović-Mihić, Liborija; Duvancić, Tomislav

    2011-01-01

    Immunotherapy through repeated administration of allergens and augmentation of doses (hyposensibilization) with the purpose of decreasing the severity of type I allergic reactions or even its complete elimination is known already for a longer period of time. This type of therapy is especially beneficial in allergies to Hymenoptera venom, allergic rhinoconjunctivitis, allergic asthma and is implemented in patients with previously proven allergy to appropriate allergens (insects, pollen, house dust mite, pet dander and other). The most common form of therapy is subcutaneous immunotherapy which includes a series of injections containing specific allergens (allergy vaccines) with increasingly larger doses administered subcutaneously during a period of 3-5 years. There are also other forms of immunotherapy (for instance sublingual immunotherapy) although these are less effective. Repetition of the hyposensibilization procedure leads to further reduction in severity of allergy disease in the majority of patients. The efficacy of immunotherapy is also proven by a lower risk of allergic rhinitis patients developing asthma as well as by prevention of new sensibilizations.

  2. Down-regulation of Th2 immune responses by sublingual administration of poly (lactic-co-glycolic) acid (PLGA)-encapsulated allergen in BALB/c mice.

    PubMed

    Salari, Farhad; Varasteh, Abdol-Reza; Vahedi, Fatemeh; Hashemi, Maryam; Sankian, Mojtaba

    2015-12-01

    The goal of this study was to investigate whether poly (lactic-co-glycolic) acid (PLGA) nanoparticles could enhance sublingual immunotherapy (SLIT) efficacy. BALB/c mice sensitized to rChe a 3 were treated sublingually either with soluble rChe a 3 (100μg/dose) or PLGA-encapsulated rChe a 3 (5, 25, or 50μg/dose). SLIT with PLGA-encapsulated rChe a 3 (equivalent to 25 and 50μg rChe a 3 per dose) led to significantly increased antigen-specific IgG2a, along with no effect on allergen-specific IgE and IgG1 antibody levels. In addition, interleukin 4 (IL-4) levels in restimulated splenocytes were significantly less, while interferon-γ (IFN-γ), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) levels, as well as Foxp3 expression, were significantly greater than in the control groups. Our findings suggest that PLGA nanoparticle-based vaccination may help rational development of sublingual immunotherapy through reduction of the needed allergen doses and also significantly enhanced systemic T regulatory (Treg) and T helper 1 (Th1) immune responses.

  3. An update on immunotherapy for food allergy

    PubMed Central

    Scurlock, Amy M.; Jones, Stacie M.

    2013-01-01

    Purpose of the review Recent investigation has resulted in significant advances toward definitive therapeutic options for food allergy. In this review, we will explore novel immunotherapeutic interventions for the active treatment of food allergy. Recent findings Because the injection route for allergen immunotherapy to foods has been associated with an unacceptable risk of severe anaphylactic reactions, use of mucosally targeted therapeutic strategies is of significant interest for food allergy. Allergen-specific immunotherapeutic approaches such as oral, sublingual, epicutaneous, and peptide immunotherapy have demonstrated efficacy in increasing threshold dose and inducing immunologic changes associated with both desensitization and oral tolerance in animal and human trials. More global immunomodulatory strategies, such as Traditional Chinese Medicine and anti-IgE therapy have been shown to effectively target the allergic response, and clinical trials are ongoing to determine the efficacy and safety in human food allergy. Summary The advent of therapies that target the mucosal immune response to promote oral tolerance have shown great promise in the treatment of food hypersensitivity. However, there is still significant risk of adverse reactions associated with these therapeutic strategies and further study is needed to carefully advance these therapeutic modalities toward general clinical implementation. PMID:20856110

  4. Immunotherapy and tumor microenvironment.

    PubMed

    Tang, Haidong; Qiao, Jian; Fu, Yang-Xin

    2016-01-01

    Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases.

  5. Microscopy of the echidna sublingual glands.

    PubMed

    Krause, William J

    2011-10-01

    The secretory units and duct system of the echidna sublingual glands exhibit subtle architectural modifications to accommodate the viscous secretion produced by these glands. The glands are compound tubular glands, the secretory units of which are elongate with open lumina and consist only of mucous cells. Closely packed spindle-shaped myoepithelial cells invest the secretory units, but are absent around the ducts. The branched secretory tubules open into an abbreviated duct system characterized by wide lumina. Striated ducts normally associated with the second portion of the intralobular duct system are absent. The duct system shows the most obvious modification of general salivary gland architecture presumably to accommodate the viscous secretion propelled from the secretory units by surrounding myoepithelial cells. PMID:21671992

  6. [Allergen-specific immunotherapy for food allergies in childhood. Current options and future perspectives].

    PubMed

    Trendelenburg, Valérie; Blümchen, Katharina

    2016-07-01

    During recent years increasing research has been conducted on casual treatment options for food allergy, with focus on oral immunotherapy (OIT) for hen's egg, cow's milk and peanut allergy. Several studies could show that OIT leads to desensitization or an increase of threshold. However, severe adverse events during this treatment are not uncommon. Whether OIT leads to a sustained, 'robust' development of tolerance in patients has not yet been thoroughly investigated. Besides OIT, some studies on sublingual (SLIT) and epicutaneous immunotherapy (EPIT) were performed, aiming to improve the safety profile. Furthermore, there are some pilot studies investigating a combined treatment of SLIT and OIT or a combined use of anti-IgE treatment or probiotic supplementation with OIT. Further placebo-controlled trials with larger sample size are needed in order to develop standardized protocols before immunotherapy may be used as a therapeutic option for food allergy outside of clinical trials. PMID:27324376

  7. Immunotherapy for mold allergy.

    PubMed

    Coop, Christopher A

    2014-12-01

    The objective of this article is to review the available studies regarding mold immunotherapy. A literature search was conducted in MEDLINE to identify peer-reviewed articles related to mold immunotherapy using the following keywords: mold, allergy, asthma, and immunotherapy. In addition, references cited within these articles were also reviewed. Articles were selected based on their relevance to the topic. Allergic responses to inhaled mold antigens are a recognized factor in allergic rhinitis and asthma. There are significant problems with respect to the production of relevant allergen material for the diagnosis and treatment of mold allergy with immunotherapy. Mold allergens contain proteases and should not be mixed with other allergens for immunotherapy. Most of the immunotherapy studies focus on two molds, Alternaria and Cladosporium. There is a lack of randomized placebo-controlled trials when evaluating the efficacy of mold immunotherapy with trials only focusing on immunotherapy to Alternaria and Cladosporium. Additional studies are needed regarding mold allergy and immunotherapy focusing on which molds are important for causing allergic disease.

  8. Immunotherapy for mold allergy.

    PubMed

    Coop, Christopher A

    2014-12-01

    The objective of this article is to review the available studies regarding mold immunotherapy. A literature search was conducted in MEDLINE to identify peer-reviewed articles related to mold immunotherapy using the following keywords: mold, allergy, asthma, and immunotherapy. In addition, references cited within these articles were also reviewed. Articles were selected based on their relevance to the topic. Allergic responses to inhaled mold antigens are a recognized factor in allergic rhinitis and asthma. There are significant problems with respect to the production of relevant allergen material for the diagnosis and treatment of mold allergy with immunotherapy. Mold allergens contain proteases and should not be mixed with other allergens for immunotherapy. Most of the immunotherapy studies focus on two molds, Alternaria and Cladosporium. There is a lack of randomized placebo-controlled trials when evaluating the efficacy of mold immunotherapy with trials only focusing on immunotherapy to Alternaria and Cladosporium. Additional studies are needed regarding mold allergy and immunotherapy focusing on which molds are important for causing allergic disease. PMID:24057512

  9. Single-dose fentanyl sublingual spray for breakthrough cancer pain.

    PubMed

    Taylor, Donald R

    2013-01-01

    Breakthrough cancer pain (BTCP) is defined as a transient exacerbation of pain that arises in patients with otherwise controlled persistent pain. BTCP typically has a rapid onset and relatively short duration, but it causes a significant amount of physical and psychological distress for patients. Several rapid-onset fentanyl formulations have been introduced in the USA to replace traditional oral opioids for the treatment of BTCP: a transmucosal lozenge, a sublingual orally disintegrating tablet, a buccal tablet, a buccal soluble film, a pectin nasal spray and, the newest formulation to enter the market, a sublingual spray. This article reviews the six rapid-onset formulations of fentanyl approved in the USA for the management of BTCP with emphasis on describing the published literature on fentanyl sublingual spray. The different fentanyl formulations vary in pharmacokinetic properties and ease of use, but all have a rapid onset and a relatively short duration of analgesia. Fentanyl sublingual spray has demonstrated absorption within 5 minutes of administration, with fentanyl plasma concentrations increasing over the first 30 minutes and remaining elevated for 60-90 minutes in pharmacokinetic studies in healthy subjects. Fentanyl sublingual spray shows linear dose proportionality, and changes in the temperature or acidity of the oral cavity do not alter its pharmacokinetic properties. In patients with BTCP, statistically significant pain relief is measurable at 5 minutes after administration of fentanyl sublingual spray, when compared with placebo, with significant pain relief lasting at least 60 minutes after administration. Adverse events are typical of opioid treatment and are considered mild to moderate in intensity. In summary, fentanyl sublingual spray provides rapid onset of analgesia and is a tolerable and effective treatment for BTCP. PMID:23901300

  10. Single-dose fentanyl sublingual spray for breakthrough cancer pain

    PubMed Central

    Taylor, Donald R

    2013-01-01

    Breakthrough cancer pain (BTCP) is defined as a transient exacerbation of pain that arises in patients with otherwise controlled persistent pain. BTCP typically has a rapid onset and relatively short duration, but it causes a significant amount of physical and psychological distress for patients. Several rapid-onset fentanyl formulations have been introduced in the USA to replace traditional oral opioids for the treatment of BTCP: a transmucosal lozenge, a sublingual orally disintegrating tablet, a buccal tablet, a buccal soluble film, a pectin nasal spray and, the newest formulation to enter the market, a sublingual spray. This article reviews the six rapid-onset formulations of fentanyl approved in the USA for the management of BTCP with emphasis on describing the published literature on fentanyl sublingual spray. The different fentanyl formulations vary in pharmacokinetic properties and ease of use, but all have a rapid onset and a relatively short duration of analgesia. Fentanyl sublingual spray has demonstrated absorption within 5 minutes of administration, with fentanyl plasma concentrations increasing over the first 30 minutes and remaining elevated for 60–90 minutes in pharmacokinetic studies in healthy subjects. Fentanyl sublingual spray shows linear dose proportionality, and changes in the temperature or acidity of the oral cavity do not alter its pharmacokinetic properties. In patients with BTCP, statistically significant pain relief is measurable at 5 minutes after administration of fentanyl sublingual spray, when compared with placebo, with significant pain relief lasting at least 60 minutes after administration. Adverse events are typical of opioid treatment and are considered mild to moderate in intensity. In summary, fentanyl sublingual spray provides rapid onset of analgesia and is a tolerable and effective treatment for BTCP. PMID:23901300

  11. [Immunotherapy of malignant diseases].

    PubMed

    Dorval, T; Michon, J; Tartour, E; Fridman, W H

    1995-01-01

    Cancer immunotherapy has been carried out since the early fifties and first involved nonspecific system (BCG, Corynebacterium parvum, levamisole...). More recently, the production of cytokines as interferons or interleukin 2, the introduction of monoclonal antibodies have allowed a new development to cancer immunotherapy. Nevertheless, these new approaches have to be considered as a step in the biological therapy of cancer.

  12. Cancer immunotherapy targeting neoantigens.

    PubMed

    Lu, Yong-Chen; Robbins, Paul F

    2016-02-01

    Neoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential benefits and obstacles to the development of effective cancer immunotherapies targeting neoantigens.

  13. [Immunotherapy of malignant diseases].

    PubMed

    Dorval, T; Michon, J; Tartour, E; Fridman, W H

    1995-01-01

    Cancer immunotherapy has been carried out since the early fifties and first involved nonspecific system (BCG, Corynebacterium parvum, levamisole...). More recently, the production of cytokines as interferons or interleukin 2, the introduction of monoclonal antibodies have allowed a new development to cancer immunotherapy. Nevertheless, these new approaches have to be considered as a step in the biological therapy of cancer. PMID:7542946

  14. High Bioavailability of Bisphenol A from Sublingual Exposure

    PubMed Central

    Gayrard, Véronique; Lacroix, Marlène Z.; Collet, Séverine H.; Viguié, Catherine; Bousquet-Melou, Alain; Picard-Hagen, Nicole

    2013-01-01

    Background: Bisphenol A (BPA) risk assessment is currently hindered by the rejection of reported higher-than-expected plasma BPA concentrations in humans after oral ingestion. These are deemed incompatible with the almost complete hepatic first-pass metabolism of BPA into its inactive glucurono-conjugated form, BPA glucuronide (BPAG). Objectives: Using dogs as a valid model, we compared plasma concentrations of BPA over a 24-hr period after intravenous, orogastric, and sublingual administration in order to establish the absolute bioavailability of BPA administered sublingually and to compare it with oral bioavailability. Methods: Six dogs were sublingually administered BPA at 0.05 mg/kg and 5 mg/kg. We compared the time course of plasma BPA concentrations with that obtained in the same dogs after intravenous administration of the same BPA doses and after a 20-mg/kg BPA dose administrated by orogastric gavage. Results: The data indicated that the systemic bioavailability of BPA deposited sublingually was high (70–90%) and that BPA transmucosal absorption from the oral cavity led to much higher BPA internal exposure than obtained for BPA absorption from the gastrointestinal tract. The concentration ratio of BPAG to BPA in plasma was approximately 100-fold lower following sublingual administration than after orogastric dosing, distinguishing the two pathways of absorption. Conclusions: Our findings demonstrate that BPA can be efficiently and very rapidly absorbed through the oral mucosa after sublingual exposure. This efficient systemic entry route of BPA may lead to far higher BPA internal exposures than known for BPA absorption from the gastrointestinal tract. PMID:23761051

  15. [Study of bioavailability of paclitaxel after sublingual administration].

    PubMed

    Samsonia, M; Lesiovskaia, E; Ghibradze, O; Kandelaki, M

    2015-05-01

    The bioavailability of sublingual form of paclitaxel, developed in the pharmacology laboratory of pharmaceutical company - Legion "Provisus" is studied. Sublingual form of paclitaxel is an alcoholic solution of paclitaxel (1 mg/ml) with penetrator - dimethyl sulfoxide (DMSO) addition. Experiments were performed on 180 white mongrel male mice each of 25-30 g. The animals were divided into three groups. The first group served for control. 10 mg/kg of taxol was injected (once) in the lateral tail vein of the first group animals. A solution was prepared by diluting taxol with physiological sodium chloride solution until to a final concentration of paclitaxel to 1 mg/ml. The dose of 10 mg/kg (single dose) was applied under the tongue of the second group animals. Paclitaxel (substance) was extracted with dichloromethane - Taxol (by liquid-liquid extraction) for the manufacturing of a sublingual form. Unlike the second group, the third group animals took the same dose of sublingual form of paclitaxel orally (by gavage). The concentration of paclitaxel in plasma was studied by reversed-phase HPLC with spectrophotometric detection at λ = 227 nm by Woo JS et al. (2003) method. Bioavailability was determined by comparing the concentration of paclitaxel in blood after sublingual and intravenous use of Taxol (as an area under the curve of concentration versus time). It is established that the bioavailability of sublingual forms of paclitaxel was 42.4%, Cmax = 615 ± 73 ng × ml(-1) and tmax = 30-35 min. The value of the initial volume of distribution of paclitaxel (Vd = 3,14 ± 0,85 l × kg(-1)) also shows its intensive penetration to the organs and tissues. The half-life of the drug on the terminal segment of concentration-time curve was averaged 1,06 ± 0,21 h. The results create the preconditions for further preclinical study of sublingual form of paclitaxel, as the bioavailability of paclitaxel after sublingual application allows to have a systemic effect on the tumor

  16. Trends in Cancer Immunotherapy

    PubMed Central

    Murphy, Joseph F.

    2010-01-01

    Modulation of the immune system for therapeutic ends has a long history, stretching back to Edward Jenner’s use of cowpox to induce immunity to smallpox in 1796. Since then, immunotherapy, in the form of prophylactic and therapeutic vaccines, has enabled doctors to treat and prevent a variety of infectious diseases, including cholera, poliomyelitis, diphtheria, measles and mumps. Immunotherapy is now increasingly being applied to oncology. Cancer immunotherapy attempts to harness the power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for cancer immunotherapy is to apply advances in cellular and molecular immunology and develop strategies that effectively and safely augment antitumor responses. PMID:20703326

  17. Immunotherapy for Cervical Cancer

    Cancer.gov

    In an early phase NCI clinical trial, two patients with metastatic cervical cancer had a complete disappearance of their tumors after receiving treatment with a form of immunotherapy called adoptive cell transfer.

  18. Cancer immunotherapy in children

    Cancer.gov

    More often than not, cancer immunotherapies that work in adults are used in modified ways in children. Seldom are new therapies developed just for children, primarily because of the small number of pediatric patients relative to the adult cancer patient

  19. IMMUNOTHERAPY IN ACUTE LEUKEMIA

    PubMed Central

    Leung, Wing

    2010-01-01

    Recent advances in immunotherapy of cancer may represent a successful example in translational research, in which progress in knowledge and technology in immunology has lead to new strategies of immunotherapy, and even past failure in many clinical trials have led to a better understanding of basic cancer immunobiology. This article reviews the latest concepts in antitumor immunology and its application in the treatment of cancer, with particular focus on acute leukemia. PMID:19100371

  20. [Cancer genetic immunotherapy].

    PubMed

    Paul, S; Regulier, E; Etienne, R

    2002-01-01

    The concept of cancer immunotherapy and the resulting technical advances have evolved considerably during the last decade. However, cancer treatment by recombinant IL-2 or IFN-alpha still represents today the best therapeutic way for the treatment of renal carcinoma, melanoma and in some cases lymphoma. The immunotherapy approaches such as vaccination, gene and cellular therapy, have not yet demonstrated a sufficient clinical efficacy for the treatment of solid tumors. The goal of this review is to summarize the different approaches to cancer immunotherapy developed today. Specific approaches such as antigenic vaccination will be first described, then non-specific approaches such as gene transfer on the tumor site of immuno-stimulating genes will be discussed. PMID:12507600

  1. Immunotherapy for colorectal cancer.

    PubMed

    Koido, Shigeo; Ohkusa, Toshifumi; Homma, Sadamu; Namiki, Yoshihisa; Takakura, Kazuki; Saito, Keisuke; Ito, Zensho; Kobayashi, Hiroko; Kajihara, Mikio; Uchiyama, Kan; Arihiro, Seiji; Arakawa, Hiroshi; Okamoto, Masato; Gong, Jianlin; Tajiri, Hisao

    2013-12-14

    The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms. PMID:24379570

  2. Immunotherapy for Gastroesophageal Cancer

    PubMed Central

    Goode, Emily F.; Smyth, Elizabeth C.

    2016-01-01

    Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1), anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4) trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients. PMID:27669318

  3. Resected tumours of the sublingual gland: 15 years' experience.

    PubMed

    Huang, Tung-Tsun; Chou, Yu-Fu; Wen, Yu-Hsuan; Chen, Peir-Rong

    2016-07-01

    Sublingual gland tumours are rare, and we have evaluated the clinical features and prognosis of patients treated at a tertiary medical centre in eastern Taiwan. We retrospectively reviewed the cases of nine patients with sublingual gland tumours that were resected from December 1993 to November 2008, four of whom were men and five women. The median (range) age at diagnosis was 52 (39-63) years. Seven had malignant tumours, of which adenoid cystic carcinoma was the most common. All patients with malignant tumours had neck dissections, and four had cervical lymph node metastases. The incidence of lymph node metastases was much higher in patients with advanced primary tumours (T1/2 compared with T3/4: one out of three compared with three out of four). All patients with malignant tumours were given adjuvant radiotherapy. There were no local failures. One patient had regional recurrence in the neck and had a successful further resection. Three patients developed distant metastases, and two died during the follow-up period. Our results suggest that radical resection with postoperative radiotherapy offers adequate local and regional control for malignant sublingual gland tumours. Neck dissection is beneficial, especially for T3/4 disease.

  4. Stinging insect allergy: current perspectives on venom immunotherapy

    PubMed Central

    Ludman, Sian W; Boyle, Robert J

    2015-01-01

    Systemic allergic reactions to insect stings affect up to 5% of the population during their lifetime, and up to 32% of beekeepers. Such reactions can be fatal, albeit very rarely, and fear of a further systemic reaction (SR) can lead to significant anxiety and quality of life impairment. A recent Cochrane systematic review confirmed that venom immunotherapy (VIT) is an effective treatment for people who have had a systemic allergic reaction to an insect sting. VIT reduces risk of a further SR (relative risk 0.10, 95% confidence interval 0.03–0.28), but VIT also reduces risk of a future large local reaction, and significantly improves disease-specific quality of life. However, health economic analysis showed that VIT is generally not cost effective for preventing future SRs; most people are stung infrequently, most SRs resolve without long-term consequences, and a fatal outcome is extremely rare. VIT only becomes cost effective if one is stung frequently (eg, beekeepers) or if quality of life improvement is considered. Thus, for most people with insect sting allergy, anxiety and quality of life impairment should be the overriding consideration when making treatment decisions, highlighting the importance of a patient-centered approach. Areas which need to be explored in future research include efforts to improve the safety and convenience of VIT such as the use of sublingual immunotherapy; quality of life effects of venom allergy in children and adolescents as well as their parents; and the optimal duration of treatment. PMID:26229493

  5. Allergen-specific immunotherapy in pediatric allergic asthma

    PubMed Central

    2016-01-01

    Allergen-specific immunotherapy (AIT) is the only curative way that can change the immunologic response to allergens and thus can modify the natural progression of allergic diseases. There are some important criteria which contributes significantly on efficacy of AIT, such as the allergen extract used for treatment, the dose and protocol, patient selection in addition to the severity and control of asthma. The initiation of AIT in allergic asthma should be considered in intermittent, mild and moderate cases which coexisting with other allergic diseases such as allergic rhinitis, and in case of unacceptable adverse effects of medications. Two important impact of AIT; steroid sparing effect and preventing from progression to asthma should be taken into account in pediatric asthma when making a decision on starting of AIT. Uncontrolled asthma remains a significant risk factor for adverse events and asthma should be controlled both before and during administration of AIT. The evidence concerning the efficacy of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) for treatment of pediatric asthma suggested that SCIT decreases asthma symptoms and medication scores, whereas SLIT can ameliorate asthma symptoms. Although the effectiveness of SCIT has been shown for both seasonal and perennial allergens, the data for SLIT is less convincing for perennial allergies in pediatric asthma. PMID:27489785

  6. Allergen-specific immunotherapy in pediatric allergic asthma.

    PubMed

    Yukselen, Ayfer

    2016-07-01

    Allergen-specific immunotherapy (AIT) is the only curative way that can change the immunologic response to allergens and thus can modify the natural progression of allergic diseases. There are some important criteria which contributes significantly on efficacy of AIT, such as the allergen extract used for treatment, the dose and protocol, patient selection in addition to the severity and control of asthma. The initiation of AIT in allergic asthma should be considered in intermittent, mild and moderate cases which coexisting with other allergic diseases such as allergic rhinitis, and in case of unacceptable adverse effects of medications. Two important impact of AIT; steroid sparing effect and preventing from progression to asthma should be taken into account in pediatric asthma when making a decision on starting of AIT. Uncontrolled asthma remains a significant risk factor for adverse events and asthma should be controlled both before and during administration of AIT. The evidence concerning the efficacy of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) for treatment of pediatric asthma suggested that SCIT decreases asthma symptoms and medication scores, whereas SLIT can ameliorate asthma symptoms. Although the effectiveness of SCIT has been shown for both seasonal and perennial allergens, the data for SLIT is less convincing for perennial allergies in pediatric asthma. PMID:27489785

  7. Active Immunotherapy of Cancer.

    PubMed

    Chodon, Thinle; Koya, Richard C; Odunsi, Kunle

    2015-01-01

    Clinical progress in the field of cancer immunotherapy has been slow for many years but within the last 5 years, breakthrough successes have brought immunotherapy to the forefront in cancer therapy. Promising results have been observed in a variety of cancers including solid tumors and hematological malignancies with adoptive cell therapy using natural host tumor infiltrating lymphocytes, host cells that have been genetically engineered with antitumor T-cell receptors or chimeric antigen receptors, immune checkpoint inhibitors like anti-CTLA-4, anti-PD-1 or PD-L1 monoclonal antibodies and oncolytic virus-based immunotherapy. However, most treatment modalities have shown limited efficacy with single therapy. The complex nature of cancer with intra- and inter-tumor antigen and genomic heterogeneity coupled with the immune suppressive microenvironment emphasizes the prospect of personalized targeted immunotherapy to manipulate the patient's own immune system against cancer. For successful, robust and long-lasting cure of cancer, a multi-modal approach is essential, combining anti-tumor cell therapy with manipulation of multiple pathways in the tumor microenvironment to ameliorate tumor-induced immunosuppression. PMID:26575466

  8. Allergen-Specific Immunotherapy in Patients 55 Years and Older: Results and Review of Literature

    PubMed Central

    Baptistella, Eduardo; Maniglia, Sergio; Malucelli, Diego Augusto; Rispoli, Daniel; Pruner de Silva, Thanara; Tsuru, Fernanda Miyoko; Becker, Renata Vecentin; Bernardi, Gustavo; Dranka, Daniela; Ferraz, Bruno

    2013-01-01

    Introduction Over the years the immune system suffers many morphologic and functional alterations, which result in a peak of function in puberty and a gradual decrease in the elderly. Aim Treat patients 55 years or older with allergic rhinitis with immunotherapy and then analyze the response to allergens. Materials and Methods From June 2009 to July 2010, 104 charts of patients 55 years or older with allergic complaints were evaluated. The patients were selected by anamnesis, physical examination, and otorhinolaryngologic exam. The patients had cutaneous test for mites before and after 1 year of sublingual specific immunotherapy. The cutaneous response was classified as negative (absent), light, moderate, or severe. Results Before vaccination, 42 (40.4%) patients were classified as having a severe form of allergy and 62 (59.6%) as having a moderate allergy. After the specific therapy, 40 (38.4%) patients were classified as negative (absent), 37 (35.6%) as light, 19 (18.3%) as moderate, and 8 (7.7%) as severe responses. Conclusion Immunotherapy, a desensitization technique, is indicated in cases which patients cannot avoid the exposure to allergens and in situations where pharmacologic therapy is not ideal. Specific immunotherapy to treat the allergic rhinitis in elderly patients was efficient and had no collateral effects, and in addition to the clinical benefit, improvement in the cutaneous test could also be observed. PMID:25992039

  9. Spontaneous sublingual space hematoma secondary to hypertension: A case report and review of literature

    PubMed Central

    Satpathy, Shouvanik; Guha, Rajdeep; Satpathy, Anupama; Guha, Paromita

    2015-01-01

    Sublingual hematoma is a rare complication of oral anticoagulant use. Spontaneous sublingual hematoma secondary to hypertension is even rarer and their management remains enigmatic. We present such a case that we successfully managed conservatively along with a review of relevant literatures. PMID:26668463

  10. Adaptive Segmentation and Feature Quantization of Sublingual Veins of Healthy Humans

    NASA Astrophysics Data System (ADS)

    Yan, Zifei; Li, Naimin

    The Sublingual Vein Diagnosis, one part of Tongue Diagnosis, plays an important role in deciding the healthy condition of humans. This paper focuses on establishing a feature quantization framework for the inspection of sublingual veins of healthy humans, composed of two parts: the segmentation of sublingual veins of healthy humans and the feature quantization of them. Firstly, a novel technique of sublingual vein segmentation is proposed here. Sublingual Vein Color Model, which combines the Bayesian Decision with CIEYxy color space, is established based on a large number of labeled sublingual images. Experiments prove that the proposed method performs well on the segmentation of images from healthy humans with weak color contrast between sublingual vein and tongue proper. And then, a chromatic system in conformity with diagnostic standard of Traditional Chinese Medicine doctors is established to describe the chromatic feature of sublingual veins. Experimental results show that the geometrical and chromatic features quantized by the proposed framework are properly consistent with the diagnostic standard summarized by TCM doctors for healthy humans.

  11. Immunotherapy in food allergy.

    PubMed

    Kamdar, Toral; Bryce, Paul J

    2010-05-01

    Food allergies are caused by immune responses to food proteins and represent a breakdown of oral tolerance. They can range from mild pruritus to life-threatening anaphylaxis. The only current consensus for treatment is food avoidance, which is fraught with compliance issues. For this reason, there has been recent interest in immunotherapy, which may induce desensitization and possibly even tolerance. Through these effects, immunotherapy may decrease the potential for adverse serious reactions with accidental ingestions while potentially leading to an overall health benefit. In this review, we discuss the mechanisms of food allergy and give an overview of the various immunotherapeutic options and current supporting evidence, as well as look towards the future of potential novel therapeutic modalities.

  12. Immunotherapy for tularemia.

    PubMed

    Skyberg, Jerod A

    2013-11-15

    Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (> 30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia.

  13. Immunotherapy of pancreatic carcinoma.

    PubMed

    Märten, Angela

    2008-05-01

    Patients with carcinoma of the exocrine pancreas have especially poor prognosis with a five-year survival rate of <1% and a median survival of 4-6 months. Pancreatic carcinoma is a systemic disease, insensitive to radiotherapy and mostly to chemotherapy. Accordingly, new treatment modalities are worth being investigated. One of the promising approaches is immunotherapy. Several phase I/II trials that have been published show interesting results, whereupon antibody-based strategies seem to fail and unspecific stimulation or vaccination with peptides look encouraging. Furthermore, phase II trials dealing with combination therapies are highly promising. One of them, a combination of chemoradiotherapy plus interferon-alpha is currently tested in a randomized phase III trial. As most of the trials had enrolled only limited numbers of patients and most of the trials were not conducted and/or reported according to the new standards it is difficult to draw final conclusions from the discussed trials. Immuno-monitoring was performed only in 40% of the discussed publications. In all cases immune responses were observed and correlation with the clinical outcome is discussed. Immunotherapy of pancreatic adenocarcinoma and especially combination therapies including immunotherapy is an up-and-coming approach and needs to be investigated in well conducted phase III randomized controlled trials accompanied by appropriate immuno-monitoring.

  14. Immunotherapy of Cancer in 2012

    PubMed Central

    Kirkwood, John M.; Butterfield, Lisa H.; Tarhini, Ahmad A.; Zarour, Hassane; Kalinski, Pawel; Ferrone, Soldano

    2012-01-01

    The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy. PMID:22576456

  15. Patients’ compliance with different administration routes for allergen immunotherapy in Germany

    PubMed Central

    Egert-Schmidt, Anne-Marie; Kolbe, Jan-Marcel; Mussler, Sabine; Thum-Oltmer, Susanne

    2014-01-01

    Background Allergen immunotherapy (AIT) is the practice of administering gradually increasing quantities of an allergen extract to an allergic subject to ameliorate the symptoms associated with the subsequent exposure to the causative allergen. It is the only treatment that may alter the natural course of allergic diseases. According to AIT guidelines and summary of product characteristics (SmPCs), the treatment should be carried out for at least 3 years. It is controversially discussed whether subcutaneous or sublingual administration routes cause higher patients’ compliance. Methods German sales data for different preparations of the allergen manufacturer Allergopharma GmbH & Co. KG were retrospectively evaluated for 5 consecutive years, based on prescriptions per patient: pollen sublingual immunotherapy (SLIT) and high-dose hypoallergenic (allergoid) or unmodified depot pollen and mite preparations for subcutaneous immunotherapy (SCIT). To identify patients’ compliance, “completed treatment years” were determined. A completed treatment year was defined by the required number of prescribed allergen preparations according to the recommended dosage scheme given in the respective SmPCs. Results Prescription data of 85,241 patients receiving pollen or mite SCIT and 706 patients receiving pollen SLIT were included in this analysis. Patients’ compliance for at least 3 treatment years with high-dose hypoallergenic pollen SCIT was higher when administered perennially (60%) compared to preseasonally (27%). Prescriptions for at least 3 years were received from 42% of patients with pollen SCIT and from 45% of patients with mite SCIT. Compliance with SLIT was lowest with only 16% of patients receiving prescriptions for at least 3 treatment years. Children and adolescents were more compliant than adults, independent of whether they received SLIT or SCIT. Conclusion In general, patients’ compliance with SCIT using high-dose hypoallergenic or unmodified depot

  16. Oral mucosal immunotherapy for allergic rhinitis: A pilot study

    PubMed Central

    Suurna, Maria V.; Rochlin, Kate; Bremberg, Maria G.; Tropper, Guy

    2016-01-01

    Background: The sublingual mucosa has been used for many years to apply allergenic extracts for the purpose of specific immunotherapy (IT). Although sublingual IT (SLIT) is both safe and efficacious, the density of antigen-presenting cells is higher in other regions of the oral cavity and vestibule, which make them a potentially desirable target for IT. Objective: To present the concept of oral mucosal IT (OMIT) and to provide pilot data for this extended application of SLIT. Methods: An open-label, 12-month, prospective study was undertaken as a preliminary step before a full-scale clinical investigation. Twenty-four individuals with allergic rhinitis received IT by applying allergenic extracts daily to either the oral vestibule plus oral cavity mucosa by using a glycerin-based toothpaste or to the sublingual mucosa by using 50% glycerin liquid drops. Adverse events, adherence rates, total combined scores, rhinoconjunctivitis quality-of-life questionnaire scores, changes in skin reactivity, and changes in serum antibody levels were measured for each participant. Results: No severe adverse events occurred in either group. The adherence rate was 80% for the OMIT group and 62% for the SLIT group (p = 0.61). Decreased total combined scores were demonstrated for both the OMIT group (15.6%) and the SLIT group (22.3%), although this decrease did not reach statistical significance in either group. Both groups achieved a meaningful clinical improvement of at least 0.5 points on rhinoconjunctivitis quality-of-life questionnaire. A statistically significant rise in specific immunoglobulin G4 (IgG4) was seen in both groups over the first 6 months of treatment. Conclusion: OMIT and SLIT demonstrated similar safety profiles and adherence rates. Measurements of clinical efficacy improved for both groups, but only changes in IgG4 achieved statistical significance. These pilot data provide enough evidence to proceed with a full-scale investigation to explore the role of OMIT in

  17. Unusually Giant Sublingual Epidermoid Cyst: A Case Report

    PubMed Central

    Nishar, Chintan-C; Ambulgekar, Vijayalaxmi-K.; Gujrathi, Atish-B.; Chavan, Pravin-T.

    2016-01-01

    Introduction: Epidermoid cysts are rare, slow‑growing, benign, developmental cysts, which are derived from abnormally situated ectodermal tissue. Epidermoid cysts of the floor of the mouth represent <0.01% of all oral cysts. So far, only a few cases have been reported. Case Report: Hereby, we present a case of a giant sublingual epidermoid cyst, which was completely asymptomatic upon presentation. However, due to its large size, it pushed the epiglottis posteriorly and created difficulty during intubation. The patient developed respiratory distress after its surgical excision and extubation, requiring tracheostomy post operatively. The patient recovered well and a successful weaning of tracheostomy was performed, giving the patient a healthy life. Conclusion: Epidermoid cyst is a rare differential diagnosis of sublingual swelling that should be kept in mind for large asymptomatic swellings in this region. The only symptom it can cause might be respiratory distress due to its large size. This can happen not only pre-operatively but also post-operatively and the surgeon should be ready for immediate tracheostomy. PMID:27602342

  18. A novel system of human submandibular/sublingual saliva collection.

    PubMed

    Wolff, A; Begleiter, A; Moskona, D

    1997-11-01

    The assessment of submandibular/sublingual (sm/sl) saliva is a procedure of increasing significance. However, the collection of these fluids by traditional techniques is difficult and therefore often neglected. To collect sm/sl saliva, we have assembled a novel, universal system consisting of four parts-collecting tubing, a buffering chamber, a storing tube, and a suction device. Submandibular/sublingual saliva samples were collected from ten healthy and ten xerostomic individuals. The system showed intra-examiner reproducibility of 0.92 for healthy and 0.89 for xerostomic subjects, and inter-examiner reproducibility of 0.93 for normal subjects and 0.80 for xerostomic individuals. The flow rates obtained by the present collecting set-up were similar to those measured by all known previous methods that were published during the last 40 years. The system was also efficient, in that more than 90% of the fluid that entered the system was eventually collected in the storing tube for analysis. The system appears to collect relatively pure sm/sl fluids, since contamination of the collected sample by a stimulant solution swabbed repeatedly over the tongue during saliva collection was minimal. The system is reliable, safe, practical, and comfortable for the patient.

  19. Formulation of ketotifen fumarate fast-melt granulation sublingual tablet.

    PubMed

    Tayel, Saadia A; Soliman, Iman I; Louis, Dina

    2010-06-01

    The purpose of this study was to prepare sublingual tablets, containing the antiasthmatic drug ketotifen fumarate which suffers an extensive first-pass effect, using the fast-melt granulation technique. The powder mixtures containing the drug were agglomerated using a blend of polyethylene glycol 400 and 6000 as meltable hydrophilic binders. Granular mannitol or granular mannitol/sucrose mixture were used as fillers. A mechanical mixer was used to prepare the granules at 40 degrees C. The method involved no water or organic solvents, which are used in conventional granulation, and hence no drying step was included, which saved time. Twelve formulations were prepared and characterized using official and non official tests. Three formulations showed the best results and were subjected to an ex vivo permeation study using excised chicken cheek pouches. The formulation F4I possessed the highest permeation coefficient due to the presence of the permeation enhancer (polyethylene glycol) in an amount which allowed maximum drug permeation, and was subjected to a pharmacokinetic study using rabbits as an animal model. The bioavailability of F4I was significantly higher than that of a commercially available dosage form (Zaditen solution-Novartis Pharma-Egypt) (p > 0.05). Thus, fast-melt granulation allowed for rapid tablet disintegration and an enhanced permeation of the drug through the sublingual mucosa, resulting in increased bioavailabililty. PMID:20407934

  20. Unusually Giant Sublingual Epidermoid Cyst: A Case Report

    PubMed Central

    Nishar, Chintan-C; Ambulgekar, Vijayalaxmi-K.; Gujrathi, Atish-B.; Chavan, Pravin-T.

    2016-01-01

    Introduction: Epidermoid cysts are rare, slow‑growing, benign, developmental cysts, which are derived from abnormally situated ectodermal tissue. Epidermoid cysts of the floor of the mouth represent <0.01% of all oral cysts. So far, only a few cases have been reported. Case Report: Hereby, we present a case of a giant sublingual epidermoid cyst, which was completely asymptomatic upon presentation. However, due to its large size, it pushed the epiglottis posteriorly and created difficulty during intubation. The patient developed respiratory distress after its surgical excision and extubation, requiring tracheostomy post operatively. The patient recovered well and a successful weaning of tracheostomy was performed, giving the patient a healthy life. Conclusion: Epidermoid cyst is a rare differential diagnosis of sublingual swelling that should be kept in mind for large asymptomatic swellings in this region. The only symptom it can cause might be respiratory distress due to its large size. This can happen not only pre-operatively but also post-operatively and the surgeon should be ready for immediate tracheostomy.

  1. Interaction of native and asialo rat sublingual glycoproteins with lectins.

    PubMed

    Wu, A M; Herp, A; Song, S C; Wu, J H; Chang, K S

    1995-01-01

    The binding properties of the rat sublingual glycoprotein (RSL) and its asialo product with lectins were characterized by quantitative precipitin(QPA) and precipitin inhibition(QPIA) assays. Among twenty lectins tested for QPA, native RSL reacted well only with Artocarpus integrifolia (jacalin), but weakly or not at all with the other lectins. However, its asialo product (asialo-RSL) reacted strongly with many Gal and GalNAc specific lectins-it bound best to three of the GalNAc alpha 1-->Ser/Thr (Tn) and/or Gal beta 1-->4GlcNAc (II) active lectins [jacalin, Wistaria floribunda and Ricinus communis agglutinins] and completely precipitated each of these three lectins. Asialo-RSL also reacted well with Abrus precatorius, Glycine max, Bauhinia purpurea alba, and Maclura pomifera agglutinins, and abrin-a, but not with Arachis hypogeae and Dolichos biflorus agglutinins. The interaction between asialo-RSL and lectins were inhibited by either Gal beta 1-->4GlcNAc, p-NO2-phenyl alpha-GalNAc or both. The mapping of the precipitation and inhibition profiles leads to the conclusion that the asialo rat sublingual glycoprotein provides important ligands for II (Gal beta 1-->4GlcNAc beta 1-->) and Tn (GalNAc alpha 1-->Ser/Thr) active lectins.

  2. Fentanyl sublingual: in breakthrough pain in opioid-tolerant adults with cancer.

    PubMed

    Chwieduk, Claudine M; McKeage, Kate

    2010-12-01

    Fentanyl is a potent opioid with a short duration of action. Fentanyl sublingual has been formulated as a rapidly disintegrating tablet that is quickly absorbed, producing a fast onset of analgesia. In two randomized, double-blind clinical trials, fentanyl sublingual as single fixed or titrated doses reduced pain intensity during breakthrough pain episodes to a significantly greater extent than placebo in opioid-tolerant cancer patients. In a fixed-dose phase II trial and a titrated-dose phase III trial, fentanyl sublingual (as a single 400 μg dose and as titrated doses) reduced mean pain intensity difference (PID) to a significantly greater extent than placebo over the entire treatment period (up to 60 minutes), reaching statistical significance 15 minutes post-dose. In the titrated-dose study, the mean sum of PID (area under the PID vs time curve) at 30 minutes post-dose was significantly greater with fentanyl sublingual than placebo, with significant improvements in PID seen at 10 minutes maintained at 60 minutes post-dose. In the phase III study, patients receiving fentanyl sublingual were more satisfied with their treatment than patients receiving placebo (measured using the Patient Global Evaluation of Medication score), and almost half of all fentanyl sublingual recipients were satisfied or very satisfied with their treatment. Fentanyl sublingual was generally well tolerated in the two trials and most adverse events were mild to moderate in intensity.

  3. Immunotherapy for Alzheimer's disease.

    PubMed

    Farlow, Martin R; Brosch, Jared R

    2013-08-01

    The immune system plays a significant role in Alzheimer disease (AD). β-Amyloid deposition in the cortex is thought to be an initiating event in AD and the widely believed amyloid hypothesis proposes removal of amyloid may delay disease progression. Human trials of active or passive immune agents have failed to show benefit and increased adverse events of vasogenic edema and microhemorrhages. Evidence suggests the illness may be too advanced by the time patients are symptomatic with dementia. Future directions include better understanding of how and where immunotherapies should be targeted and treating patients at earlier stages of the illness.

  4. [Immunotherapy for Alzheimer's disease].

    PubMed

    Falkentoft, Alexander Christian; Hasselbalch, Steen Gregers

    2016-01-18

    Passive anti-beta-amyloid (Aß) immunotherapy has been shown to clear brain Aß deposits. Results from phase III clinical trials in mild-to-moderate Alzheimer's disease (AD) patients with two monoclonal antibodies bapineuzumab and solanezumab and intravenous immunoglobulin have been disappointing. Subsequent analysis of pooled data from both phase III trials with solanezumab showed a reduction in cognitive decline in patients with mild AD. Solanezumab and new monoclonal antibodies are being tested in patients with prodromal and preclinical AD in search for a disease-modifying treatment. PMID:26815584

  5. Immunotherapy for TB.

    PubMed

    Doherty, T Mark

    2012-06-01

    Mycobacterium tuberculosis was one of the first human pathogens to be identified as the cause of a specific disease--TB. TB was also one of the first specific diseases for which immunotherapy was attempted. In more than a century since, multiple different immunotherapies have been attempted, alongside vaccination and antibiotic treatment, with varying degrees of success. Despite this, TB remains a major worldwide health problem that causes nearly 2 million deaths annually and has infected an estimated 2 billion people. A major reason for this is that M. tuberculosis is an ancient human pathogen that has evolved complex strategies for persistence in the human host. It has thus been long understood that, to effectively control TB, we will need to address the ability of the pathogen to establish a persistent, latent infection in most infected individuals. This review discusses what is presently known about the interaction of M. tuberculosis with the immune system, and how this knowledge has been used to design immunotherapeutic strategies.

  6. Immunotherapy for house dust mite sensitivity: where are the knowledge gaps?

    PubMed

    Biagtan, Mark; Viswanathan, Ravi; Bush, Robert K

    2014-12-01

    House dust mites (HDMs) are found in the environments where human habitation exists. Their density is dependent on environmental relative humidity; therefore, higher populations are present in areas of the world with higher humidity levels, e.g., coastal areas and tropics. To date, 24 HDM allergens have been identified. Many of these represent digestive enzymes since HDM feces are the major source of allergen exposure. IgE- medicated sensitization to HDM allergens is an important factor in the pathogenesis of allergic diseases since it is the most common aeroallergen detected by skin testing or in vitro IgE assays. Sensitization to HDM allergens often occurs early in life and appears to play an important role in the progression from allergic rhinitis to asthma (the so-called Allergic March) in children. HDM sensitization is also associated with asthma across all age groups. Efforts to control environmental exposure to HDM allergens have often proven to be unsuccessful. While medications can improve symptoms, only immunotherapy currently provides disease-modifying effects in allergic rhinitis and asthma. Several systemic reviews and meta-analysis indicate that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective in the treatment of allergic rhinitis and asthma for HDM sensitivity. In this report, we review recent studies and the evidence for the use of HDM SCIT and SLIT. Fundamental gaps in knowledge are identified which could lead to improved approaches to HDM allergy. PMID:25354663

  7. Modified immunotherapy for alopecia areata.

    PubMed

    Yoshimasu, Takashi; Furukawa, Fukumi

    2016-07-01

    Squaric acid dibutylester (SADBE) is a commonly used contact sensitizer in immunotherapy for alopecia areata (AA). Severe contact dermatitis is induced by the currently high recommended sensitization dose of 1%-2% SADBE, often decreasing patient compliance. We assessed a modified immunotherapy for AA using SADBE at a starting concentration of 0.01% without sensitization. After one or two weeks of initial 0.01% SADBE application, the concentration of SADBE was increased gradually to 0.025%, 0.05%, 0.1%, 0.25%, 0.5%, 1% and 2% until the patients felt itching or erythema at the AA lesion site. The modified immunotherapy showed a response rate of 69.4% (25/36), equivalent to conventional immunotherapy using SADBE starting at 1%-2% sensitization. Furthermore, we investigated the combination therapy of SADBE and multiple courses of steroid pulses for AA. The response rate for combination therapy was 73.7% (28/38); however, the group receiving combination therapy showed a significant prevalence of severe AA compared with the group receiving modified immunotherapy only. We reviewed the efficacy and safety of modified immunotherapy without initial sensitization and combination therapy with immunotherapy and multiple courses of pulses for AA.

  8. Mouse Models of Tumor Immunotherapy.

    PubMed

    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients.

  9. Sublingual atropine drops for the treatment of pediatric sialorrhea.

    PubMed

    Rapoport, Adam

    2010-11-01

    Excess oral secretions or sialorrhea is a common problem affecting children and adults with neurological disorders, as well as those approaching the end of life because of a variety of underlying illnesses. Systemic anticholinergic medications are often prescribed in an attempt to improve quality of life and reduce complications; yet, response rates are variable, and a sizable proportion of patients discontinue these drugs as a result of intolerable side effects. This report describes the successful use of a local treatment, sublingually delivered ophthalmic atropine drops, to reduce sialorrhea in a child receiving palliative care. In addition, medical evidence for the safety and efficacy of traditionally prescribed systemic medications for the treatment of pediatric sialorrhea is reviewed.

  10. Abuse and diversion of buprenorphine sublingual tablets and film.

    PubMed

    Lavonas, Eric J; Severtson, S Geoffrey; Martinez, Erin M; Bucher-Bartelson, Becki; Le Lait, Marie-Claire; Green, Jody L; Murrelle, Lenn E; Cicero, Theodore J; Kurtz, Steven P; Rosenblum, Andrew; Surratt, Hilary L; Dart, Richard C

    2014-07-01

    Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants' Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ("unique recipients of a dispensed drug," URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned.

  11. Abuse and diversion of buprenorphine sublingual tablets and film.

    PubMed

    Lavonas, Eric J; Severtson, S Geoffrey; Martinez, Erin M; Bucher-Bartelson, Becki; Le Lait, Marie-Claire; Green, Jody L; Murrelle, Lenn E; Cicero, Theodore J; Kurtz, Steven P; Rosenblum, Andrew; Surratt, Hilary L; Dart, Richard C

    2014-07-01

    Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants' Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ("unique recipients of a dispensed drug," URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned. PMID:24680219

  12. Alteration of the sublingual microvascular glycocalyx in critically ill patients.

    PubMed

    Donati, Abele; Damiani, Elisa; Domizi, Roberta; Romano, Rocco; Adrario, Erica; Pelaia, Paolo; Ince, Can; Singer, Mervyn

    2013-11-01

    Glycocalyx degradation may contribute to microvascular dysfunction and tissue hypoperfusion during systemic inflammation and sepsis. In this observational study we evaluated the alteration of the sublingual microvascular glycocalyx in 16 healthy volunteers and 50 critically ill patients. Sidestream Dark Field images of the sublingual microcirculation were automatically analyzed by dedicated software. The Perfused Boundary Region (PBR) was calculated as the dimensions of the permeable part of the glycocalyx allowing the penetration of circulating red blood cells, providing an index of glycocalyx damage. The PBR was increased in ICU patients compared to healthy controls (2.7 [2.59-2.88] vs. 2.46 [2.37-2.59]μm, p<0.0001) and tended to be higher in the 32 septic patients compared to non-septics (2.77 [2.62-2.93] vs. 2.67 [2.55-2.75]μm, p=0.05), suggesting more severe glycocalyx alterations. A PBR of 2.76 showed the best discriminative ability towards the presence of sepsis (sensitivity: 50%, specificity: 83%; area under the receiver operating characteristic curve: 0.67, 95% CI 0.52-0.82, p=0.05). A weak positive correlation was found between PBR and heart rate (r=0.3, p=0.03). In 17 septic patients, a correlation was found between PBR and number of rolling leukocytes in post-capillary venules (RL/venule) (r=0.55, p=0.02), confirming that glycocalyx shedding enhances leukocyte-endothelium interaction.

  13. Sublingual buprenorphine for chronic pain: A survey of clinician prescribing practices

    PubMed Central

    Rosen, Kristen; Gutierrez, Antonio; Haller, Deborah; Potter, Jennifer Sharpe

    2013-01-01

    Objectives Sublingual buprenorphine, with and without naloxone, is indicated for the treatment of opioid use disorders. Although not approved for pain, some evidence suggests it may be a safe and effective alternative to conventional opioid analgesics, particularly for those with addiction problems. This study surveyed pain specialists to examine the extent to which sublingual buprenorphine was prescribed for chronic pain and explore associated clinician attitudes and characteristics. Method A 36-item survey examining clinician attitudes and characteristics related to sublingual buprenorphine and other opioids was distributed to 1,307 members of the American Pain Society, a multi-disciplinary professional group. Members were provided a paper copy of the survey and URL to an on-line version. A follow up letter was mailed after 2 weeks. Results Overall, 230 completed surveys were returned (18.5%). Of clinicians who prescribed opioids for chronic pain (92.5%), 19.7% reported prescribing sublingual buprenorphine for chronic pain at least once; of these prescribers, 39.6% did not have a DEA X-waiver to prescribe sublingual buprenorphine for opioid dependance. Prescribers were more likely than non-prescribers to find sublingual buprenorphine effective for chronic pain. Prescribers were also significantly more likely to view sublingual buprenorphine as safer than full agonists in terms of addiction, overdose, and drug interaction. No differences emerged between prescribers and non-prescribers regarding perceptions of potential for drug diversion or in terms of overall opioid prescribing behaviors. Discussion Results suggest that sublingual buprenorphine is indeed being used to treat chronic pain; however, the circumstances when this occurs are not entirely clear. PMID:23727654

  14. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

    PubMed Central

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in two open-label studies. In study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order: (i) 15.0 mg of sublingual artemether (5 × 3.0 actuations), (ii) 30.0 mg of sublingual artemether (10 × 3.0 mg), (iii) 30.0 mg of sublingual artemether (5 × 6.0 mg), and (iv) 30.0 mg of artemether in tablet form. In study 2, 16 healthy males were randomized to eight 30.0-mg doses of sublingual artemether given over 5 days as either 10 3.0-mg or 5 6.0-mg actuations. Frequent blood samples were drawn postdose. Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (≥1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (≥1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing. PMID:25801553

  15. Dual ectopic thyroid gland: sonography and scintigraphy of lingual and sublingual thyroid.

    PubMed

    Marković, Vinko; Glavina, Gordana; Eterović, Davor; Punda, Ante; Brdar, Dubravka

    2014-06-01

    Dual ectopic lingual and sublingual thyroid gland is an extraordinarily rare condition. We present 1 patient with subclinical hypothyroidism. The clinical examination revealed that the thyroid gland was not palpable in its usual cervical location, whereas ultrasonography confirmed an empty thyroid bed without any ectopic thyroid tissue in the rest of the neck. The final diagnosis of dual ectopic lingual and sublingual thyroid was established by ultrasound examination through the mouth floor and confirmed by scintigraphy and CT thereafter.

  16. A bilateral, superficial location of human sublingual glands: report of a case.

    PubMed

    Moss-Salentijn, L; Hendricks-Klyvert, M

    1987-11-01

    During a routine dissection of a cadaver, the unusual, completely superficial position of both sublingual glandular masses was noticed. Histologically, the glandular masses consisted of a group of minor sublingual glands. It is suggested that the existence of a wide gap between the anterior and posterior parts of the mylohyoid muscle, which was revealed during further dissection, was the primary embryologic anomaly that was responsible for the unusual location of the glands.

  17. Imaging Biomarkers in Immunotherapy

    PubMed Central

    Juergens, Rosalyn A.; Zukotynski, Katherine A.; Singnurkar, Amit; Snider, Denis P.; Valliant, John F.; Gulenchyn, Karen Y.

    2016-01-01

    Immune-based therapies have been in use for decades but recent work with immune checkpoint inhibitors has now changed the landscape of cancer treatment as a whole. While these advances are encouraging, clinicians still do not have a consistent biomarker they can rely on that can accurately select patients or monitor response. Molecular imaging technology provides a noninvasive mechanism to evaluate tumors and may be an ideal candidate for these purposes. This review provides an overview of the mechanism of action of varied immunotherapies and the current strategies for monitoring patients with imaging. We then describe some of the key researches in the preclinical and clinical literature on the current uses of molecular imaging of the immune system and cancer. PMID:26949344

  18. Immunotherapy in Lung Cancer.

    PubMed

    Castellanos, Emily H; Horn, Leora

    2016-01-01

    Lung cancer has not traditionally been viewed as an immune-responsive tumor. However, it is becoming evident that tumor-induced immune suppression is vital to malignant progression. Immunotherapies act by enhancing the patient's innate immune response and hold promise for inducing long-term responses in select patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Immune checkpoint inhibitors, in particular, inhibitors to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have shown promise in early studies and are currently in clinical trials in both small cell lung cancer and non-small cell lung cancer patients. Two large randomized phase III trials recently demonstrated superior overall survival (OS) in patients treated with anti-PD-1 therapy compared to chemotherapy in the second-line setting.

  19. Tau immunotherapy and imaging.

    PubMed

    Sigurdsson, Einar M

    2014-01-01

    Disappointing findings from recent phase III trials on amyloid-β (Aβ) immunotherapy for Alzheimer's disease (AD) have shifted the focus of such treatments to the tau protein. As tau pathology correlates better with the degree of dementia than Aβ plaque burden, it is a more attractive target once cognitive impairments are evident, while Aβ therapies may be better suited for the presymptomatic phase of the disease. Over 12 years ago, we initiated a tau immunotherapy program, seeking to alleviate the functional impairments associated with tau lesions in tauopathies. We have reported that various active and passive tau immunizations diminish tau pathology and improve function, including cognition, in different mouse models. Both extra- and intracellular pathways are likely involved. The antibodies may block the spread of tau pathology via microglial phagocytosis of the antibody-tau complex and facilitate lysosomal tau clearance in neurons after endosomal uptake. We have observed such antibody internalization following intracarotid injection in mice and in various culture models. These include brain slices and primary neurons from tangle mice as well as human neuroblastoma cell lines. Antibody targeting of different intracellular protein aggregates, including α-synuclein, Aβ and superoxide dismutase has been reported by others. Now, several laboratories have confirmed and extended our findings using various active and passive tau immunizations in different models, thereby clearly establishing the feasibility of this approach for clinical trials. We are also working on imaging approaches to monitor tau pathology, its consequences and the efficacy of treatments. Dire need exists for such diagnostic methods for tauopathies. Overall, therapies and diagnostic tools targeting tau pathology have a great potential for AD and other tauopathies.

  20. Genomic determinants of cancer immunotherapy.

    PubMed

    Miao, Diana; Van Allen, Eliezer M

    2016-08-01

    Cancer immunotherapies - including therapeutic vaccines, adoptive cell transfer, oncolytic viruses, and immune checkpoint blockade - yield durable responses in many cancer types, but understanding of predictors of response is incomplete. Genomic characterization of human cancers has already contributed to the success of targeted therapies; in cancer immunotherapy, identification of tumor-specific antigens through whole-exome sequencing may be key to designing individualized, highly immunogenic therapeutic vaccines. Additionally, pre-treatment tumor mutational and gene expression signatures can predict which patients are most likely to benefit from cancer immunotherapy. Continued work in harnessing genomic, transcriptomic, and immunological data from clinical cohorts of immunotherapy-treated patients will bring the promises of precision medicine to immuno-oncology.

  1. Monitoring Microcirculatory Blood Flow with a New Sublingual Tonometer in a Porcine Model of Hemorrhagic Shock.

    PubMed

    Palágyi, Péter; Kaszaki, József; Rostás, Andrea; Érces, Dániel; Németh, Márton; Boros, Mihály; Molnár, Zsolt

    2015-01-01

    Tissue capnometry may be suitable for the indirect evaluation of regional hypoperfusion. We tested the performance of a new sublingual capillary tonometer in experimental hemorrhage. Thirty-six anesthetized, ventilated mini pigs were divided into sham-operated (n = 9) and shock groups (n = 27). Hemorrhagic shock was induced by reducing mean arterial pressure (MAP) to 40 mmHg for 60 min, after which fluid resuscitation started aiming to increase MAP to 75% of the baseline value (60-180 min). Sublingual carbon-dioxide partial pressure was measured by tonometry, using a specially coiled silicone rubber tube. Mucosal red blood cell velocity (RBCV) and capillary perfusion rate (CPR) were assessed by orthogonal polarization spectral (OPS) imaging. In the 60 min shock phase a significant drop in cardiac index was accompanied by reduction in sublingual RBCV and CPR and significant increase in the sublingual mucosal-to-arterial PCO2 gap (PSLCO2 gap), which significantly improved during the 120 min resuscitation phase. There was significant correlation between PSLCO2 gap and sublingual RBCV (r = -0.65, p < 0.0001), CPR (r = -0.64, p < 0.0001), central venous oxygen saturation (r = -0.50, p < 0.0001), and central venous-to-arterial PCO2 difference (r = 0.62, p < 0.0001). This new sublingual tonometer may be an appropriate tool for the indirect evaluation of circulatory changes in shock. PMID:26504837

  2. Vaginal Versus Sublingual Misoprostol for Labor Induction at Term and Post Term: a Randomized Prospective Study

    PubMed Central

    Ayati, Sedigheh; Vahidroodsari, Fatemeh; Farshidi, Farnoosh; Shahabian, Masoud; Afzal Aghaee, Monavar

    2014-01-01

    We want to compare the efficacy and safety of vaginal versus sublingual misoprostol for cervical ripening and induction of labor. This randomized clinical trial was performed on 140 women with medical or obstetric indications for labor induction. The patients were randomly divided into two groups: vaginal and sublingual administration of misoprostol. In first group, 25 µg misoprostol was placed in the posterior fornix of the vagina and second group received 25 µg misoprostol sublingually, every 6 hours for 24 h. Maternal and neonatal outcomes were analyzed. There was no significant difference in the demographic characteristics between two groups. The main indication for cesarean section in both groups was fetal distress, followed by absence of active labor progress. Evaluation of cesarean indication was not significantly different in two groups; including fetal distress, absence of active labor, uterine over activity and failure to progress. The maternal complication in sublingual group included residual placenta (2%), tachysystole (2%), vomiting (12%), atoni (3.3%) and abdominal pain (5.5%), although there was no significant difference between two groups. Sublingual misoprostol is as effective as vaginal misoprostol for induction of labor at term. However, sublingual misoprostol has the advantage of easy administration and may be more suitable than vaginal misoprostol. PMID:24734084

  3. Monitoring Microcirculatory Blood Flow with a New Sublingual Tonometer in a Porcine Model of Hemorrhagic Shock

    PubMed Central

    Palágyi, Péter; Kaszaki, József; Rostás, Andrea; Érces, Dániel; Németh, Márton; Boros, Mihály; Molnár, Zsolt

    2015-01-01

    Tissue capnometry may be suitable for the indirect evaluation of regional hypoperfusion. We tested the performance of a new sublingual capillary tonometer in experimental hemorrhage. Thirty-six anesthetized, ventilated mini pigs were divided into sham-operated (n = 9) and shock groups (n = 27). Hemorrhagic shock was induced by reducing mean arterial pressure (MAP) to 40 mmHg for 60 min, after which fluid resuscitation started aiming to increase MAP to 75% of the baseline value (60–180 min). Sublingual carbon-dioxide partial pressure was measured by tonometry, using a specially coiled silicone rubber tube. Mucosal red blood cell velocity (RBCV) and capillary perfusion rate (CPR) were assessed by orthogonal polarization spectral (OPS) imaging. In the 60 min shock phase a significant drop in cardiac index was accompanied by reduction in sublingual RBCV and CPR and significant increase in the sublingual mucosal-to-arterial PCO2 gap (PSLCO2 gap), which significantly improved during the 120 min resuscitation phase. There was significant correlation between PSLCO2 gap and sublingual RBCV (r = −0.65, p < 0.0001), CPR (r = −0.64, p < 0.0001), central venous oxygen saturation (r = −0.50, p < 0.0001), and central venous-to-arterial PCO2 difference (r = 0.62, p < 0.0001). This new sublingual tonometer may be an appropriate tool for the indirect evaluation of circulatory changes in shock. PMID:26504837

  4. Immunotherapy of allergic contact dermatitis.

    PubMed

    Spiewak, Radoslaw

    2011-08-01

    The term 'immunotherapy' refers to treating diseases by inducing, enhancing or suppressing immune responses. As allergy is an excessive, detrimental immune reaction to otherwise harmless environmental substances, immunotherapy of allergic disease is aimed at the induction of tolerance toward sensitizing antigens. This article focuses on the historical developments, present state and future outlook for immunotherapy with haptens as a therapeutic modality for allergic contact dermatitis. Inspired by the effectiveness of immunotherapy in respiratory allergies, attempts were undertaken at curing allergic contact dermatitis by means of controlled administration of the sensitizing haptens. Animal and human experiments confirmed that tolerance to haptens can be induced most effectively when the induction of tolerance precedes attempted sensitization. In real life, however, therapy is sought by people who are already sensitized and an effective reversal of hypersensitivity seems more difficult to achieve. Decades of research on Rhus hypersensitivity led to a conclusion that immunotherapy can suppress Rhus dermatitis, however, only to a limited degree, for a short period of time, and at a high risk of side effects, which makes this method therapeutically unprofitable. Methodological problems with most available studies of immunotherapy of contact allergy to nickel make any definite conclusions impossible at this stage.

  5. Local reactions from subcutaneous allergen immunotherapy.

    PubMed

    Coop, Christopher A

    2013-12-01

    Local reactions from subcutaneous allergen immunotherapy are very common during the course of immunotherapy. These local reactions are not bothersome to patients. Local reactions from immunotherapy also do not predict future local or systemic reactions. This review discusses the studies that show that local reactions are not predictive of future reactions and that dose adjustments for local reactions from allergen immunotherapy are unnecessary. The article also focuses on factors that lead to patient noncompliance with immunotherapy and evaluates methods to prevent local reactions from subcutaneous allergen immunotherapy. PMID:24283844

  6. Local reactions from subcutaneous allergen immunotherapy.

    PubMed

    Coop, Christopher A

    2013-12-01

    Local reactions from subcutaneous allergen immunotherapy are very common during the course of immunotherapy. These local reactions are not bothersome to patients. Local reactions from immunotherapy also do not predict future local or systemic reactions. This review discusses the studies that show that local reactions are not predictive of future reactions and that dose adjustments for local reactions from allergen immunotherapy are unnecessary. The article also focuses on factors that lead to patient noncompliance with immunotherapy and evaluates methods to prevent local reactions from subcutaneous allergen immunotherapy.

  7. Immunotherapy for lung cancer.

    PubMed

    Bradbury, Penelope A; Shepherd, Frances A

    2008-06-01

    Reports of tumor regression after infection date back as far as 1550 bc. In the twentieth century, Dr. William Coley, witnessing regression of a malignant tumor in one of his patients after a bacterial infection, developed the first cancer treatment vaccine derived from killed bacteria, with some reported success. However, despite decades of research, no specific, active tumor vaccine has been approved for the treatment of cancer. In lung cancer, initial attempts to modulate the immune system with nonspecific therapies were unsuccessful. However, more sophisticated specific vaccines have now been developed, and an increasing number are being evaluated in randomized phase 3 trials, raising hopes that vaccines may be an additional novel therapy for patients with lung cancer. This article reviews the following seven vaccines, which have entered randomized trials: L-BLP25 (Stimuvax), BEC-2, 1E10, PF-3512676 (Promune), melanoma-associated antigen A3 immunotherapeutic, granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy, and belagenpumatucel-L (Lucanix).

  8. Immunotherapy for Drug Abuse

    PubMed Central

    Shen, Xiaoyun; Kosten, Thomas R.

    2013-01-01

    Substance use disorders continue to be major medical and social problems worldwide. Current medications for substance use disorders have many limitations such as cost, availability, medication compliance, dependence, diversion of some to illicit use and relapse to addiction after discontinuing their use. Immunotherapies using either passive monoclonal antibodies or active vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They have great potential to help the patient achieve and sustain abstinence and have fewer of the above limitations. This review covers the cocaine vaccine development in detail and provides an overview of directions for developing anti-addiction vaccines against the abuse of other substances. The notable success of the first placebo-controlled clinical trial of a cocaine vaccine, TA-CD, has led to an ongoing multi-site, Phase IIb clinical trial in 300 subjects. The results from these trials are encouarging further development of the cocaine vacine as one of the first anti-addiction vaccines to go forward to the U.S. Food and Drug Administration for review and approval for human use. PMID:22229313

  9. Immunotherapy of Brain Cancer.

    PubMed

    Roth, Patrick; Preusser, Matthias; Weller, Michael

    2016-01-01

    The brain has long been considered an immune-privileged site precluding potent immune responses. Nevertheless, because of the failure of conventional anti-cancer treatments to achieve sustained control of intracranial neoplasms, immunotherapy has been considered as a promising strategy for decades. However, several efforts aimed at exploiting the immune system as a therapeutic weapon were largely unsuccessful. The situation only changed with the introduction of the checkpoint inhibitors, which target immune cell receptors that interfere with the activation of immune effector cells. Following the observation of striking effects of drugs that target CTLA-4 or PD-1 against melanoma and other tumor entities, it was recognized that these drugs may also be active against metastatic tumor lesions in the brain. Their therapeutic activity against primary brain tumors is currently being investigated within clinical trials. In parallel, other immunotherapeutics such as peptide vaccines are at an advanced stage of clinical development. Further immunotherapeutic strategies currently under investigation comprise adoptive immune cell transfer as well as inhibitors of metabolic pathways involved in the local immunosuppression frequently found in brain tumors. Thus, the ongoing implementation of immunotherapeutic concepts into clinical routine may represent a powerful addition to the therapeutic arsenal against various brain tumors. PMID:27260656

  10. Immunotherapy of Colorectal Cancer.

    PubMed

    Jäger, Dirk; Halama, Niels; Zörnig, Inka; Klug, Paula; Krauss, Jürgen; Haag, Georg-Martin

    2016-01-01

    It is known that the immune response, reflected by high T cell infiltrates in primary tumors and metastases, influences the clinical course of colorectal cancer (CRC). Therefore, immunotherapy concepts have been adapted from other tumor entities, which typically rely on the activation of T cells in the tumor microenvironment (e.g. blockade of the immune checkpoint molecules PD-1 and CTLA-4). However, most of the strategies using the approved checkpoint inhibitors and/or combination strategies have more or less failed to produce impressive results in early phase trials in CRC. Therefore, a number of novel targets for checkpoint inhibition are currently in early phase clinical testing (TIM-3, Lag-3, OX40, GITR, 4-1BB, CD40, CD70). A simple activation of infiltrating T cells will not, however, lead to a meaningful anti-tumor response without modulating the environmental factors in CRC. Thus, it is absolutely necessary to improve our understanding of the complex regulation of the tumor microenvironment in CRC to design individual combination treatments leading to effective immune control. PMID:27259331

  11. Immunotherapy for malignant glioma.

    PubMed

    Suryadevara, Carter M; Verla, Terence; Sanchez-Perez, Luis; Reap, Elizabeth A; Choi, Bryan D; Fecci, Peter E; Sampson, John H

    2015-01-01

    Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

  12. Lymphoma Immunotherapy: Current Status

    PubMed Central

    Zappasodi, Roberta; de Braud, Filippo; Di Nicola, Massimo

    2015-01-01

    The rationale to treat lymphomas with immunotherapy comes from long-standing evidence on their distinctive immune responsiveness. Indolent B-cell non-Hodgkin lymphomas, in particular, establish key interactions with the immune microenvironment to ensure prosurvival signals and prevent antitumor immune activation. However, reports of spontaneous regressions indicate that, under certain circumstances, patients develop therapeutic antitumor immunity. Several immunotherapeutic approaches have been thus developed to boost these effects in all patients. To date, targeting CD20 on malignant B cells with the antibody rituximab has been the most clinically effective strategy. However, relapse and resistance prevent to cure approximately half of B-NHL patients, underscoring the need of more effective therapies. The recognition of B-cell receptor variable regions as B-NHL unique antigens promoted the development of specific vaccines to immunize patients against their own tumor. Despite initial promising results, this strategy has not yet demonstrated a sufficient clinical benefit to reach the regulatory approval. Several novel agents are now available to stimulate immune effector functions or counteract immunosuppressive mechanisms, such as engineered antitumor T cells, co-stimulatory receptor agonist, and immune checkpoint-blocking antibodies. Thus, multiple elements can now be exploited in more effective combinations to break the barriers for the induction of anti-lymphoma immunity. PMID:26388871

  13. Solitary fibrous tumor with malignant potential arising in sublingual gland.

    PubMed

    Ogawa, Ikuko; Sato, Sunao; Kudo, Yasusei; Miyauchi, Mutsumi; Sugiyama, Masaru; Suei, Yoshikazu; Takata, Takashi

    2003-01-01

    A rare case is described of a solitary fibrous tumor (SFT) with malignant potential arising in the sublingual gland. A 59-year-old man presented with a 4-month history of a slowly enlarging painless mass in the center of the floor of the mouth. The tumor was a well-demarcated, firm mass with a multicystic lesion. The tumor exhibited highly cellular areas of spindle cells with patternless architecture alternating with hypocellular areas. The tumor cells were positive for CD34 and bcl-2 as well as vimentin, and negative for epithelial, myogenic, neurogenic and histiocytic markers. The tumor cells formed multiple satellite nodules around dilated ducts in the multicystic lesion, indicating infiltrative growth. In addition, areas exhibiting higher cellularity with increased mitoses were noticed in the satellite nodules, although cellular atypia was not obvious. These findings led to a final diagnosis of SFT with malignant potential. There has been no recurrence or metastasis for 27 months after the surgery. Solitary fibrous tumor of the salivary gland must be differentiated from various spindle cell neoplasms including myogenic, peripheral nerve sheath, fibroblastic and fibro-histiocytic spindle cell neoplasms, hemangiopericytoma and myoepithelioma. In addition to characteristic morphological features, an immunohistochemical positivity for CD34 and bcl-2 may aid in the diagnosis of SFT.

  14. COMPARISON BETWEEN SUBLINGUAL AND VAGINAL ROUTE OF MISOPROSTOL IN MANAGEMENT OF FIRST TRIMESTER MISCARRIAGE MISSING

    PubMed Central

    Dehbashi, Zahra; Moosazadeh, Mahmood; Afshari, Mahdi

    2016-01-01

    Background: Each year, more than forty million abortions are occurred whole of the world. Misoprostol is a prostaglandin analogue with a strong uterotonic effect. The present study aimed to compare the efficacy of Misoprostol in first trimester abortion through two sublingual and vaginal routes of administration. Methods: This randomized clinical trial was conducted on 52 consecutive women in first trimester candidate for pregnancy termination because of fetal IUFD or missed abortion in sonography reports. The patients were hospitalized and then randomly assigned to receive sublingual Misoprostol (400 µg, n 27) or vaginal Misoprostol (400 µg placed in posterior fornix, n = 25). Findings: None of the pregnant in the sublingual group developed complete abortion at the end of follow-up time, while 36% of women inducted with vaginal misoprostol experienced complete abortion indicating a intergroup significant difference (p = 0.001). Compared with vaginal group, those women in sublingual group experienced more complications including diarrhea (22.2% versus 20.0%), nausea and vomiting (22.2% versus 0.0%), and abdominal pain (3.7% versus 0.0%). Conclusion: The use of Misoprostol in vaginal route results in more abortion completeness as well as lower complication rate as compared to sublingual prescription of the drug.

  15. Discrepancy between Bioavailability and Hypotensive Effect of Oral and Sublingual Nifedipine.

    PubMed

    Palma-Aguirre, J. A.; Montoya-Cabrera, M. A.; du Souich, P.; Hoyo-Vadillo, C.; Flores-Murrieta, F. J.; Castañeda-Hernández, G.

    1995-01-01

    Nifedipine, 10-mg capsules, were given orally and sublingually to six healthy volunteers according to a randomized crossover design. Nifedipine plasma levels, blood pressure, and heart rate were determined at several times after medication. C(max) was higher (134 plus minus 17 vs. 93 plus minus 2 ng ml(minus sign1), mean plus minus SD, P < 0.01) and occurred earlier (0.5 vs. 1 h) with oral than with sublingual nifedipine. However, there was no significant difference in AUC (268 plus minus 56 vs. 288 plus minus 35 ng h ml(minus sign1)) nor in t(1/2) (1.8 plus minus 0.2 vs. 1.9 plus minus 0.3 h), indicating that sublingual administration decreased the rate but not the extent of nifedipine absorption. Notwithstanding the difference in C(max), both routes yielded a similar reduction in diastolic blood pressure of 13 plus minus 1 mm Hg. Heart rate increase, which reflects the activation of homeostatic mechanisms, was greater with oral than with sublingual nifedipine, that is, 18 plus minus 1 vs. 13 plus minus 1 beats min(minus sign1), P < 0.01. It is concluded that slower absorption after sublingual administration increases nifedipine hypotensive efficiency by producing less counteracting homeostatic responses than the more rapidly absorbed oral nifedipine.

  16. Sublingual Vaccination Induces Mucosal and Systemic Adaptive Immunity for Protection against Lung Tumor Challenge

    PubMed Central

    Singh, Shailbala; Yang, Guojun; Schluns, Kimberly S.; Anthony, Scott M.; Sastry, K. Jagannadha

    2014-01-01

    Sublingual route offers a safer and more practical approach for delivering vaccines relative to other systemic and mucosal immunization strategies. Here we present evidence demonstrating protection against ovalbumin expressing B16 (B16-OVA) metastatic melanoma lung tumor formation by sublingual vaccination with the model tumor antigen OVA plus synthetic glycolipid alpha-galactosylceramide (aGalCer) for harnessing the adjuvant potential of natural killer T (NKT) cells, which effectively bridge innate and adaptive arms of the immune system. The protective efficacy of immunization with OVA plus aGalCer was antigen-specific as immunized mice challenged with parental B16 tumors lacking OVA expression were not protected. Multiple sublingual immunizations in the presence, but not in the absence of aGalCer, resulted in repeated activation of NKT cells in the draining lymph nodes, spleens, and lungs of immunized animals concurrent with progressively increasing OVA-specific CD8+ T cell responses as well as serum IgG and vaginal IgA levels. Furthermore, sublingual administration of the antigen only in the presence of the aGalCer adjuvant effectively boosted the OVA-specific immune responses. These results support potential clinical utility of sublingual route of vaccination with aGalCer-for prevention of pulmonary metastases. PMID:24599269

  17. Assessment of carcinoma in the sublingual region based on magnetic resonance imaging.

    PubMed

    Asaumi, Jun-Ichi; Shigehara, Hiroshi; Konouchi, Hironobu; Yanagi, Yoshinobu; Hisatomi, Miki; Matsuzaki, Hidenobu; Kishi, Kanji

    2002-01-01

    In the present study, we attempted to diagnose and detect the extent of tumors in the sublingual region using magnetic resonance imaging (MRI) and dynamic MRI. MRI with or without gadopentetate dimeglumine (Gd-DTPA)-enhancement in seven lesions of the sublingual regions was performed. The seven lesions included four cases of mucoepidermoid carcinoma (mucoepidermoid Ca), two cases of adenoid cystic carcinoma (ACC), and one case of squamous cell carcinoma (SCC). Whether the tumor was malignant or benign, as well as the differential diagnosis, could not be determined on the basis of the MR signals, even when enhancement was performed. Dynamic MRI was performed in five cases, two cases of ACC, two cases of mucoepidermoid Ca, and one case of SCC. The dynamic MRI showed a rapid enhancement at 30-45 sec in all five cases before the normal sublingual gland began to be enhanced. The early phases at 30-45 sec of the dynamic MRI in five cases showed marked enhancement before the normal sublingual glands were enhanced, and therefore could clearly show the extent of the lesions. In conclusion, the dynamic MRI may be useful in differentiating malignant from benign tumors, and in detecting the extent of the tumors in the sublingual carcinomas.

  18. Monoclonal antibodies in cancer immunotherapy.

    PubMed

    Reisfeld, R A

    1992-06-01

    The preceding article focused on some novel approaches for the adjuvant treatment of human melanoma and neuroblastoma with mAbs against antigens preferentially expressed on these tumors. It should be emphasized that the major goal of the immunotherapy modalities described here is to apply them in an adjuvant setting for the treatment of micrometastases. The major aim is to decrease the rate of development of metastases in a setting of very low tumor burden and ultimately achieve a prolongation in life span. The combination of powerful modern technologies achieving genetic engineering of mAbs, resulting in more human-like molecules, will lead to a reevaluation of these reagents alone or in combination with molecularly defined cytokines and growth factors for the immunotherapy of cancer. The initial, albeit anectodal, findings, of phase I clinical trials mentioned in this article lead to cautious optimism that immunotherapy may find a place and will eventually contribute to the adjuvant treatment of cancer.

  19. Emerging nanotechnologies for cancer immunotherapy.

    PubMed

    Shukla, Sourabh; Steinmetz, Nicole F

    2016-05-01

    Founded on the growing insight into the complex cancer-immune system interactions, adjuvant immunotherapies are rapidly emerging and being adapted for the treatment of various human malignancies. Immune checkpoint inhibitors, for example, have already shown clinical success. Nevertheless, many approaches are not optimized, require frequent administration, are associated with systemic toxicities and only show modest efficacy as monotherapies. Nanotechnology can potentially enhance the efficacy of such immunotherapies by improving the delivery, retention and release of immunostimulatory agents and biologicals in targeted cell populations and tissues. This review presents the current status and emerging trends in such nanotechnology-based cancer immunotherapies including the role of nanoparticles as carriers of immunomodulators, nanoparticles-based cancer vaccines, and depots for sustained immunostimulation. Also highlighted are key translational challenges and opportunities in this rapidly growing field.

  20. Immunotherapy of Childhood Sarcomas.

    PubMed

    Roberts, Stephen S; Chou, Alexander J; Cheung, Nai-Kong V

    2015-01-01

    Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing's family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed.

  1. Hypoallergenic molecules for subcutaneous immunotherapy.

    PubMed

    Jongejan, Laurian; van Ree, Ronald; Poulsen, Lars K

    2016-01-01

    Although a large part of the population suffers from allergies, a cure is not yet available. Allergen-specific immunotherapy (AIT) offers promise for these patients. AIT has proven successful in insect and venom allergies; however, for food allergy this is still unclear. In this editorial we focus on the recent advances in a proof of concept study in food allergy, FAST (Food allergy specific immunotherapy), which may increase interest within the biomolecular and pharmaceutical industry to embark on similar projects of immunology driven precision medicine within the allergy field.

  2. Cancer immunotherapy using tumor cryoablation.

    PubMed

    Sidana, Abhinav

    2014-01-01

    Cryoablation is increasingly being used as a primary treatment for localized cancers and as a salvage therapy for metastatic cancers. Anecdotal clinical reports and animal experiments have confirmed an induction of systemic antitumor immune response by tumor cryoablation. To capitalize on the stimulatory effects of cryoablation for cancer immunotherapy, this response must be intensified using other immunomodulatory agents. This article reviews the preclinical and clinical evidence and discusses the mechanism of the antitumor immune response generated by cryoablation. The rationale and evidence behind several immunotherapy approaches that can be combined with cryoablation to devise a cryoimmunotherapeutic strategy with a potential to impact the progression of metastatic disease are described.

  3. Hypoallergenic molecules for subcutaneous immunotherapy.

    PubMed

    Jongejan, Laurian; van Ree, Ronald; Poulsen, Lars K

    2016-01-01

    Although a large part of the population suffers from allergies, a cure is not yet available. Allergen-specific immunotherapy (AIT) offers promise for these patients. AIT has proven successful in insect and venom allergies; however, for food allergy this is still unclear. In this editorial we focus on the recent advances in a proof of concept study in food allergy, FAST (Food allergy specific immunotherapy), which may increase interest within the biomolecular and pharmaceutical industry to embark on similar projects of immunology driven precision medicine within the allergy field. PMID:26558320

  4. Evaluation of atropine 1% ophthalmic solution administered sublingually for the management of terminal respiratory secretions.

    PubMed

    Protus, Bridget McCrate; Grauer, Phyllis A; Kimbrel, Jason M

    2013-06-01

    Terminal respiratory secretions (TRS) or "death rattle" is a common symptom in the dying patient. Current practice for the prevention and treatment of TRS involves the use of oral, sublingual, transdermal, or parenteral anticholinergic medications. A retrospective chart review of patients admitted to a hospice inpatient unit for terminal care and treated with sublingual atropine 1% ophthalmic drops for TRS was conducted. A total of 19 of 22 patients treated with atropine had documented reduction or resolution of TRS. This study suggests that atropine 1% ophthalmic drops administered sublingually are a reasonable option for the management of TRS. Problematic cardiac or central nervous system symptoms were not found in the present study. Results should aid hospice programs who are seeking guidance on the management of TRS with atropine 1% ophthalmic drops.

  5. Accidental displacement of a dental implant into the sublingual space: A Case report

    PubMed Central

    Fernández-Solís, José; Marín-Fernández, Ana-Belén; Valencia-Laseca, Alfredo; Monsalve-Iglesias, Fernando

    2016-01-01

    Dental implant surgery is continuously expanding. In fact, every day more and more surgeons are choosing dental implants for allowing great results in the field of oral rehabilitation. However, these procedures are not exempt from complications. This report presents the case of a 66 years old man underwent implant surgery by a specialized dentist. No problems were reported during implant placement. Despite this, three months later, it was displaced into the sublingual space at the time of uncovering. Against this backdrop, the patient was referred to an expert maxillofacial surgeon. Next day, the implant was removed using an intraoral approach to reach the sublingual space. According with our knowledge, there are no cases reported in the literature that describe this complication. Key words:Dental implant, sublingual space, bone atrophy, complications of oral surgery. PMID:27703616

  6. Intraductal papilloma arising from sublingual minor salivary gland: case report and immunohistochemical study.

    PubMed

    Aikawa, Tomonao; Tomonao, Aikawa; Kishino, Mitsunobu; Masuda, Tomotake; Isomura, Emiko T; Tanaka, Susumu; Namikawa, Mari; Iida, Seiji

    2009-05-01

    Intraductal papilloma is a rare benign salivary gland tumor. This lesion is commonly observed in the duct of the minor salivary gland, predominantly in lip and buccal mucosa, but the case in the sublingual region is quite rare. This report shows a first case of intraductal papilloma developed in minor salivary gland of sublingual region. A 47-year-old Japanese male was referred to our hospital with painless submucosal nodule in the right sublingual region beside Wharton's duct orifice. The excised specimen was histologically diagnosed as intraductal papilloma of minor salivary gland, according to the microscopic finding of the papillary growth of ductal epithelium into the ductal space with fibrovascular core. Immunohistochemical study showed the tumor cells originated from ductal luminal cells because of positive Cytokeratin 18 and 7 staining in both types of cells.

  7. [Transcutaneous excision of the submandibular and sublingual glands: notes on anatomy and surgical technique].

    PubMed

    Fornaro, Rosario; Frascio, Marco; Stabilini, Cesare; Ricci, Barbara; Mandolfino, Francesca; Sticchi, Camilla; Gianetta, Ezio

    2007-01-01

    Removal of the submandibular and sublingual glands requires in-depth knowledge of the anatomy and scrupulous technique for the purposes of limiting the functional and aesthetic damage, which is unjustifiable above all in the treatment of benign lesions (sialodenitis, lithiasis). After presenting the main aspects of the surgical anatomy of the submandibular space, the operative technique for its dissection with removal of the submandibular gland and excision of the sublingual gland is described. The complexity of the anatomical structures that may be involved in submandibular and sublingual gland lesions is the cause of unsatisfactory functional and aesthetic outcomes in some cases. The most feared complications are lesions to nerve formations, due both to the resulting deficits and the possible legal implications.

  8. Update on Allergy Immunotherapy

    PubMed Central

    2005-01-01

    This article summarizes and provides commentary regarding guidelines on the administration of immunotherapy (IT) for allergic airway disease. Recent investigations have provided important insights into the immunologic mechanism of IT and the prominent role of interleukin-10-producing regulatory T lymphocytes. The most important aspect of successful IT is the administration of an appropriate dose of an extract containing a sufficient concentration of the relevant allergen. This is largely possible now only with standardized extracts. When the major allergen content of successful IT extracts was quantified, efficacy was demonstrated across a surprisingly narrow concentration range (approximately 5-24 μg per injection), irrespective of the extract. This presumably reflects the concentration of an antigen that drives an immune response toward tolerance. It may be predicted that as major allergen content is quantified in currently nonstandardized extracts, effective IT will also be achieved by administering a dose in this range, in contrast to current practices involving fairly arbitrary dosing decisions. With the availability of nonsedating antihistamines, intranasal corticosteroids, and the leukotriene modifiers, inadequate pharmacologic response or intolerable side effects are less commonly the major indications for starting IT for allergic rhinitis (AR). However, with the recognition that a relatively short course (3-5 years) of IT can provide long-term immunomodulation and clinical benefit, a desire to avoid long-term pharmacotherapy and the associated high costs may be the primary indication for IT in AR cases. While evidence overwhelmingly supports the beneficial influences of IT in asthma cases, the positioning of IT for this disorder is not established. The observed prevention of asthma in children who have AR is intriguing, but further studies are required to assess the extent to which the prevalence and severity of chronic asthma will be reduced when these

  9. Differentially expressed protein markers in human submandibular and sublingual secretions.

    PubMed

    Hu, Shen; Denny, Patricia; Denny, Paul; Xie, Yongming; Loo, Joseph A; Wolinsky, Lawrence E; Li, Yang; McBride, Jim; Ogorzalek Loo, Rachel R; Navazesh, Mavash; Wong, David T

    2004-11-01

    Proteome analysis of secretions from individual salivary glands is important for understanding the health of the oral cavity and pathogenesis of certain diseases. However, cross-contamination of submandibular (SM) and sublingual (SL) glandular secretions can occur. The close anatomic relationship of the SM and SL ductal orifices can lead to such contamination. Additionally, these glands may share common ducts. To insure the purity of SM/SL secretions for proteomic analysis, it is important to develop unique biomarkers which could be used to verify the integrity of the individual glandular saliva. In this study, a proteomics approach based on mass spectrometry and gel electrophoresis techniques was utilized to identify and verify a set of proteins (cystatin C, calgranulin B and MUC5B mucin), which are differentially expressed in SM/SL secretions. SM/SL fluids were obtained from nine healthy subjects. Cystatin C was found to be an SM-selective protein as it was found in all SM fluids but not detected in two SL fluids. MUC5B mucin and calgranulin B, on the other hand, were found to be SL-selective proteins. All SL samples contained MUC5B mucin, whereas MUC5B mucin was not detected in four SM samples. Eight of the SL samples contained calgranulin B; however, calgranulin B was absent in eight SM samples. This set of protein markers, especially calgranulin B, can be used to determine the purity of SM/SL samples, and therefore identify potential individuals who do not exhibit cross-contaminated SM/SL secretions, an important requirement for subsequent proteome analysis of pure SM and SL secretions.

  10. Disialoganglioside directed immunotherapy of neuroblastoma.

    PubMed

    Modak, Shakeel; Cheung, Nai-Kong V

    2007-02-01

    Achieving a cure for metastatic neuroblastoma remains a challenge despite sensitivity to chemotherapy and radiotherapy. Most patients achieve remission, but a failure to eliminate minimal residual disease (MRD) often leads to relapse. Immunotherapy is potentially useful for chemotherapy-resistant disease and may be particularly effective for low levels of MRD that are below the threshold for detection by routine radiological and histological methods. Disialoganglioside (GD2), a surface glycolipid antigen that is ubiquitous and abundant on neuroblastoma cells is an ideal target for immunotherapy. Anti-GD2 monoclonal antibodies currently form the mainstay of neuroblastoma immunotherapy and their safety profile has been well-established. Although responses in patients with gross disease have been observed infrequently, histologic responses of bone marrow disease are consistently achieved in >75 percent of patients with primary refractory neuroblastoma. The advent of highly sensitive and specific molecular assays to measure MRD has confirmed the efficacy anti-GD2 antibody immunotherapy in patients with subclinical disease. Such markers will allow further optimization of other anti-MRD therapies. We review the current status of anti-GD2 clinical trials for neuroblastoma and novel preclinical GD2-targeted strategies for this rare but often lethal childhood cancer.

  11. Technological advances in adoptive immunotherapy.

    PubMed

    Oelke, Mathias; Krueger, Christine; Schneck, Jonathan P

    2005-01-01

    Adoptive immunotherapy is an attractive and elegant strategy for treating a variety of life-threatening diseases. Several approaches have been developed to generate antigen-specific CD4+ and CD8+ T cells for adoptive T-cell therapy in cancer and infectious diseases. Currently, many approaches are based on either the use of autologous peptide pulsed dendritic cells as antigen-presenting cells or nonspecific expansion of T cells. Unfortunately, current approaches lack the ability to serve as reproducible and economically viable methods. Several groups are developing new artificial approaches to overcome problems associated with dendritic cells and the nonspecific expansion of T-cell clones in order to make adoptive immunotherapy more feasible and effective. Thus, by increasing the availability of adoptive immunotherapy, we will be able to better determine the efficacy of the approaches in the treatment of a variety of diseases. In this review, we focus on technological advances that will facilitate adoptive immunotherapy. Specifically, we summarize current strategies which are either based on artificial antigen-presenting cells or on T-cell receptor gene transfer. PMID:15753966

  12. Immunotherapy toxic in obese mice.

    PubMed

    2015-01-01

    New research shows immunotherapy can cause lethal inflammation in both young and aged mice that are obese. Restricting calories in aged mice protected them from toxicity, and giving young obese mice a drug for autoimmune disease prevented the fatal reactions. PMID:25583780

  13. Classification of current anticancer immunotherapies.

    PubMed

    Galluzzi, Lorenzo; Vacchelli, Erika; Bravo-San Pedro, José-Manuel; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P; Coussens, Lisa; Dhodapkar, Madhav V; Eggermont, Alexander M; Fearon, Douglas T; Fridman, Wolf H; Fučíková, Jitka; Gabrilovich, Dmitry I; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M; Klein, Eva; Knuth, Alexander; Lewis, Claire E; Liblau, Roland; Lotze, Michael T; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J; Mittendorf, Elizabeth A; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E; Pienta, Kenneth J; Porgador, Angel; Prendergast, George C; Rabinovich, Gabriel A; Restifo, Nicholas P; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J; Speiser, Daniel E; Spisek, Radek; Srivastava, Pramod K; Talmadge, James E; Tartour, Eric; Van Der Burg, Sjoerd H; Van Den Eynde, Benoît J; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S; Whiteside, Theresa L; Wolchok, Jedd D; Zitvogel, Laurence; Zou, Weiping; Kroemer, Guido

    2014-12-30

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

  14. Classification of current anticancer immunotherapies

    PubMed Central

    Vacchelli, Erika; Pedro, José-Manuel Bravo-San; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N.; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P.; Coussens, Lisa; Dhodapkar, Madhav V.; Eggermont, Alexander M.; Fearon, Douglas T.; Fridman, Wolf H.; Fučíková, Jitka; Gabrilovich, Dmitry I.; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M.; Klein, Eva; Knuth, Alexander; Lewis, Claire E.; Liblau, Roland; Lotze, Michael T.; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J.; Mittendorf, Elizabeth A.; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E.; Pienta, Kenneth J.; Porgador, Angel; Prendergast, George C.; Rabinovich, Gabriel A.; Restifo, Nicholas P.; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J.; Speiser, Daniel E.; Spisek, Radek; Srivastava, Pramod K.; Talmadge, James E.; Tartour, Eric; Van Der Burg, Sjoerd H.; Van Den Eynde, Benoît J.; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S.; Whiteside, Theresa L.; Wolchok, Jedd D.; Zitvogel, Laurence; Zou, Weiping

    2014-01-01

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

  15. Classification of current anticancer immunotherapies.

    PubMed

    Galluzzi, Lorenzo; Vacchelli, Erika; Bravo-San Pedro, José-Manuel; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P; Coussens, Lisa; Dhodapkar, Madhav V; Eggermont, Alexander M; Fearon, Douglas T; Fridman, Wolf H; Fučíková, Jitka; Gabrilovich, Dmitry I; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M; Klein, Eva; Knuth, Alexander; Lewis, Claire E; Liblau, Roland; Lotze, Michael T; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J; Mittendorf, Elizabeth A; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E; Pienta, Kenneth J; Porgador, Angel; Prendergast, George C; Rabinovich, Gabriel A; Restifo, Nicholas P; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J; Speiser, Daniel E; Spisek, Radek; Srivastava, Pramod K; Talmadge, James E; Tartour, Eric; Van Der Burg, Sjoerd H; Van Den Eynde, Benoît J; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S; Whiteside, Theresa L; Wolchok, Jedd D; Zitvogel, Laurence; Zou, Weiping; Kroemer, Guido

    2014-12-30

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

  16. Future perspectives in cancer immunotherapy

    PubMed Central

    Mountzios, Giannis; Curigliano, Giuseppe

    2016-01-01

    The advent of immunotherapy has transformed the treatment paradigm of several solid tumors and is expected to influence the therapeutic algorithm even more in the future following the results of numerous ongoing clinical trials in a wide range of malignancies. Exploiting the anti-cancer effect of the immune system with the use of vaccines, viral vectors, and more lately with immune check-point inhibitors and chimeric antigen receptor modification, has been proven a successful therapeutic strategy in a broad spectrum of tumors. In particular, immune check-point inhibition in melanoma, non-small-cell lung cancer and renal cancer, peptide vaccination in prostate cancer and glioblastoma, and oncolytic immunotherapy in melanoma are well-established therapeutic modalities that have obtained approval by regulatory authorities and are already in clinical use. A large number of ongoing clinical trials involving thousands of patients are currently seeking to define the appropriate tumor type, therapeutic setting, treatment combination and patient populations in order to maximize clinical benefit from immunotherapeutic agents. In this context, identification of the patients whose tumors are most likely to respond to immunotherapy by the use of appropriate biomarkers will be crucial for the optimal implementation of immunotherapy into the therapeutic armamentarium. PMID:27563660

  17. Engineering opportunities in cancer immunotherapy.

    PubMed

    Jeanbart, Laura; Swartz, Melody A

    2015-11-24

    Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges.

  18. Management of sublingual ulceration in a 12-month-old child.

    PubMed

    Bafna, Yash; Khandelwal, Vishal; Bafna, Madhulika; Nayak, Prathibha Anand

    2013-01-01

    The case of sublingual ulceration associated with erupted primary mandibular incisors in a 1-year-old child is presented. Sublingual ulceration is termed as Riga-Fede disease if the patient is less than 2 years old. Generally, the treatment methods for Riga-Fede's disease are discing and extraction of the traumatised teeth. Here, the child was treated with photo-polymerised composite resin coverage of the incisal edges of erupted mandibular incisors. The photo-polymerised resin coverage proved to help in the rapid healing of the ulcerations. PMID:23975923

  19. Efficacy of a Novel Sublingual Spray Formulation of Artemether in African Children with Plasmodium falciparum Malaria

    PubMed Central

    Rulisa, Stephen; Ansah, Patrick; Sirima, Sodiomon

    2015-01-01

    The efficacy of sublingual artemether (ArTiMist) was investigated in two studies. In study 1, 31 children were randomized to sublingual artemether (n = 16) or intravenous (i.v.) quinine (n = 15). In study 2, 151 children were randomized to sublingual artemether (n = 77) or i.v. quinine (n = 74). For both studies, patients weighed between 5 and 15 kg and had either severe or complicated malaria based on WHO criteria, or they had uncomplicated malaria but were unable to tolerate oral medication as a result of nausea, vomiting, or diarrhea. Patients received either 3 mg/kg of body weight of sublingual artemether or a loading dose of 20 mg/kg of i.v. quinine followed by 10 mg/kg every 8 h i.v. thereafter. The primary endpoint was parasitological success, defined as a reduction in parasite count of ≥90% of that at baseline at 24 h after the first dose. Other endpoints based on parasite clearance and clinical response were evaluated. In study 1, there were parasitological success rates of 93.3% (14/15) and 66.7% (10/15) for the sublingual artemether and quinine treatments, respectively. In study 2, 94.3% (66/70) of the ArTiMist-treated patients and 39.4% (28/71) of the quinine-treated patients had parasitological success (P < 0.0001). Indicators of parasite clearance (parasite clearance time [PCT], time for parasite count to fall by 50% [PCT50], time for parasite count to fall by 90% [PCT90], and percent reduction in parasitemia from baseline at 24 h [PRR24]) were significantly superior for children treated with sublingual artemether compared to those treated with i.v. quinine. There were no differences between treatments for the clinical endpoints, such as fever clearance time. The local tolerability of sublingual artemether was good. Sublingual artemether leads to rapid parasite clearance and clinical recovery. (Studies 1 and 2 are registered at ClinicalTrials.gov under registration numbers NCT01047436 and NCT01258049, respectively.) PMID:26303805

  20. Carcinoma ex pleomorphic adenoma of the sublingual gland: a case report.

    PubMed

    Ariyoshi, Yasunori; Shimahara, Masashi; Konda, Toshiyuki; Tsuji, Motomu

    2012-03-01

    We report a case of carcinoma ex pleomorphic adenoma of a sublingual gland in a 70-year-old man. Under a clinical diagnosis of benign salivary gland tumor, excision of the mass with the sublingual salivary gland in an en bloc fashion via an intraoral approach was performed. Histopathologically, there was a rupture of the fibrous capsule and diffuse cell-rich sheets composed of myoepithelial cells with round nuclei were also seen. Immunohistochemically, the cells that composed of cell rich sheets were positive to smooth muscle actin. Final diagnosis of myoepithelial carcinoma ex pleomorphic adenoma was made.

  1. Efficacy of Buprenorphine/Naloxone Rapidly Dissolving Sublingual Tablets (BNX-RDT) After Switching From BNX Sublingual Film

    PubMed Central

    Gunderson, Erik W.; Sumner, Michael

    2016-01-01

    Objectives: The aim of the study was to evaluate treatment retention, efficacy, and preference ratings among opioid-dependent patients transitioning between a buprenorphine/naloxone rapidly dissolving sublingual tablet formulation (BNX-RDT) and BNX film. Methods: After a 2-day, blinded, fixed-dose induction with BNX-RDT (5.7/1.4 mg and 5.7/1.4 or 11.4/2.8 mg, respectively) or buprenorphine (8 mg and 8 or 16 mg, respectively), patients received open-label titrated doses of BNX-RDT or BNX film (generic buprenorphine induction group) during days 3 to 14. On day 15, patients switched treatment (using a conversion ratio of 5.7–8 mg) and continued switched treatment through day 22. Assessments included treatment retention, opioid withdrawal (Clinical and Subjective Opiate Withdrawal scales), opioid cravings (0–100 visual analog scale [VAS]), and preference ratings. Results: Of the 287 patients who switched from BNX-RDT to BNX film and 279 patients who switched from BNX film to BNX-RDT at day 15, 8.7% and 6.1% withdrew, respectively. Reductions in opioid withdrawal and cravings were similar with both formulations through day 15; after switching treatment, reductions were maintained through day 22 in both groups. Preference ratings at day 22 (patients had received both formulations) favored BNX-RDT for taste, mouthfeel, ease of administration, and overall preference (all P < 0.0001). Conclusions: In both patient groups who switched treatment at day 15, more than 90% were retained in treatment, and reductions in opioid withdrawal and cravings were sustained. A significant majority of patients preferred BNX-RDT over BNX film, the clinical impact of which requires further study. PMID:26918662

  2. Allergen immunotherapy: clinical and practical education of Italian trainees in allergy and clinical immunology schools.

    PubMed

    Ridolo, E; Incorvaia, C; Senna, G E; Montagni, M; Olivieri, E; Canonica, G W

    2013-10-01

    We performed a survey, based on a questionnaire including 20 items, submitted anonymously to Italian trainees in Allergology and Clinical Immunology, in order to obtain information about their specific allergen immunotherapy (AIT) practices. The questionnaire was sent to 40 trainees, who had attended the last two years of the training course. Thirty-four subjects (mean age: 27 years, 65% females) adequately completed the survey. The answers to the questionnaire showed that only 60% of the training programs included lectures on AIT. Among the trainees using AIT, only 40% declared being able to prescribe it independently, while 60% were guided by a tutor. Of the trainees who were able to prescribe AIT autonomously, 60% were familiar with both routes of administration, i.e. subcutaneous (SCIT) and sublingual immunotherapy (SLIT), while 25% of these used only SLIT. In 80% of the training institutions involved, the trainees could attend a dedicated AIT outpatient ward for SCIT administration; only 40% administered AIT personally, and in half of these cases, they were guided by a tutor. Only 70% of trainees had experience in the follow-up of patients still under treatment and of patients who had completed treatment. Analysis of the answers obtained for questions on venom immunotherapy (VIT) showed that, in 90% of cases, the trainees attended a dedicated outpatients ward where VIT is administered, but with a role limited to observation/cooperation. Only 30% were involved in the follow-up of patients who were under treatment or who had completed VIT. Only 20% of the trainees felt confident enough about VIT to prescribe this treatment independently, 80% knew there were several administration protocols, and the majority prescribed products from three different manufacturers. These findings suggest that there is significant room for improving the instructions provided regarding allergology and clinical immunology to trainees in Italy with respect to AIT.

  3. Improving the safety of oral immunotherapy for food allergy.

    PubMed

    Vazquez-Ortiz, Marta; Turner, Paul J

    2016-03-01

    Food allergy is a major public health problem in children, impacting upon the affected individual, their families and others charged with their care, for example educational establishments, and the food industry. In contrast to most other paediatric diseases, there is no established cure: current management is based upon dietary avoidance and the provision of rescue medication in the event of accidental reactions, which are common. This strategy has significant limitations and impacts adversely on health-related quality of life. In the last decade, research into disease-modifying treatments for food allergy has emerged, predominantly for peanut, egg and cow's milk. Most studies have used the oral route (oral immunotherapy, OIT), in which increasing amounts of allergen are given over weeks-months. OIT has proven effective to induce immune modulation and 'desensitization' - that is, an increase in the amount of food allergen that can be consumed, so long as regular (typically daily) doses are continued. However, its ability to induce permanent tolerance once ongoing exposure has stopped seems limited. Additionally, the short- and long-term safety of OIT is often poorly reported, raising concerns about its implementation in routine practice. Most patients experience allergic reactions and, although generally mild, severe reactions have occurred. Long-term adherence is unclear, which rises concerns given the low rates of long-term tolerance induction. Current research focuses on improving current limitations, especially safety. Strategies include alternative routes (sublingual, epicutaneous), modified hypoallergenic products and adjuvants (anti-IgE, pre-/probiotics). Biomarkers of safe/successful OIT are also under investigation. PMID:26593873

  4. Improving the safety of oral immunotherapy for food allergy.

    PubMed

    Vazquez-Ortiz, Marta; Turner, Paul J

    2016-03-01

    Food allergy is a major public health problem in children, impacting upon the affected individual, their families and others charged with their care, for example educational establishments, and the food industry. In contrast to most other paediatric diseases, there is no established cure: current management is based upon dietary avoidance and the provision of rescue medication in the event of accidental reactions, which are common. This strategy has significant limitations and impacts adversely on health-related quality of life. In the last decade, research into disease-modifying treatments for food allergy has emerged, predominantly for peanut, egg and cow's milk. Most studies have used the oral route (oral immunotherapy, OIT), in which increasing amounts of allergen are given over weeks-months. OIT has proven effective to induce immune modulation and 'desensitization' - that is, an increase in the amount of food allergen that can be consumed, so long as regular (typically daily) doses are continued. However, its ability to induce permanent tolerance once ongoing exposure has stopped seems limited. Additionally, the short- and long-term safety of OIT is often poorly reported, raising concerns about its implementation in routine practice. Most patients experience allergic reactions and, although generally mild, severe reactions have occurred. Long-term adherence is unclear, which rises concerns given the low rates of long-term tolerance induction. Current research focuses on improving current limitations, especially safety. Strategies include alternative routes (sublingual, epicutaneous), modified hypoallergenic products and adjuvants (anti-IgE, pre-/probiotics). Biomarkers of safe/successful OIT are also under investigation.

  5. Sublingual fistula in a masked booby (Sula dactylatra) and possible role of ectoparasites in its etiology.

    PubMed

    Hughes, B John; Martin, Graham R; Wearn, Colin P; Reynolds, S James

    2013-04-01

    A sublingual fistula is an opening through the ventral skin of the buccal cavity through which the tongue can protrude. The cause is unknown. Masked Boobies (Sula dactylatra) are the third avian species to be reported with this condition. We argue that ectoparasite infestation of hatchlings may be an initial cause.

  6. Fulminant hepatic failure after intravenous injection of sublingual buprenorphine in a patient with hepatitis C.

    PubMed

    French, Janine; Mujumdar, Avik; Angus, Peter; Gow, Paul

    2015-08-01

    A 20-year-old indigenous Australian male was admitted to the intensive care unit with fulminant hepatic failure secondary to intravenous use of buprenorphine, which had been prescribed sublingually for opioid dependence. Intravenous buprenorphine-induced hepatitis is well recognized, however, life-threatening fulminant hepatic failure has not previously been reported.

  7. Sublingual fistula in a masked booby (Sula dactylatra) and possible role of ectoparasites in its etiology.

    PubMed

    Hughes, B John; Martin, Graham R; Wearn, Colin P; Reynolds, S James

    2013-04-01

    A sublingual fistula is an opening through the ventral skin of the buccal cavity through which the tongue can protrude. The cause is unknown. Masked Boobies (Sula dactylatra) are the third avian species to be reported with this condition. We argue that ectoparasite infestation of hatchlings may be an initial cause. PMID:23568928

  8. Isolated Langerhans cell histiocytosis of the sublingual gland in an adult

    PubMed Central

    Yang, Shaodong; Chen, Xinming; Zhang, Jiali; Fang, Qiong

    2015-01-01

    Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of pathologic Langerhans cells. Its clinical presentation is highly variable, that range from single-system, limited disease to severe, multi-organ disease with high mortality. LCH usually affects children and young adults. The most frequent sites for LCH are the bone, skin, lung, pituitary gland, and lymph nodes. Salivary gland involvement by LCH is extremely rare, and only a few cases of LHC involving the parotid glands have been reported in the English literature. To our knowledge, the involvement of the sublingual gland as a part of single or multisystem LCH has not been previously described. Herein we reported the first case of primary LCH of the sublingual gland. A 40-year-old woman presented with a 2-month history of a painless mass on the right sublingual area. Excision of the lesion including the right sublingual gland was performed. Histopathological diagnosis of LCH was rendered. The patient remains free of symptoms 17 months after surgery. PMID:26722591

  9. Neutrophils negatively regulate induction of mucosal IgA responses after sublingual immunization

    PubMed Central

    Jee, Junbae; Bonnegarde-Bernard, Astrid; Duverger, Alexandra; Iwakura, Yoichiro; Cormet-Boyaka, Estelle; Martin, Tara L.; Steiner, Haley E.; Bachman, Ryan C.; Boyaka, Prosper N.

    2015-01-01

    Induction of mucosal IgA capable of providing a first line of defense against bacterial and viral pathogens remains a major goal of needle-free vaccines given via mucosal routes. Innate immune cells are known to play a central role in induction of IgA responses by mucosal vaccines, but the relative contribution of myeloid cell subsets to these responses has not firmly been established. Using an in vivo model of sublingual vaccination with Bacillus anthracis edema toxin (EdTx) as adjuvant, we examined the role of myeloid cell subsets for mucosal secretory IgA responses. Sublingual immunization of wild-type mice resulted in a transient increase of neutrophils in sublingual tissues and cervical lymph nodes. These mice later developed Ag-specific serum IgG responses, but not serum or mucosal IgA. Interestingly, EdTx failed to increase neutrophils in sublingual tissues of IKKβΔMye mice, and these mice developed IgA responses. Partial depletion of neutrophils before immunization of wild-type mice allowed the development of both mucosal and serum IgA responses. Finally, co-culture of B cells with neutrophils from either wild-type or IKKβΔMye mice suppressed production of IgA, but not IgM or IgG. These results identify a new role for neutrophils as negative regulators of IgA responses. PMID:25563500

  10. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route

    PubMed Central

    Sharabi, Amir; Cohen, Eytan; Sulkes, Jaqueline; Garty, Moshe

    2003-01-01

    Aims To compare the efficacy of sublingual and oral administration of 500 µg of cobalamin in subjects with cobalamin deficiency. Materials and results Thirty subjects with low serum concentrations of cobalamin participated in the study. Subjects were randomly allocated to receive one tablet daily of 500 µg cobalamin sublingually or orally, or two tablets daily of a vitamin B complex. Serum cobalamin concentrations before treatment were 94 ± 30 pmol l−1, 108 ± 17 pmol l−1 and 98 ± 14 pmol l−1 in the sublingual B12, oral B12 and oral B-complex groups, respectively. After 4 weeks, concentrations rose to 288 ± 74 pmol l−1, 286 ± 87 pmol l−1 and 293 ± 78 pmol l−1, respectively. The increase in each group across time was statistically significant (P = 0.0001, differences [95% confidence intervals] 194.2 (114.5, 273.9), 178.3 (104.2, 252.4), and 195.1 (135.0, 255.2) pmol l−1, respectively). There was no significant difference in concentrations between the treatment groups. Conclusion A dose of 500 µg of cobalamin given either sublingually or orally is effective in correcting cobalamin deficiency. PMID:14616423

  11. A functional and chemical study of radiation effects on rat parotid and submandibular/sublingual glands

    SciTech Connect

    Vissink, A.; S-Gravenmade, E.J.; Ligeon, E.E.; Konings, W.T. )

    1990-12-01

    The aim of this study was to monitor composition and rate of secretion of rat parotid and submandibular/sublingual saliva following local single doses of X-rays ranging from 5 to 20 Gy. Pilocarpine-stimulated samples of parotid and submandibular/sublingual saliva were simultaneously collected with miniaturized Lashley cups before and 1-30 days after irradiation. The lag phase (period between injection of pilocarpine and start of the secretion) and flow rate were recorded and the concentrations of sodium, potassium, calcium, phosphate, and amylase were measured. With increasing dose and time, the salivary flow rate as well as sodium concentration decreased, while potassium concentrations increased throughout the follow-up period. The lag phase and the concentration of amylase reached their maximum at 3 and 10 days after irradiation, respectively. The changes in lag phase and flow rate were most obvious after doses of 15 or 20 Gy and showed a great similarity for parotid and submandibular/sublingual saliva. No dose-response relationship was observed for the changes in concentrations of calcium and phosphate. It is concluded that for radiation doses of 10 Gy and above, irreversible changes (lag phase, flow rate, potassium, sodium) were observed. A saturation of the irradiation effects (lag phase, flow rate) seems to exist at doses larger than 15 Gy. No significant differences were observed between the radiation-induced functional changes in parotid and submandibular/sublingual salivary gland tissue.

  12. [Cancer immunotherapy by immuno-checkpoint blockade].

    PubMed

    Kawakami, Yutaka

    2015-10-01

    As cancer immunotherapies utilizing anti-tumor T-cell responses, immuno-checkpoint blockade and adoptive T-cell immunotherapy have recently achieved durable responses even in advanced cancer patients with metastases. Administration of antibodies on the T-cell surface, CTLA-4 and PD-1 (or PD-1 ligand PD-L1), resulted in tumor regression of not only melanoma and renal cell cancer which were known to be relatively sensitive to immunotherapy, but also various malignancies including lung, bladder, ovarian, gastric, and head and neck cancers, as well as hematological malignancies such as Hodgkin and B-cell malignant lymphomas. These findings have changed the status of immunotherapy in the development of cancer treatments. Currently, development of combinations employing cancer immunotherapy with immuno-checkpoint blockade, as well as personalized cancer immunotherapy based on the evaluation of pretreatment immune status, are in progress.

  13. Targeted cytokines for cancer immunotherapy.

    PubMed

    Lode, H N; Reisfeld, R A

    2000-01-01

    Targeting of cytokines into the tumor microenvironment using antibody-cytokine fusion proteins, called immunocytokines, represents a novel approach in cancer immunotherapy. This article summarizes therapeutic efficacy and immune mechanisms involved in targeting interleukin-2 (IL-2) to neuroectodermal tumors using ganglioside GD2-specific antibody-IL-2 fusion protein (ch14.18-IL-2). Treatment of established melanoma metastases with ch14.18-IL-2 resulted in eradication of disease followed by a vaccination effect protecting mice from lethal challenges with wild-type tumor calls. In a syngeneic neuroblastoma model, targeted IL-2 was effective in the amplification of a weak memory immune response previously induced by IL-12 gene therapy using an engineered linear version of this heterodimeric cytokine. These findings show that targeted IL-2 may provide an effective tool in cancer immunotherapy and establish the missing link between T cell-mediated vaccination and objective clinical responses.

  14. RESEARCH ADVANCES IN NEUROBLASTOMA IMMUNOTHERAPY.

    PubMed

    Booker, Latania Y; Ishola, Titilope A; Bowen, Kanika A; Chung, Dai H

    2009-05-01

    Neuroblastoma is the third most common pediatric cancer in the United States and is responsible for 15% of pediatric cancer-related deaths. Despite major advances in multimodal therapy, the clinical outcome for several patients remains poor. Due to the desperate need for innovativation and improved success in the treatment and management of neuroblastoma, research interests in immunotherapy have been on the rise in recent years. Current immunotherapeutic approaches under investigation include antibodies targeting the neuroblastoma antigen GD2, cytokine stimulation of immune cells, use of immunocytokine conjugates, radioimmunotherapy, and tumor-primed dendritic cells. Immunotherapy could serve as a safe alternative or adjunct to current therapeutic protocols and would presumptively have fewer deleterious effects making it more favorable to patients.

  15. Lentiviral vectors in cancer immunotherapy.

    PubMed

    Oldham, Robyn Aa; Berinstein, Elliot M; Medin, Jeffrey A

    2015-01-01

    Basic science advances in cancer immunotherapy have resulted in various treatments that have recently shown success in the clinic. Many of these therapies require the insertion of genes into cells to directly kill them or to redirect the host's cells to induce potent immune responses. Other analogous therapies work by modifying effector cells for improved targeting and enhanced killing of tumor cells. Initial studies done using γ-retroviruses were promising, but safety concerns centered on the potential for insertional mutagenesis have highlighted the desire to develop other options for gene delivery. Lentiviral vectors (LVs) have been identified as potentially more effective and safer alternative delivery vehicles. LVs are now in use in clinical trials for many different types of inherited and acquired disorders, including cancer. This review will discuss current knowledge of LVs and the applications of this viral vector-based delivery vehicle to cancer immunotherapy.

  16. New strategies for allergen immunotherapy.

    PubMed

    Carnés, Jerónimo; Robinson, Douglas S

    2008-06-01

    Specific allergen immunotherapy, consisting in the administration of increasing amounts of offending allergens into sensitive patients was first used nearly one hundred years ago and remains in use worldwide for treatment of allergic rhinitis and asthma. It has been recognised as the only effective treatment for type I allergic diseases when the appropriate quantities of allergens are used. The immunological mechanisms by which specific immunotherapy is effective include the modulation of T cells and the response of B-cells and is accompanied by significant decreases of specific IgE and increases in allergen specific IgG antibodies, mainly IgG4. While specific allergen injection immunotherapy is highly effective and the most common way of administration other routes such as oral or intranasal ways have been considered as and alternative to subcutaneous injections. During the last century, allergenic vaccines have been prepared using individual allergens adsorbed to different adjuvant substances. These vaccines have demonstrated efficacy and good results in different clinical trials. However, many novel approaches to allergen immunotherapy have been developed in the last years in order to increase the safety and efficacy of allergenic vaccines. In that way, different and modern vaccines have been prepared including more purified products such as depigmented allergen extracts; allergoids, consisting on big molecules of thousands of kDa, which contain all the individual allergens and show a significant decrease in severe adverse reactions; peptides or small aminoacid sequences; recombinant allergens; hypoallergenic vaccines where the IgE binding sites have been modified; or allergen-CpG fusion molecules. New presentations are under study and new treatments will be developed in the near future with the objective that the prevention of allergic disease may become a reality. The review article also discuss recent patent related to the field. PMID:19075996

  17. Morphology and morphometry of the human sublingual glands in mouth floor enlargements of edentulous patients

    PubMed Central

    de SÁ, Josiane Costa Rodrigues; TOLENTINO, Elen de Souza; AZEVEDO-ALANIS, Luciana Reis; IWAKI FILHO, Liogi; LARA, Vanessa Soares; DAMANTE, José Humberto

    2013-01-01

    Asymptomatic mouth floor enlargements may be observed in edentulous patients. These masses, which protrude from the mouth floor, may complicate the fitting of dentures and require surgery. Whether this "entity" may be considered an anatomical variation of the mouth floor or represent specific alterations in the sublingual gland is not known. Objective The aim of this work is to investigate the morphological and morphometric aspects of the sublingual glands of edentulous patients with mouth floor enlargements and compare the glands of these patients with the sublingual glands of human cadavers. Material and Methods Microscopic evaluation was performed on human sublingual glands from edentulous patients with mouth floor enlargements (n=20) and edentulous cadavers (n=20). The patients and cadavers were of similar ages. The data were compared using Mann-Whitney U, Fisher's exact and Student's t tests (p<0.05). Results Acinar atrophy, duct-like structures, mononuclear infiltrates, replacement of parenchyma with fibrous/adipose tissue, mucous extravasation and oncocytosis were similar between the groups (p>0.05). Only the variables "autolysis" and "congested blood vessels" presented statistical difference between groups (p=0.014; p=0.043). The morphometric study revealed that the volume densities of acini, ducts, stroma and adipose tissue were similar between the groups (p>0.05). Conclusion The microscopic characteristics of the sublingual glands in mouth floor enlargements in edentulous patients correspond to characteristics associated with the normal aging process. The glands are not pathological and represent an age-related alteration that occurs with or without the presence of the mouth floor enlargements. PMID:24473720

  18. Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate.

    PubMed

    Allam, Ayat; Fetih, Gihan

    2016-01-01

    The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug's bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate. PMID:27536063

  19. Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate

    PubMed Central

    Allam, Ayat; Fetih, Gihan

    2016-01-01

    The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug’s bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate. PMID:27536063

  20. Novel immunotherapies in lymphoid malignancies

    PubMed Central

    Batlevi, Connie Lee; Matsuki, Eri; Brentjens, Renier J.; Younes, Anas

    2016-01-01

    The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID:26525683

  1. House dust allergy and immunotherapy

    PubMed Central

    Thomas, Wayne R.

    2012-01-01

    HDM allergy is associated with asthma, allergic rhinitis and atopic dermatitis. In many countries childhood asthma is predominantly found in HDM-allergic children with their probability of developing disease being proportional to their IgE antibody titers and the early development of Th2 responses. While the pathogenesis is complex and increasingly linked to infection the immunologically-based allergen immunotherapy and anti-IgE antibody therapy are highly beneficial. Immunotherapy could be a short-term treatment providing lifelong relief but the current regimens depend on repeated administration of allergen over years. Immunological investigations point to a contribution of responses outside the Th2 pathway and multiple potential but unproven control mechanisms. Over half of the IgE antibodies are directed to the group 1 and 2 allergens with most of remainder to the group 4, 5, 7 and 21 allergens. This hierarchy found in high and low responders provides a platform for introducing defined allergens into immunotherapy and defined reagents for investigation. PMID:22894952

  2. [Current Approaches in Cancer Immunotherapy].

    PubMed

    Otáhal, P; Trněný, M

    2015-01-01

    Methods of cancer immunotherapy have finally entered clinical medicine after years of preclinical research. Currently, there are several methods, which have proven to be very effective even in cases of incurable cancer. Antitumor monoclonal antibodies are among major therapeutic anti-cancer drugs and have been successfully used for many ears. Novel group of antibodies are immunomodulatory antibodies which can break tumor -specific immune tolerance and induce regression of tumors by nonspecific activation of immune system. Bispecific antibodies represent a novel class of anticancer agents which can induce expansion of T cells in vivo, blinatumomab is an example of such agents and is currently available for the treatment of acute B -cell leukemia. Cellular immunotherapy is also very effective, especially the use of Chimeric receptor modified T-cells for the therapy of B- cell lymphoproliferative diseases. Although it is a very complicated and expensive method, it is highly effective approach which can induce remission even in previously hopeless conditions. The goal of this article is to explain the basic principles of cancer immunotherapy and summarize the newest findings in this field.

  3. Immunotherapy Not Working? Check Your Microbiota.

    PubMed

    West, Nathan R; Powrie, Fiona

    2015-12-14

    Gut microbes have ascended to prominence as key modulators of host immunity, raising the possibility that they could influence the outcome of cancer immunotherapy. Two recent studies address this question by identifying specific gut-resident bacteria as drivers of checkpoint blockade immunotherapy in pre-clinical tumor models. PMID:26678336

  4. Neoantigen-based cancer immunotherapy.

    PubMed

    Bobisse, Sara; Foukas, Periklis G; Coukos, George; Harari, Alexandre

    2016-07-01

    Emerging clinical evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy in all cancer types. Recent clinical data clearly demonstrated that human tumor cells express antigenic peptides (epitopes) that can be recognized by autologous tumor-specific T cells and that enhancement of such immune reactivity can potentially lead to cancer control and cancer regression in patients with advanced disease. However, in most cases, it is unclear which tumor antigens (Ags) mediated cancer regression. Mounting evidence indicates that numerous endogenous mutated cancer proteins, a hallmark of tumor cells, can be processed into peptides and presented on the surface of tumor cells, leading to their immune recognition in vivo as "non-self" or foreign. Massively parallel sequencing has now overcome the challenge of rapidly identifying the comprehensive mutational spectrum of individual tumors (i.e., the "mutanome") and current technologies, as well as computational tools, have emerged that allow the identification of private epitopes derived from their mutanome and called neoantigens (neoAgs). On this basis, both CD4(+) and CD8(+) neoantigen-specific T cells have been identified in multiple human cancers and shown to be associated with a favorable clinical outcome. Notably, emerging data also indicate that neoantigen recognition represents a major factor in the activity of clinical immunotherapies. In the post-genome era, the mutanome holds promise as a long-awaited 'gold mine' for the discovery of unique cancer cell targets, which are exclusively tumor-specific and unlikely to drive immune tolerance, hence offering the chance for highly promising clinical programs of cancer immunotherapy. PMID:27563649

  5. Neoantigen-based cancer immunotherapy

    PubMed Central

    Bobisse, Sara; Coukos, George; Harari, Alexandre

    2016-01-01

    Emerging clinical evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy in all cancer types. Recent clinical data clearly demonstrated that human tumor cells express antigenic peptides (epitopes) that can be recognized by autologous tumor-specific T cells and that enhancement of such immune reactivity can potentially lead to cancer control and cancer regression in patients with advanced disease. However, in most cases, it is unclear which tumor antigens (Ags) mediated cancer regression. Mounting evidence indicates that numerous endogenous mutated cancer proteins, a hallmark of tumor cells, can be processed into peptides and presented on the surface of tumor cells, leading to their immune recognition in vivo as “non-self” or foreign. Massively parallel sequencing has now overcome the challenge of rapidly identifying the comprehensive mutational spectrum of individual tumors (i.e., the “mutanome”) and current technologies, as well as computational tools, have emerged that allow the identification of private epitopes derived from their mutanome and called neoantigens (neoAgs). On this basis, both CD4+ and CD8+ neoantigen-specific T cells have been identified in multiple human cancers and shown to be associated with a favorable clinical outcome. Notably, emerging data also indicate that neoantigen recognition represents a major factor in the activity of clinical immunotherapies. In the post-genome era, the mutanome holds promise as a long-awaited ‘gold mine’ for the discovery of unique cancer cell targets, which are exclusively tumor-specific and unlikely to drive immune tolerance, hence offering the chance for highly promising clinical programs of cancer immunotherapy. PMID:27563649

  6. Oral Immunotherapy for Food Allergy.

    PubMed

    Burbank, Allison J; Sood, Puja; Vickery, Brian P; Wood, Robert A

    2016-02-01

    Food allergy is a potentially life-threatening condition with no approved therapies, apart from avoidance and injectable epinephrine for acute allergic reactions. Oral immunotherapy (OIT) is an experimental treatment in which food-allergic patients consume gradually increasing quantities of the food to increase their threshold for allergic reaction. This therapy carries significant risk of allergic reactions. The ability of OIT to desensitize patients to particular foods is well-documented, although the ability to induce tolerance has not been established. This review focuses on recent studies for the treatment of food allergies such as cow's milk, hen's egg, and peanut.

  7. Immunology and Immunotherapy of Neuroblastoma

    PubMed Central

    Seeger, Robert C.

    2012-01-01

    Purpose This review demonstrates the importance of immunobiology and immunotherapy research for understanding and treating neuroblastoma. Principal results The first suggestions of immune system-neuroblastoma interactions came from in vitro experiments showing that lymphocytes from patients were cytotoxic for their own tumor cells and from evaluations of tumors from patients that showed infiltrations of immune system cells. With the development of monoclonal antibody (mAb) technology, a number of mAbs were generated against neuroblastoma cells lines and were used to define tumor associated antigens. Disialoganglioside (GD2) is one such antigen that is highly expressed by virtually all neuroblastoma cells and so is a useful target for both identification and treatment of tumor cells with mAbs. Preclinical research using in vitro and transplantable tumor models of neuroblastoma has demonstrated that cytotoxic T lymphocytes (CTLs) can specifically recognize and kill tumor cells as a result of vaccination or of genetic engineering that endows them with chimeric antigen receptors. However, CTL based clinical trials have not progressed beyond pilot and phase I studies. In contrast, anti-GD2 mAbs have been extensively studied and modified in pre-clinical experiments and have progressed from phase I through phase III clinical trials. Thus, the one proven beneficial immunotherapy for patients with high-risk neuroblastoma uses a chimeric anti-GD2 mAb combined with IL-2 and GM-CSF to treat patients after they have received intensive cyto-reductive chemotherapy, irradiation, and surgery. Ongoing pre-clinical and clinical research emphasizes vaccine, adoptive cell therapy, and mAb strategies. Recently it was shown that the neuroblastoma microenvironment is immunosuppressive and tumor growth promoting, and strategies to overcome this are being developed to enhance anti-tumor immunotherapy. Conclusions Our understanding of the immunobiology of neuroblastoma has increased

  8. Synthetic biology in cellular immunotherapy

    PubMed Central

    Chakravarti, Deboki; Wong, Wilson W.

    2015-01-01

    The adoptive transfer of genetically engineered T cells with cancer-targeting receptors has shown tremendous promise for eradicating tumors in clinical trials. This form of cellular immunotherapy presents a unique opportunity to incorporate advanced systems and synthetic biology approaches to create cancer therapeutics with novel functions. Here, we first review the development of synthetic receptors, switches, and circuits to control the location, duration, and strength of T cell activity against tumors. In addition, we discuss the cellular engineering and genome editing of host cells (or the chassis) to improve the efficacy of cell-based cancer therapeutics, and to reduce the time and cost of manufacturing. PMID:26088008

  9. Oral Immunotherapy for Food Allergy.

    PubMed

    Burbank, Allison J; Sood, Puja; Vickery, Brian P; Wood, Robert A

    2016-02-01

    Food allergy is a potentially life-threatening condition with no approved therapies, apart from avoidance and injectable epinephrine for acute allergic reactions. Oral immunotherapy (OIT) is an experimental treatment in which food-allergic patients consume gradually increasing quantities of the food to increase their threshold for allergic reaction. This therapy carries significant risk of allergic reactions. The ability of OIT to desensitize patients to particular foods is well-documented, although the ability to induce tolerance has not been established. This review focuses on recent studies for the treatment of food allergies such as cow's milk, hen's egg, and peanut. PMID:26617227

  10. Immunotherapy: It Takes a Village

    PubMed Central

    Pardoll, Drew

    2016-01-01

    We in the cancer immunology and immunotherapy community are thrilled that Science named “Cancer immunotherapy” as 2013’s Breakthrough of the Year (J. Couzin-Frankel, 20 December 2013, p. 1432). The rapid succession of clinical successes by blocking antibodies to two immune checkpoints, CTLA-4 and PD-1, and by chimeric antigen-receptor-transduced T cells, shows the power of basic immunology when translated to therapy. As such, I write to acknowledge some of the key scientists whose basic discoveries paved the way for the clinical successes outlined in the Breakthrough issue. PMID:24723594

  11. Immunity of foot-and-mouth disease serotype Asia 1 by sublingual vaccination.

    PubMed

    Chen, Hao-tai; Liu, Yong-sheng

    2013-01-01

    Foot-and-mouth disease virus (FMDV) causes vesicular disease of cloven-hoofed animals, with severe agricultural and economic losses. Here we present study using a sublingual (SL) route with the killed serotype Asia 1 FMDV vaccine. Guinea pigs were vaccinated using a commercially available vaccine formulation at the manufacturer's recommended full, 1/4, and 1/16 antigen doses. Animals were challenged with homologous FMDV Asia1 strain at various times following vaccination. All control guinea pigs exhibited clinical disease, including fever, viremia, and lesions, specifically vesicle formation in feet. Animals vaccinated with the 1/16 and 1/4 doses were protected after challenge at days 7, 28, and 35 post vaccination. These data suggest that effective protection against foot-and-mouth disease can be achieved with 1/16 of the recommended vaccine dose using SL vaccination, indicating that the sublingual route is an attractive alternative for the administration of the FMDV vaccine. PMID:23717497

  12. An accelerometric measure of the gait pattern in horses after the administration of sublingual detomidine.

    PubMed

    López-Sanromán, F J; de la Riva Andrés, S; Holmbak-Petersen, R; Pérez-Nogués, M; Forés Jackson, P; Santos González, M

    2014-10-01

    The locomotor pattern alterations produced after the administration of a sublingual detomidine gel was measured by an accelerometric method in horses. Using a randomized two-way crossover design, all animals (n = 6) randomly received either detomidine gel or a placebo administered sublingually. A triaxial accelerometric device was used for gait assessment 15 minutes before (baseline) and every 10 minutes after each treatment for a period of 180 minutes. Eight different parameters were calculated, including speed, stride frequency, stride length, regularity, dorsoventral, propulsion, mediolateral, and total power. Force of acceleration and the three components of power were also calculated. Significant statistical differences were observed between groups in all the parameters but stride length. The majority of significant changes started between 30 and 70 minutes after drug administration and lasted for 160 minutes. This route of administration is definitely useful in horses in which a prolonged sedation is required, with stability being a major concern.

  13. No more Doritos and lobster tails: a case report of life-threatening sublingual hematoma.

    PubMed

    Kausar, Huma; Gilani, Javed M; Khan, Omar A

    2009-07-01

    This case report highlights a life-threatening complication of mild hemophilia A. We report the onset of airway compromise through a massive sublingual hematoma in a 67-year-old male suffering from the mild form of hemophilia A. This case emphasizes the need for prompt medical attention and recognition of potentially serious complications of the disease in patients suffering with even mild form of this bleeding diathesis. PMID:19902776

  14. [Dendritic cells in cancer immunotherapy].

    PubMed

    Gato, M; Liechtenstein, T; Blanco-Luquín, I; Zudaire, M I; Kochan, G; Escors, D

    2015-01-01

    Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities. PMID:26486534

  15. Cancer immunotherapy and immunological memory.

    PubMed

    Murata, Kenji; Tsukahara, Tomohide; Torigoe, Toshihiko

    2016-01-01

      Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy.

  16. Novel immunotherapies for hematological malignancies

    PubMed Central

    Nelson, Michelle H.; Paulos, Chrystal M.

    2014-01-01

    Summary The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise the state of the art in immunotherapy with a focus on strategies that exploit the patient’s immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematological malignancies, including (i) conventional monoclonal therapies like rituximab, (ii) engineered monoclonal antibodies called bispecific T cell engagers (BiTEs), (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4 and IDO), and (iv) adoptive cell transfer (ACT) therapy with T cells engineered to express chimeric antigen receptors (CARs) or T-cell receptors (TCRs). We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients. PMID:25510273

  17. Cancer immunotherapy and immunological memory.

    PubMed

    Murata, Kenji; Tsukahara, Tomohide; Torigoe, Toshihiko

    2016-01-01

      Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy. PMID:27181230

  18. Rapid-Onset Sildenafil Sublingual Drug Delivery Systems: In Vitro Evaluation and In Vivo Pharmacokinetic Studies in Rabbits.

    PubMed

    Sheu, Ming-Thau; Hsieh, Chien-Ming; Chen, Ray-Neng; Chou, Po-Yu; Ho, Hsiu-O

    2016-09-01

    The aim of the present study was to prepare sublingual delivery systems for sildenafil and evaluate its relative bioavailability after sublingual administration in rabbits to attain a rapid onset of action with good efficacy at lower doses. For sublingual application, sildenafil and its citrate were formulated in 2 different dosage forms: the first was a sublingual spray consisting of sildenafil in 2 microemulsion systems, oleic acid or propylene glycol (PG), and the second was sublingual tablets prepared with various granulated sublingual sprays adsorbed onto a silicate adsorbant (Florite(®) R), binders (Cyclocel(®) or EMDEX(®)), and disintegrants (Ac-Di-Sol(®) or Kollidon(®) CL). Results showed that sublingual absorption of sildenafil spray prepared with PG was fairly rapid. At a 0.5-mg dose, the mean onset of action was 1.3 ± 0.6 min and lasted for about 1.5 h according to the pharmacokinetic studies. In vivo studies also showed that for sublingual tablets formulated with sildenafil in PG adsorbed onto Florite(®) R at a 1:1 weight ratio then mixed with Cycloel(®) and Ac-Di-Sol(®), the onset action was fast at 1.9 ± 0.4 min and lasted for about 1 h at 0.5 mg. These findings suggest the potential for the sublingual delivery of sildenafil instead of the conventional oral administration. PMID:26987948

  19. Anterograde excision of a sublingual gland: new surgical technique for the treatment of ranulas.

    PubMed

    Liu, Zhigang; Wang, Bin

    2016-02-01

    Wharton's duct is dissected in a retrograde direction from the orifice of the duct to the hilum of the submandibular gland when the gland is being excised conventionally. Here we describe an anterograde technique, in which Wharton's duct is dissected in an anterograde direction from the hilum of the submandibular gland to the orifice of the duct. This prospective clinical study included 50 consecutive patients with ranulas who had anterograde excision of the sublingual gland between May 2012 and January 2015. The intraoral incision was similar to that for conventional excision. Wharton's duct and other important anatomical structures located in the space behind the sublingual gland were all identified at the beginning of the procedure, followed by anterograde dissection of Wharton's duct. After the glandular tissue lateral to the duct had been incised completely, the duct was exposed and the gland cut into two parts. Finally, the two parts were removed, and the ranula ruptured. The patients were followed up from 6 months-2 years. There were no complications. Anterograde excision of the sublingual gland is based on the anatomy, and this reduces the risk of complications after removal of a ranula.

  20. Sublingual Nucleotides Prolong Run Time to Exhaustion in Young Physically Active Men

    PubMed Central

    Ostojic, Sergej M.; Idrizovic, Kemal; Stojanovic, Marko D.

    2013-01-01

    Although dietary nucleotides have been determined to be required for normal immune function, there is limited direct interventional evidence confirming performance-enhancing effects of sublingual nucleotides in humans. A double-blind, placebo-controlled, randomized trial was conducted to evaluate the effect of sublingual nucleotides (50 mg/day) administered for 14 days in thirty young healthy physically active males, on endurance performance and immune responses. Fasting white blood cell count, natural killer cells (NKC) number, NKC cytotoxic activity, and serum immunoglobulin (IgA, IgM, IgG), and time to exhaustion, peak rate of perceived exertion, peak heart rate, and peak running speed during the exercise test were measured at baseline (day 0) and post-intervention (day 14). Time to exhaustion, as well as serum immunoglobulin A and NKC cytotoxic activity, were significantly higher at day 14 (p < 0.05) in participants supplemented with nucleotides compared with those who consumed placebo. No significant differences in other parameters were observed between groups at post-intervention. No volunteers withdrew before the end of the study nor reported any vexatious side effects of supplementation. The results of the present study suggest that sublingual nucleotides may provide pertinent benefit as both an ergogenic and immunostimulatory additive in active males. PMID:24284618

  1. A novel application of electrospinning technique in sublingual membrane: characterization, permeation and in vivo study.

    PubMed

    Chen, Jianting; Wang, Xiaoyu; Zhang, Wenji; Yu, Shihui; Fan, Jinwu; Cheng, Bingchao; Yang, Xinggang; Pan, Weisan

    2016-08-01

    Isosorbide dinitrate-polyvinylpyrrolidone (ISDN-PVP) electrospinning fibers were formulated and explored as potentially sublingual membrane. The addition of polyethylene glycol (PEG) to the formulation improved flexibility and reduced fluffiness of the fiber mat. The scanning electron microscopy (SEM) demonstrated that the fibers tended to be cross-linking, and the crosslinking degree increased with the increase of PEG amount. The differential scanning calorimetry (DSC) indicated that ISDN existed in non-crystalline state in the fibers (except at the highest drug content). The infrared spectroscopy suggested that ISDN had better compatibility with the ingredients owing to the hydrogen bonding (or hydrophobic interactions). The fibers were highly favorable for the fabrication of sublingual membrane due to neutral pH, large folding endurance and rapid drug release (complete dissolution within 120 s). The permeation study of ISDN through both dialysis membrane (DM) and porcine sublingual mucosa (SM) were carried out. A significant relationship of drug permeation rate through DM and SM was built up, which indicated that DM could be used to partly simulate SM and assess formulation. The pharmacokinetic study in rats demonstrated that the electrospinning fiber membrane had a higher Cmax and lower Tmax compared to the reference preparation, and the relative bioavailability of the fiber membrane was 151.6%.

  2. Improved Endpoints for Cancer Immunotherapy Trials

    PubMed Central

    Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd

    2010-01-01

    Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737

  3. Potentiality of immunotherapy against hepatocellular carcinoma.

    PubMed

    Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

    2015-09-28

    Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the new-found field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future.

  4. Immunotherapy and chemotherapy in children with neuroblastoma.

    PubMed

    Nesbit, M E; Kersey, J; Finklestein, J; Weiner, J; Simmons, R

    1976-09-01

    Recent advances with immunotherapy in animal tumors suggested that trials with a combination of chemotherapy and immunotherapy in human malignant tumors might be worthwhile. A pilot program with Vibrio cholera neuraminidase-treated tumor cells plus BCG was tested in 3 patients who had had chemotherapy for disseminated neuroblastoma. Two of these children were in "complete remission" after radiation therapy and chemotherapy before the administration of immunotherapy. Relapse occurred in 5-6 months in all 3 patients. These disappointing results are discussed in relation to problems of current chemotherapy in disseminated neuroblastoma including results obtained at second-look operations in patients obtaining "complete remission."

  5. Rationale for combining immunotherapy with chemotherapy.

    PubMed

    Dalgleish, Angus G

    2015-01-01

    Immunotherapy has usually been considered as an alternative to more traditional modalities. Moreover, it has previously been felt that chemotherapy is inherently immunosuppressive and not suitable for combining with immunotherapy. In this review, the concept of combining different modalities that result in cell death, such as radiotherapy and chemotherapy, with immunotherapy is explored. Tumors actively cause immune suppression which can be reversed by their removal but when this is not possible, enhancing the immune response with nonspecific immune stimulation can enhance the response to other modalities, such as radiotherapy and chemotherapy. Additionally, several chemotherapy agents at low doses selectively inhibit regulatory and suppressor cells.

  6. Immunotherapy

    MedlinePlus

    ... Information Specialist Financial Support Online Chats Support Groups Peer-to-Peer Support LLS Community Blogs Caregiver Support Other Helpful ... Information Specialist Financial Support Online Chats Support Groups Peer-to-Peer Support LLS Community Blogs Caregiver Support ...

  7. Immunotherapy. Neuroblastoma as a model.

    PubMed

    Cheung, N K

    1991-04-01

    Combinations of aggressive therapy and radiotherapy directed at the primary tumor site as well as dose intensive chemotherapy against metastases can effectively induce complete remissions in patients with stage IV neuroblastomas. By virtue of its tumor specificity, the use of immunotherapy at the time when microscopic residual disease is present holds great promise in eradicating the tumors permanently. Monoclonal antibodies can accumulate selectively and at high concentrations in neuroblastomas. They have the potential of initiating complement activation and inflammation at the tumor site. Hematopoietic factors and cytokines can reinforce the body with tumoricidal leukocytes. Ex vivo activation of autologous white cells as well as arming by genetic manipulation can also produce tumor-seeking vehicles that may be therapeutically useful. As the knowledge of tumor and host immunobiology accumulates, the optimal combination of these approaches will become apparent.

  8. Targeting neoantigens for cancer immunotherapy.

    PubMed

    Lu, Yong-Chen; Robbins, Paul F

    2016-07-01

    Studies first carried out in the 1980s have demonstrated murine T cells can recognize mutated gene products, known as neoantigens, and that these T cells are capable of mediating tumor rejection. The first human tumor antigens isolated in the early 1990s were the products of non-mutated genes expressed in a tissue-specific manner; subsequent studies have indicated that tumor-infiltrating lymphocytes that are cultured in vitro frequently recognize mutated gene products. In addition, correlative studies indicate that clinical responses to therapies involving the use of antibodies directed against checkpoint inhibitors such as CTLA-4 and PD-1 may be associated with mutational burden, providing indirect evidence that these responses may primarily be mediated by neoantigen-reactive T cells. The importance of neoantigen-reactive T cells may be elucidated by the results of ongoing and future studies aimed at leveraging information gained from mutational profiling to enhance the potency of immunotherapies.

  9. Dendritic cell immunotherapy: clinical outcomes

    PubMed Central

    Apostolopoulos, Vasso; Pietersz, Geoffrey A; Tsibanis, Anastasios; Tsikkinis, Annivas; Stojanovska, Lily; McKenzie, Ian FC; Vassilaros, Stamatis

    2014-01-01

    The use of tumour-associated antigens for cancer immunotherapy studies is exacerbated by tolerance to these self-antigens. Tolerance may be broken by using ex vivo monocyte-derived dendritic cells (DCs) pulsed with self-antigens. Targeting tumour-associated antigens directly to DCs in vivo is an alternative and simpler strategy. The identification of cell surface receptors on DCs, and targeting antigens to DC receptors, has become a popular approach for inducing effective immune responses against cancer antigens. Many years ago, we demonstrated that targeting the mannose receptor on macrophages using the carbohydrate mannan to DCs led to appropriate immune responses and tumour protection in animal models. We conducted Phase I, I/II and II, clinical trials demonstrating the effectiveness of oxidised mannan-MUC1 in patients with adenocarcinomas. Here we summarise DC targeting approaches and their efficacy in human clinical trials. PMID:25505969

  10. New treatments for allergen immunotherapy.

    PubMed

    Akdis, Mübeccel

    2014-01-01

    Allergen-specific immunotherapy (SIT) represents the only curative and specific way for the treatment of allergic diseases, which have reached a pandemic dimension in industrial countries affecting up to 20-30% of the population. Although applied for 100 years to cure allergy, SIT still faces several problems related to side effects and limited efficacy. Currently, allergen-SIT is performed with vaccines based on allergen extracts that can cause severe, often life threatening, anaphylactic reactions as well as new IgE sensitization to other allergens present in the extract. Low patient adherence and high costs due to long duration (3 to 5 years) of treatment have been commonly reported. Several strategies have been developed to tackle these issues and it became possible to produce recombinant allergen-SIT vaccines with reduced allergenic activity.

  11. New treatments for allergen immunotherapy

    PubMed Central

    2014-01-01

    Allergen-specific immunotherapy (SIT) represents the only curative and specific way for the treatment of allergic diseases, which have reached a pandemic dimension in industrial countries affecting up to 20-30% of the population. Although applied for 100 years to cure allergy, SIT still faces several problems related to side effects and limited efficacy. Currently, allergen-SIT is performed with vaccines based on allergen extracts that can cause severe, often life threatening, anaphylactic reactions as well as new IgE sensitization to other allergens present in the extract. Low patient adherence and high costs due to long duration (3 to 5 years) of treatment have been commonly reported. Several strategies have been developed to tackle these issues and it became possible to produce recombinant allergen-SIT vaccines with reduced allergenic activity. PMID:25258656

  12. Topical Immunotherapy in Alopecia Areata

    PubMed Central

    Singh, Gurcharan; Lavanya, MS

    2010-01-01

    Alopecia Areata (AA) is a common non-scarring alopecia directed against the anagenic hair follicle. Various treatment modalities have been used for the treatment of severe AA. Topical immunotherapy is the best documented treatment so far for severe and refractory AA. Dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphencyprone (DPCP) are the contact allergens used for this purpose. DNCB has been found to be mutagenic by the Ames test and is largely replaced by DPCP and SADBE. DPCP and SADBE are both known to be non-mutagenic compounds and have comparable efficacy results and relapse rates. SADBE requires special solvents and additives to maintain its potency and is more expensive than the rest. DPCP has a response rate varying from 60% in severe Alopecia Areata to 17% in patients with alopecia totalis or universalis, and shows about 88 to 100% high response rate in patients with patchy Alopecia Areata. PMID:21188022

  13. [Current immunotherapy of multiple sclerosis].

    PubMed

    Paul, F; Ruprecht, K

    2015-08-01

    Following the introduction of interferon beta 1b as the first immunomodulatory therapy for multiple sclerosis (MS) in 1993, there are currently nine substances or substance classes approved for the treatment of MS (i.e. alemtuzumab, azathioprine, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab and teriflunomide). Major developments during the last 5 years include the approval of orally administered medications (i.e. fingolimod, teriflunomide and dimethyl fumarate), a monoclonal antibody (alemtuzumab), as well as glatiramer acetate with an administration frequency three times a week and a pegylated formulation of interferon beta 1a. The broadened therapeutic options enable a more differentiated and individualized therapy of MS; however, evidence-based data for therapeutic decision-making relevant in clinical practice are not always available. Rare but potentially severe and even life-threatening side effects of immunotherapies for MS require continuous pharmacovigilance and adherence to risk management plans. PMID:26253589

  14. Oral Immunotherapy for Food Allergies.

    PubMed

    Feuille, Elizabeth; Nowak-Węgrzyn, Anna

    2016-01-01

    Oral immunotherapy (OIT) is a promising investigational therapy for food allergy. Clinical trials in peanut, milk, egg, and wheat allergy provide evidence that OIT can effectively desensitize a majority of individuals to a food allergen. While a portion of subjects demonstrate sustained unresponsiveness, the majority regain sensitivity with allergen avoidance. The safety and tolerability of OIT continue to limit its use in some patients. Virtually all studies report adverse reactions that are more frequent during dose escalation but may also occur during maintenance therapy. Recent studies have identified adjunctive therapies (such as omalizumab) which may mitigate adverse effects. There is a paucity of data on the long-term safety and efficacy of OIT. Further study is required before OIT is ready for routine clinical practice. This review is intended to provide the reader with an up-to-date understanding of OIT, including its mechanisms, efficacy, safety profile, and potential utility in clinical practice. PMID:27355816

  15. Who Will Benefit from Cancer Immunotherapy?

    Cancer.gov

    Researchers have identified a “genetic signature” in the tumors of patients with advanced melanoma who responded to a form of immunotherapy called checkpoint blockade. The results could be the basis for a test that identifies likely responders.

  16. Immunotherapy: Disrupting the Cancer Treatment World

    MedlinePlus

    ... ACS » + - Text Size Immunotherapy: Disrupting the Cancer Treatment World By Elizabeth Mendes June 16, 2014 This story ... of cancer research in depth. The cancer research world is dedicating increasing energy to a rapidly evolving ...

  17. PROSTVAC® targeted immunotherapy candidate for prostate cancer.

    PubMed

    Shore, Neal D

    2014-01-01

    Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

  18. Oral immunotherapy for allergic diseases using transgenic rice seeds: current state and future prospects.

    PubMed

    Saeki, Mayumi; Nishimura, Tomoe; Kaminuma, Osamu; Mori, Akio; Hiroi, Takachika

    2013-01-01

    Allergen-specific immunotherapy (IT) has been shown to provide clinical benefit for patients with allergic diseases. At present, subcutaneous and sublingual ITs are mainly authorized for clinical treatment. Oral administration of allergens seems to be the easiest way to achieve IT, though it has yet to be translated to the clinical setting, mainly due to the requirement of a large amount of allergens. Plants, especially rice seeds, have recently been recognized as superior allergen carriers for oral administration, because of their high productivity, stability and safety. Therefore, in order to establish clinically applicable oral IT, we have been developing transgenic rice seeds (Tg rice), in which major epitopes of cedar pollen allergens or house-dust mites (HDM) are expressed. The efficacy of this orally administered Tg rice was confirmed in murine models of allergic rhinitis and bronchial asthma. In the safety study of the Tg rice, no adverse effects on cynomolgus macaques were observed. In this review, we summarized the current state and future prospects of allergen-specific IT, focusing particularly on oral IT with allergen-expressing Tg rice.

  19. Sublingual vaccination with sonicated Salmonella proteins and mucosal adjuvant induces mucosal and systemic immunity and protects mice from lethal enteritis.

    PubMed

    Huang, Ching-Feng; Wu, Tzee-Chung; Wu, Chia-Chao; Lee, Chin-Cheng; Lo, Wen-Tsung; Hwang, Kwei-Shuai; Hsu, Mu-Ling; Peng, Ho-Jen

    2011-07-01

    Salmonella enteritidis is one of the most common pathogens of enteritis. Most experimental vaccines against Salmonella infection have been applied through injections. This is a new trial to explore the effect of sublingual administration of Salmonella vaccines on systemic and mucosal immunity. Adult BALB/c mice were sublingually vaccinated with sonicated Salmonella proteins (SSP) alone, or plus adjuvant CpG DNA (CpG) or cholera toxin (CT). They were boosted 2 weeks later. Saliva specific secretory IgA (SIgA) antibody responses were significantly stimulated in the mice vaccinated with SSP only or together with CpG or CT. Whereas the mice sublingually vaccinated with SSP and CpG had higher spleen cell IFN-γ production and serum specific IgG2a antibody responses, those receiving SSP and CT showed enhanced spleen cell IL-4, IL-5 and IL-6 production, and serum specific IgG1 antibody responses. After oral challenge with live S. enteritidis, the same strain of the source of SSP, immune protection in those sublingually vaccinated with SSP and CpG or CT was found to prevent intestinal necrosis and to render a higher survival rate. In conclusion, sublingual vaccination together with mucosal adjuvant CpG or CT is a simple but effective way against enteric bacterial pathogens. PMID:21635554

  20. Allergen-specific immunotherapy in atopic eczema.

    PubMed

    Darsow, Ulf; Forer, Ingeborg; Ring, Johannes

    2011-08-01

    Aeroallergens are relevant eliciting factors of allergic rhinoconjunctivitis and bronchial asthma but also of atopic eczema. The use of allergen-specific immunotherapy as in respiratory atopic diseases is controversial in patients with atopic eczema, but refined diagnostic methods to characterize subgroups of patients with relevant allergies and the results of smaller controlled studies give rise to new approaches in this field. This article reviews the theoretical problems and practical results associated with allergen-specific immunotherapy in atopic eczema. PMID:21461718

  1. Defining the critical hurdles in cancer immunotherapy

    PubMed Central

    2011-01-01

    Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. PMID:22168571

  2. Defining the critical hurdles in cancer immunotherapy.

    PubMed

    Fox, Bernard A; Schendel, Dolores J; Butterfield, Lisa H; Aamdal, Steinar; Allison, James P; Ascierto, Paolo Antonio; Atkins, Michael B; Bartunkova, Jirina; Bergmann, Lothar; Berinstein, Neil; Bonorino, Cristina C; Borden, Ernest; Bramson, Jonathan L; Britten, Cedrik M; Cao, Xuetao; Carson, William E; Chang, Alfred E; Characiejus, Dainius; Choudhury, A Raja; Coukos, George; de Gruijl, Tanja; Dillman, Robert O; Dolstra, Harry; Dranoff, Glenn; Durrant, Lindy G; Finke, James H; Galon, Jerome; Gollob, Jared A; Gouttefangeas, Cécile; Grizzi, Fabio; Guida, Michele; Håkansson, Leif; Hege, Kristen; Herberman, Ronald B; Hodi, F Stephen; Hoos, Axel; Huber, Christoph; Hwu, Patrick; Imai, Kohzoh; Jaffee, Elizabeth M; Janetzki, Sylvia; June, Carl H; Kalinski, Pawel; Kaufman, Howard L; Kawakami, Koji; Kawakami, Yutaka; Keilholtz, Ulrich; Khleif, Samir N; Kiessling, Rolf; Kotlan, Beatrix; Kroemer, Guido; Lapointe, Rejean; Levitsky, Hyam I; Lotze, Michael T; Maccalli, Cristina; Maio, Michele; Marschner, Jens-Peter; Mastrangelo, Michael J; Masucci, Giuseppe; Melero, Ignacio; Melief, Cornelius; Murphy, William J; Nelson, Brad; Nicolini, Andrea; Nishimura, Michael I; Odunsi, Kunle; Ohashi, Pamela S; O'Donnell-Tormey, Jill; Old, Lloyd J; Ottensmeier, Christian; Papamichail, Michael; Parmiani, Giorgio; Pawelec, Graham; Proietti, Enrico; Qin, Shukui; Rees, Robert; Ribas, Antoni; Ridolfi, Ruggero; Ritter, Gerd; Rivoltini, Licia; Romero, Pedro J; Salem, Mohamed L; Scheper, Rik J; Seliger, Barbara; Sharma, Padmanee; Shiku, Hiroshi; Singh-Jasuja, Harpreet; Song, Wenru; Straten, Per Thor; Tahara, Hideaki; Tian, Zhigang; van Der Burg, Sjoerd H; von Hoegen, Paul; Wang, Ena; Welters, Marij Jp; Winter, Hauke; Withington, Tara; Wolchok, Jedd D; Xiao, Weihua; Zitvogel, Laurence; Zwierzina, Heinz; Marincola, Francesco M; Gajewski, Thomas F; Wigginton, Jon M; Disis, Mary L

    2011-01-01

    Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. PMID:22168571

  3. Cancer Immunotherapy: A Treatment for the Masses

    NASA Astrophysics Data System (ADS)

    Blattman, Joseph N.; Greenberg, Philip D.

    2004-07-01

    Cancer immunotherapy attempts to harness the exquisite power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is clearly capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for immunotherapy is to use advances in cellular and molecular immunology to develop strategies that effectively and safely augment antitumor responses.

  4. Defining the critical hurdles in cancer immunotherapy.

    PubMed

    Fox, Bernard A; Schendel, Dolores J; Butterfield, Lisa H; Aamdal, Steinar; Allison, James P; Ascierto, Paolo Antonio; Atkins, Michael B; Bartunkova, Jirina; Bergmann, Lothar; Berinstein, Neil; Bonorino, Cristina C; Borden, Ernest; Bramson, Jonathan L; Britten, Cedrik M; Cao, Xuetao; Carson, William E; Chang, Alfred E; Characiejus, Dainius; Choudhury, A Raja; Coukos, George; de Gruijl, Tanja; Dillman, Robert O; Dolstra, Harry; Dranoff, Glenn; Durrant, Lindy G; Finke, James H; Galon, Jerome; Gollob, Jared A; Gouttefangeas, Cécile; Grizzi, Fabio; Guida, Michele; Håkansson, Leif; Hege, Kristen; Herberman, Ronald B; Hodi, F Stephen; Hoos, Axel; Huber, Christoph; Hwu, Patrick; Imai, Kohzoh; Jaffee, Elizabeth M; Janetzki, Sylvia; June, Carl H; Kalinski, Pawel; Kaufman, Howard L; Kawakami, Koji; Kawakami, Yutaka; Keilholtz, Ulrich; Khleif, Samir N; Kiessling, Rolf; Kotlan, Beatrix; Kroemer, Guido; Lapointe, Rejean; Levitsky, Hyam I; Lotze, Michael T; Maccalli, Cristina; Maio, Michele; Marschner, Jens-Peter; Mastrangelo, Michael J; Masucci, Giuseppe; Melero, Ignacio; Melief, Cornelius; Murphy, William J; Nelson, Brad; Nicolini, Andrea; Nishimura, Michael I; Odunsi, Kunle; Ohashi, Pamela S; O'Donnell-Tormey, Jill; Old, Lloyd J; Ottensmeier, Christian; Papamichail, Michael; Parmiani, Giorgio; Pawelec, Graham; Proietti, Enrico; Qin, Shukui; Rees, Robert; Ribas, Antoni; Ridolfi, Ruggero; Ritter, Gerd; Rivoltini, Licia; Romero, Pedro J; Salem, Mohamed L; Scheper, Rik J; Seliger, Barbara; Sharma, Padmanee; Shiku, Hiroshi; Singh-Jasuja, Harpreet; Song, Wenru; Straten, Per Thor; Tahara, Hideaki; Tian, Zhigang; van Der Burg, Sjoerd H; von Hoegen, Paul; Wang, Ena; Welters, Marij Jp; Winter, Hauke; Withington, Tara; Wolchok, Jedd D; Xiao, Weihua; Zitvogel, Laurence; Zwierzina, Heinz; Marincola, Francesco M; Gajewski, Thomas F; Wigginton, Jon M; Disis, Mary L

    2011-12-14

    Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

  5. Developments in immunotherapy for gastrointestinal cancer.

    PubMed

    Diaz, J L; Wanta, S M; Fishbein, T M; Kroemer, A

    2015-08-01

    Gastrointestinal (GI) cancers are the most commonly occurring cancer worldwide. Colorectal cancer (CRC) is the second and third most commonly diagnosed cancer in women and men, respectively. Despite the advent of screening and the declining incidence of CRC overall, most patients are not diagnosed at an early, localized stage. Due to resistance to chemotherapy, recurrence, and metastatic disease, those diagnosed with advanced disease have only a 12% 5-year survival rate. Given the overwhelming global impact of CRC, the need for advanced therapy is crucial. Targeted immunotherapy in addition to surgical resection, traditional chemotherapy, and radiation therapy is on the rise. For the purpose of this review, we focused on the advances of immunotherapy, particularly in CRC, with mention of research pertaining to particular advances in immunotherapy for other aspects of the GI system. We review basic immunology and the microenvironment surrounding colorectal tumors that lead to immune system evasion and poor responses to chemotherapy. We also examined the way these obstacles are proving to be the targets of tumor specific immunotherapy. We will present current FDA approved immunotherapies such as monoclonal antibodies (mAb) targeting tumor specific antigens, as well as vaccines, adoptive cell therapy, cytokines, and check-point inhibitors. A summation of prior research, current clinical trials, and prospective therapies in murine models help delineate our current status and future strategies on CRC immunotherapy.

  6. Oncolytic Immunotherapy for Treatment of Cancer.

    PubMed

    Tsun, A; Miao, X N; Wang, C M; Yu, D C

    2016-01-01

    Immunotherapy entails the treatment of disease by modulation of the immune system. As detailed in the previous chapters, the different modes of achieving immune modulation are many, including the use of small/large molecules, cellular therapy, and radiation. Oncolytic viruses that can specifically attack, replicate within, and destroy tumors represent one of the most promising classes of agents for cancer immunotherapy (recently termed as oncolytic immunotherapy). The notion of oncolytic immunotherapy is considered as the way in which virus-induced tumor cell death (known as immunogenic cancer cell death (ICD)) allows the immune system to recognize tumor cells and provide long-lasting antitumor immunity. Both immune responses toward the virus and ICD together contribute toward successful antitumor efficacy. What is now becoming increasingly clear is that monotherapies, through any of the modalities detailed in this book, are neither sufficient in eradicating tumors nor in providing long-lasting antitumor immune responses and that combination therapies may deliver enhanced efficacy. After the rise of the genetic engineering era, it has been possible to engineer viruses to harbor combination-like characteristics to enhance their potency in cancer immunotherapy. This chapter provides a historical background on oncolytic virotherapy and its future application in cancer immunotherapy, especially as a combination therapy with other treatment modalities.

  7. Cancer immunotherapy out of the gate: the 22nd annual Cancer Research Institute International Immunotherapy Symposium.

    PubMed

    Tontonoz, Matthew; Gee, Connie E

    2015-05-01

    The 22nd annual Cancer Research Institute (CRI) International Immunotherapy Symposium was held from October 5-8, 2014, in New York City. Titled "Cancer Immunotherapy: Out of the Gate," the symposium began with a Cancer Immunotherapy Consortium satellite meeting focused on issues in immunotherapy drug development, followed by five speaker sessions and a poster session devoted to basic and clinical cancer immunology research. The second annual William B. Coley lecture was delivered by Lieping Chen, one of the four recipients of the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology; the other three recipients were Gordon Freeman, Tasuku Honjo, and Arlene Sharpe. Prominent themes of the conference were the use of genomic technologies to identify neoantigens and the emergence of new immune modulatory molecules, beyond CTLA-4 and PD-1/PD-L1, as new therapeutic targets for immunotherapy.

  8. Cancer immunotherapy out of the gate: the 22nd annual Cancer Research Institute International Immunotherapy Symposium.

    PubMed

    Tontonoz, Matthew; Gee, Connie E

    2015-05-01

    The 22nd annual Cancer Research Institute (CRI) International Immunotherapy Symposium was held from October 5-8, 2014, in New York City. Titled "Cancer Immunotherapy: Out of the Gate," the symposium began with a Cancer Immunotherapy Consortium satellite meeting focused on issues in immunotherapy drug development, followed by five speaker sessions and a poster session devoted to basic and clinical cancer immunology research. The second annual William B. Coley lecture was delivered by Lieping Chen, one of the four recipients of the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology; the other three recipients were Gordon Freeman, Tasuku Honjo, and Arlene Sharpe. Prominent themes of the conference were the use of genomic technologies to identify neoantigens and the emergence of new immune modulatory molecules, beyond CTLA-4 and PD-1/PD-L1, as new therapeutic targets for immunotherapy. PMID:25941356

  9. Assessment of the effectiveness of a sublingual, ergogenic spray on muscle strength and power.

    PubMed

    Jacobson, Bert H; Smith, Doug B; Warren, Aric J; Glass, Rob G; Kline, Crishel; Fedick, Joanna L; Stemm, John

    2009-11-01

    Nutrients, chemicals, and drugs may be applied sublingually to provide faster absorption. Sublingual absorption occurs when a substance comes in contact with the buccal mucosa, where it diffuses through a membrane of the dense capillaries. The purpose of this study was to assess the effectiveness of a sublingual, ergogenic product containing vitamins, minerals, amino acids, and a coenzyme on muscle performance. National Collegiate Athletic Association Division I linemen (n = 23) voluntarily participated in the study. All participants (20.11 +/- 1.45 years, 132.1 +/- 9.85 kg, 191.19 +/- 3.85 cm) were tested on 102.1 kg (225 lb) bench press repetitions, vertical jump, and grip strength. One week later, participants were either a placebo or the experimental treatment before they were tested again. Repeated-measures analyses of variance (ANOVAs) yielded a significant (p = 0.046) gain for the bench press. A Newman-Keuls post hoc test revealed a significant change in the treatment group but not in the placebo group. While the treatment group demonstrated greater improvement over the placebo group for each of the remaining variables, none were significant: vertical jump (p = 0.65) and grip strength (p = 0.74). The inconsistency of the results may be due to several factors. First, the spray may not be an ergogenic agent; second, the standardized dose may be too small for those weighing >or=290 lb and should be administered based on weight. Furthermore, the coenzyme and amino acids may not possess the molecular size, solubility, chemical stability, or hydrophilic character to be easily absorbed. Lastly, the data were generated by field tests and may not be sensitive enough to elicit subtle responses.

  10. Sedation and mechanical hypoalgesia after sublingual administration of detomidine hydrochloride gel to donkeys.

    PubMed

    Lizarraga, Ignacio; Castillo-Alcala, Fernanda; Varner, Kelley M; Robinson, Lauren S

    2016-07-01

    OBJECTIVE To compare sedative and mechanical hypoalgesic effects of sublingual administration of 2 doses of detomidine gel to donkeys. DESIGN Randomized blinded controlled trial. ANIMALS 6 healthy castrated male donkeys. PROCEDURES In a crossover study design, donkeys received each of the following sublingual treatments 1 week apart in a randomly assigned order: 1 mL of molasses (D0) or detomidine hydrochloride gel at 20 μg/kg (9 μg/lb; D20) or 40 μg/kg (18 μg/lb; D40). Sedation score (SS), head height above the ground (HHAG), and mechanical nociceptive threshold (MNT) were assessed before and for 180 minutes after treatment. Areas under the effect change-versus-time curves (AUCs) from 0 to 30, 30 to 60, 60 to 120, and 120 to 180 minutes after administration were computed for SS, HHAG, and MNT and compared among treatments. RESULTS D20 and D40 resulted in greater SS AUCs from 60 to 120 minutes and smaller HHAG AUCs from 30 through 180 minutes than did D0. The D40 resulted in smaller HHAG AUCs from 60 to 120 minutes than did D20. Compared with D0 values, MNT AUCs from 60 to 120 minutes were higher for D20, whereas MNT AUCs from 30 through 180 minutes were higher for D40. CONCLUSIONS AND CLINICAL RELEVANCE D20 and D40 induced sedation and mechanical hypoalgesia in donkeys by > 30 minutes after administration, but only sedation was dose dependent. Sublingual administration of detomidine gel at 40 μg/kg may be useful for sedation of standing donkeys prior to potentially painful minor procedures. PMID:27308886

  11. Sublingual Immunization of Trivalent Human Papillomavirus DNA Vaccine in Baculovirus Nanovector for Protection against Vaginal Challenge

    PubMed Central

    Lee, Hee-Jung; Cho, Hansam; Kim, Mi-Gyeong; Heo, Yoon-Ki; Cho, Yeondong; Gwon, Yong-Dae; Park, Ki Hoon; Jin, Hyerim; Kim, Jinyoung; Oh, Yu-Kyoung; Kim, Young Bong

    2015-01-01

    Here, we report the immunogenicity of a sublingually delivered, trivalent human papillomavirus (HPV) DNA vaccine encapsidated in a human endogenous retrovirus (HERV) envelope-coated, nonreplicable, baculovirus nanovector. The HERV envelope-coated, nonreplicable, baculovirus-based DNA vaccine, encoding HPV16L1, -18L1 and -58L1 (AcHERV-triHPV), was constructed and sublingually administered to mice without adjuvant. Following sublingual (SL) administration, AcHERV-triHPV was absorbed and distributed throughout the body. At 15 minutes and 1 day post-dose, the distribution of AcHERV-triHPV to the lung was higher than that to other tissues. At 30 days post-dose, the levels of AcHERV-triHPV had diminished throughout the body. Six weeks after the first of three doses, 1×108 copies of SL AcHERV-triHPV induced HPV type-specific serum IgG and neutralizing antibodies to a degree comparable to that of IM immunization with 1×109 copies. AcHERV-triHPV induced HPV type-specific vaginal IgA titers in a dose-dependent manner. SL immunization with 1×1010 copies of AcHERV-triHPV induced Th1 and Th2 cellular responses comparable to IM immunization with 1×109 copies. Molecular imaging revealed that SL AcHERV-triHPV in mice provided complete protection against vaginal challenge with HPV16, HPV18, and HPV58 pseudoviruses. These results support the potential of SL immunization using multivalent DNA vaccine in baculovirus nanovector for induction of mucosal, systemic, and cellular immune responses. PMID:25789464

  12. Sedation and mechanical hypoalgesia after sublingual administration of detomidine hydrochloride gel to donkeys.

    PubMed

    Lizarraga, Ignacio; Castillo-Alcala, Fernanda; Varner, Kelley M; Robinson, Lauren S

    2016-07-01

    OBJECTIVE To compare sedative and mechanical hypoalgesic effects of sublingual administration of 2 doses of detomidine gel to donkeys. DESIGN Randomized blinded controlled trial. ANIMALS 6 healthy castrated male donkeys. PROCEDURES In a crossover study design, donkeys received each of the following sublingual treatments 1 week apart in a randomly assigned order: 1 mL of molasses (D0) or detomidine hydrochloride gel at 20 μg/kg (9 μg/lb; D20) or 40 μg/kg (18 μg/lb; D40). Sedation score (SS), head height above the ground (HHAG), and mechanical nociceptive threshold (MNT) were assessed before and for 180 minutes after treatment. Areas under the effect change-versus-time curves (AUCs) from 0 to 30, 30 to 60, 60 to 120, and 120 to 180 minutes after administration were computed for SS, HHAG, and MNT and compared among treatments. RESULTS D20 and D40 resulted in greater SS AUCs from 60 to 120 minutes and smaller HHAG AUCs from 30 through 180 minutes than did D0. The D40 resulted in smaller HHAG AUCs from 60 to 120 minutes than did D20. Compared with D0 values, MNT AUCs from 60 to 120 minutes were higher for D20, whereas MNT AUCs from 30 through 180 minutes were higher for D40. CONCLUSIONS AND CLINICAL RELEVANCE D20 and D40 induced sedation and mechanical hypoalgesia in donkeys by > 30 minutes after administration, but only sedation was dose dependent. Sublingual administration of detomidine gel at 40 μg/kg may be useful for sedation of standing donkeys prior to potentially painful minor procedures.

  13. Ultrastructural changes in the sublingual salivary gland of prenatal buffalo (Bubalus bubalis)

    PubMed Central

    Singh, A. D.; Singh, Opinder

    2016-01-01

    Aim: The present study was aimed to elucidate ultrastructural changes in the development of sublingual salivary gland of buffalo during prenatal life. Materials and Methods: The study was carried out on sublingual salivary gland of 36 buffalo fetuses ranging from 13.2 cm curved crown-rump length (CVRL) (88th day) to full term. The fetuses were categorized into three groups based on their CVRL. Results: The cells lining the terminal tubules were undifferentiated with poorly developed cytoplasmic organelles but lacked secretory granules (SGs) at 13.2 cm CVRL (88th day). The SGs appeared first in the form of membrane-bound secretory vesicles with homogeneous electron-dense as well as electron-lucent contents at 21.2 cm CVRL (122nd day); however, mucous acinar cells contained electron-lucent granules, while serous secretory cells as well as serous demilunes showed electron-dense granules at 34 cm CVRL (150th day) of prenatal life. At 53.5 cm CVRL (194th day), both mucous and serous acini were differentiated by the density of SGs. Conclusion: The cytoplasm of acinar cells was filled with mitochondria, rough endoplasmic reticulum, and Golgi profiles in mid and late fetal age groups. The SGs were increased in number during the late fetal age group. The myoepithelial cells (MECs) were located at the base of the acinar cells as well as intercalated and striated ducts and were stellate in shape. The ultrastructure of MEC revealed a parallel stream of myofilaments in the cytoplasm and its processes. The mucous cells were predominantly present in the sublingual salivary gland and were pyramidal in shape. PMID:27057120

  14. Fentanyl citrate sublingual formulation (Vellofent®) for quick BTcP hindering.

    PubMed

    Romualdi, Patrizia; Candeletti, Sanzio

    2016-04-01

    The management of cancer pain presents manifold challenges: even though background pain is adequately controlled, patients frequently experience episodes of acute pain exacerbation known as breakthrough cancer pain (BTcP). The characteristics of BTcP are a rapid onset, a short duration, and a severe intensity. An innovative sublingual fentanyl citrate formulation (Vellofent®) has been developed to target BTcP. The new formulation allows to increase the solubility of fentanyl and to provide optimal oromucosal conditions for rapid drug absorption, thus featuring a shorter time to onset of pain relief (from 6 minutes post-administration).

  15. Fluid resuscitation guided by sublingual partial pressure of carbon dioxide during hemorrhagic shock in a porcine model.

    PubMed

    Xu, Jiefeng; Ma, Linhao; Sun, Shijie; Lu, Xiaoye; Wu, Xiaobo; Li, Zilong; Tang, Wanchun

    2013-04-01

    To avoid aggressive fluid resuscitation during hemorrhagic shock, fluid resuscitation is best guided by a specific measurement of tissue perfusion. We investigated whether fluid resuscitation guided by sublingual PCO2 would reduce the amount of resuscitation fluid without compromising the outcomes of hemorrhagic shock. Ten male domestic pigs weighing between 34 and 37 kg were used. Forty-five percent of estimated blood volume was removed during an interval of 1 h. The animals were then randomized to receive fluid resuscitation based on either sublingual PCO2 or blood pressure (BP). In the sublingual PCO2-guided group, resuscitation was initiated when sublingual PCO2 exceeded 70 Torr and stopped when it decreased to 50 Torr. In the BP-guided group, resuscitation was initiated when mean aortic pressure decreased to 60 mmHg and stopped when it increased to 90 mmHg. First, Ringer's lactate solution (RLS) of 30 mL kg was administered; subsequently, the shed blood was transfused if sublingual PCO2 remained greater than 50 Torr in the sublingual PCO2-guided group or mean aortic pressure was less than 90 mmHg in the BP-guided group. All the animals were monitored for 4 h and observed for an additional 68 h. In the sublingual PCO2-guided group, fluid resuscitation was required in only 40% of the animals. In addition, a significantly lower volume of RLS (170 ± 239 mL, P = 0.005 vs. BP-guided group) was administered without the need for blood infusion in this group. However, in the BP-guided group, all the animals required a significantly larger volume of fluid (955 ± 381 mL), including both RLS and blood. There were no differences in postresuscitation tissue microcirculation, myocardial and neurologic function, and 72-h survival between groups. During hemorrhagic shock, fluid resuscitation guided by sublingual PCO2 significantly reduced the amount of resuscitation fluid without compromising the outcomes of hemorrhagic shock. PMID:23364438

  16. New routes for allergen immunotherapy

    PubMed Central

    Johansen, Pål; von Moos, Seraina; Mohanan, Deepa; Kündig, Thomas M.; Senti, Gabriela

    2012-01-01

    IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review. PMID:23095873

  17. International consensus on allergy immunotherapy.

    PubMed

    Jutel, Marek; Agache, Ioana; Bonini, Sergio; Burks, A Wesley; Calderon, Moises; Canonica, Walter; Cox, Linda; Demoly, Pascal; Frew, Antony J; O'Hehir, Robin; Kleine-Tebbe, Jörg; Muraro, Antonella; Lack, Gideon; Larenas, Désirée; Levin, Michael; Nelson, Harald; Pawankar, Ruby; Pfaar, Oliver; van Ree, Ronald; Sampson, Hugh; Santos, Alexandra F; Du Toit, George; Werfel, Thomas; Gerth van Wijk, Roy; Zhang, Luo; Akdis, Cezmi A

    2015-09-01

    Allergen immunotherapy (AIT) has been used to treat allergic disease since the early 1900s. Despite numerous clinical trials and meta-analyses proving AIT efficacious, it remains underused and is estimated to be used in less than 10% of patients with allergic rhinitis or asthma worldwide. In addition, there are large differences between regions, which are not only due to socioeconomic status. There is practically no controversy about the use of AIT in the treatment of allergic rhinitis and allergic asthma, but for atopic dermatitis or food allergy, the indications for AIT are not well defined. The elaboration of a wider consensus is of utmost importance because AIT is the only treatment that can change the course of allergic disease by preventing the development of asthma and new allergen sensitizations and by inducing allergen-specific immune tolerance. Safer and more effective AIT strategies are being continuously developed both through elaboration of new allergen preparations and adjuvants and alternate routes of administration. A number of guidelines, consensus documents, or both are available on both the international and national levels. The international community of allergy specialists recognizes the need to develop a comprehensive consensus report to harmonize, disseminate, and implement the best AIT practice. Consequently, the International Collaboration in Asthma, Allergy and Immunology, formed by the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the World Allergy Organization, has decided to issue an international consensus on AIT.

  18. Melanoma immunotherapy dominates the field.

    PubMed

    Diamantopoulos, Panagiotis; Gogas, Helen

    2016-07-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  19. Melanoma immunotherapy dominates the field

    PubMed Central

    Diamantopoulos, Panagiotis

    2016-01-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  20. Immunotherapy for acute myeloid leukemia.

    PubMed

    Jurcic, Joseph G

    2005-09-01

    Immunotherapeutic strategies have become part of standard cancer treatment. Chimeric and humanized antibodies have demonstrated activity against a variety of tumors. Although the humanized anti-CD33 antibody HuM195 has only modest activity against overt acute myeloid leukemia (AML), it can eliminate minimal residual disease in acute promyelocytic leukemia. High-dose radioimmunotherapy with b-particle-emitting isotopes targeting CD33, CD45, and CD66 can potentially allow intensification of antileukemic therapy before hematopoietic stem cell transplantation. Conversely, a-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumor cell kill while sparing surrounding normal tissues. Targeted chemotherapy with the anti-CD33- calicheamicin construct gemtuzumab ozogamicin has produced remissions in relapsed AML and appears promising when used in combination with standard chemotherapy for newly diagnosed AML. T-cell recognition of peptide antigens presented on the cell surface in combination with major histocompatibility complex antigen provides another potentially promising approach for the treatment of AML. PMID:16091194

  1. Advances in the understanding of cancer immunotherapy.

    PubMed

    Shore, Neal D

    2015-09-01

    The principal role of the immune system is to prevent and eradicate pathogens and infections. The key characteristics or features of an effective immune response include specificity, trafficking, antigen spread and durability (memory). The immune system is recognised to have a critical role in controlling cancer through a dynamic relationship with tumour cells. Normally, at the early stages of tumour development, the immune system is capable of eliminating tumour cells or keeping tumour growth abated; however, tumour cells may evolve multiple pathways over time to evade immune control. Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumour burden, in whom disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve. Because immunotherapies may have a different mechanism of action from traditional cytotoxic or targeted biological agents, immunotherapy techniques have the potential to combine synergistically with traditional therapies.

  2. Immunotherapy for Alzheimer’s Disease

    PubMed Central

    Morgan, Dave

    2010-01-01

    Summary In 1999 a vaccine approach was found to reduce amyloid deposits in transgenic mice overproducing the amyloid precursor protein. This was followed closely by demonstrations that vaccines or passive immunotherapy could rescue memory deficits in these mice. Initial human clinical trials revealed apparent autoimmune reactions in a subset of patients, but also some cases of cognitive benefit and amyloid clearance. Further work with passive immunotherapy in mouse models confirmed exceptional clearing abilities of anti-amyloid antibodies even in older mice. However, in parallel with parenchymal amyloid clearance was the appearance of microhemorrhages and increased vascular amyloid deposition. Additional clinical trials with passive immunotherapy confirmed occasional appearance of microhemorrhage and occurrence of vasogenic edema in some patients, particularly those with the apolipoprotein E4 genotype. Recent data with positron emission tomography demonstrates trial participants passively immunized with anti-Aβ antibodies have reduced signals with amyloid binding ligands after 18 mo of therapy. Several anti-Aβ immunotherapies have reached phase 3 testing and immunotherapy is likely to be the first test of the amyloid hypothesis of Alzheimer’s disease. Identifying antibody variants that retain amyloid clearance with fewer adverse reactions remains a major focus of translational research in this area. PMID:21158978

  3. Immunotherapy for tuberculosis: what's the better choice?

    PubMed

    Guo, Shuliang; Zhao, Jinqiu

    2012-06-01

    A Th1/Th2 imbalance in tuberculosis (TB) patients caused by a decreased Th1 response and an increased Th2 response is a significant factor in the pathogenesis and development of TB. Protective immune responses to TB include bacteriostatic and bactericidal responses. Unfortunately, however, immunoprotection and immune pathology co-exist in TB patients. Immunotherapy for TB principally aims to restore the Th1/Th2 balance by enhancing the Th1 response and suppressing the excessive Th2 response. Immunotherapy for TB can be classified into three categories: immune-enhancing therapy using cytokines, immunosuppressive therapy, and immunomodulatory therapy. Immunomodulatory therapy targets the Th1/Th2 imbalance and includes cytokine regulation therapy, antibody regulation therapy, a multi-dose heat-inactivated Mycobacterium vaccae vaccine, thymosin hormones and a DNA vaccine. A new approach in supplementary TB immunotherapy is to simultaneously up-regulate the Th1 response and down-regulate the Th2 response. While immunotherapy can contribute to TB treatment, it may also cause immunopathological injury. Therefore, immunotherapy needs to be improved and further studied to maximize its potential.

  4. Immunity of Foot-and-Mouth Disease Serotype Asia 1 by Sublingual Vaccination

    PubMed Central

    Chen, Hao-tai; Liu, Yong-sheng

    2013-01-01

    Foot-and-mouth disease virus (FMDV) causes vesicular disease of cloven-hoofed animals, with severe agricultural and economic losses. Here we present study using a sublingual (SL) route with the killed serotype Asia 1 FMDV vaccine. Guinea pigs were vaccinated using a commercially available vaccine formulation at the manufacturer’s recommended full, 1/4, and 1/16 antigen doses. Animals were challenged with homologous FMDV Asia1 strain at various times following vaccination. All control guinea pigs exhibited clinical disease, including fever, viremia, and lesions, specifically vesicle formation in feet. Animals vaccinated with the 1/16 and 1/4 doses were protected after challenge at days 7, 28, and 35 post vaccination. These data suggest that effective protection against foot-and-mouth disease can be achieved with 1/16 of the recommended vaccine dose using SL vaccination, indicating that the sublingual route is an attractive alternative for the administration of the FMDV vaccine. PMID:23717497

  5. High doses of oral folate and sublingual vitamin B12 in dialysis patients with hyperhomocysteinemia

    PubMed Central

    Naseri, Mitra; Sarvari, Gholam-Reza; Esmaeeli, Mohammad; Azarfar, Anoush; Rasouli, Zahra; Moeenolroayaa, Giti; Jahanshahi, Shohre; Farhadi, Simin; Heydari, Zohreh; Sagheb-Taghipoor, Narges

    2016-01-01

    Introduction: Folic acid and vitamin B12, alone or in combination have been used to reduce homocysteine (Hcy) levels in dialysis patients. Objectives: We aimed to assess the efficacy of high doses of oral folate and vitamin B12 in reducing plasma Hcy levels after a 12-week treatment. Patients and Methods: Thirty-two dialysis patients aged 10-324 months screened for hyperhomocysteinuria. Then cases with hyperhomocysteinemia received oral folate 10 mg/day with sublingual methylcobalamin 1 mg/day for 12 weeks. In pre- and post-intervention phases plasma Hcy concentration, serum folate, and vitamin B12 levels were measured. Changes in plasma Hcy, serum folate, and vitamin B12 concentrations were analyzed by paired t tests, and P values < 0.05 were considered significant. Results: Eighteen (56.2%) patients had hyperhomocysteinuria. Vitamin B12 and folate levels were normal or high in all cases. Two patients were lost due to transplant or irregular drugs consumption. Plasma Hcy levels were reduced in all, and reached normal values in 50%. A statistically significant differences between first Hcy levels with levels after intervention was found (95% CI, 5.1–8.9, P = 0.0001). Conclusion: Oral folate 10 mg/day in combination with sublingual vitamin B12, 1 mg/day can be considered as a favorable treatment for hyperhomocysteinemia in dialysis patients. PMID:27689109

  6. Acinar autolysis and mucous extravasation in human sublingual glands: a microscopic postmortem study

    PubMed Central

    AZEVEDO-ALANIS, Luciana Reis; TOLENTINO, Elen de Souza; de ASSIS, Gerson Francisco; CESTARI, Tânia Mary; LARA, Vanessa Soares; DAMANTE, José Humberto

    2015-01-01

    Although some morphological investigations on aged human sublingual glands (HSG) found eventual phenomena identified as autolysis and mucous extravasation, the exact meaning of these findings has not been elucidated. Objective The aim of this work is to investigate whether acinar autolysis and mucous extravasation are related to the aging process in human sublingual glands. We also speculate if autolytic changes may assist forensic pathologists in determining time of death. Material and Methods 186 cadavers’ glands were allocated to age groups: I (0–30 years); II (31–60), and III (61–90). Time and mode of death were also recorded. Acinar autolysis and mucous extravasation were classified as present or absent. Ultrastructural analysis was performed using transmission electron microscopy (TEM). Data were compared using Mann-Whitney U, Spearman’s correlation coefficient, Kruskal-Wallis, and Dunn tests (p<0.05). Results There was correlation between age and acinar autolysis (r=0.38; p=0.0001). However, there was no correlation between autolysis and time of death. No differences were observed between genders. TEM showed mucous and serous cells presenting nuclear and membrane alterations and mucous cells were more susceptible to autolysis. Conclusion Acinar autolysis occurred in all age groups and increased with age while mucous extravasation was rarely found. Both findings are independent. Autolysis degrees in HSG could not be used to determine time of death. PMID:26537715

  7. Space Flight Effects on Intracellular Ions in Sublingual Cells of Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Dotsenko, R.; Fung, P.; Navidi, M.; Silver, B.; Wade, Charles E. (Technical Monitor)

    1994-01-01

    We have used a novel technique that quantifies minerals and electrolytes from smears of sublingual cells by x-ray microanalysis to monitor metabolic changes in bed rest subjects. Increases in intracellular calcium (Ca), phosphorus (P), and potassium (K) were characteristic of subjects whose exercise regimen was inadequate to maintain calcium metabolism. To test the effects of space flight on intracellular ions, we analyzed cells from 2-4 kg Rhesus monkeys before and after 2 weeks in space or chair restraint (CR). There were increases in sublingual cell Ca, P and K after space flight which paralleled the clinical estimates of metabolic status of the animals and exceeded the levels found during CR on R+11. Increases after 2 weeks CR were 26% in Ca, 6% in P and 29% in K. Species similarity ill responses of intracellular ions to inactivity imposed by bed rest, restraint or microgravity suggest that this innovative non-invasive technique would be a useful in-flight monitor of exercise countermeasures directed toward maintaining calcium balance.

  8. High doses of oral folate and sublingual vitamin B12 in dialysis patients with hyperhomocysteinemia

    PubMed Central

    Naseri, Mitra; Sarvari, Gholam-Reza; Esmaeeli, Mohammad; Azarfar, Anoush; Rasouli, Zahra; Moeenolroayaa, Giti; Jahanshahi, Shohre; Farhadi, Simin; Heydari, Zohreh; Sagheb-Taghipoor, Narges

    2016-01-01

    Introduction: Folic acid and vitamin B12, alone or in combination have been used to reduce homocysteine (Hcy) levels in dialysis patients. Objectives: We aimed to assess the efficacy of high doses of oral folate and vitamin B12 in reducing plasma Hcy levels after a 12-week treatment. Patients and Methods: Thirty-two dialysis patients aged 10-324 months screened for hyperhomocysteinuria. Then cases with hyperhomocysteinemia received oral folate 10 mg/day with sublingual methylcobalamin 1 mg/day for 12 weeks. In pre- and post-intervention phases plasma Hcy concentration, serum folate, and vitamin B12 levels were measured. Changes in plasma Hcy, serum folate, and vitamin B12 concentrations were analyzed by paired t tests, and P values < 0.05 were considered significant. Results: Eighteen (56.2%) patients had hyperhomocysteinuria. Vitamin B12 and folate levels were normal or high in all cases. Two patients were lost due to transplant or irregular drugs consumption. Plasma Hcy levels were reduced in all, and reached normal values in 50%. A statistically significant differences between first Hcy levels with levels after intervention was found (95% CI, 5.1–8.9, P = 0.0001). Conclusion: Oral folate 10 mg/day in combination with sublingual vitamin B12, 1 mg/day can be considered as a favorable treatment for hyperhomocysteinemia in dialysis patients.

  9. Cancer Immunotherapy for Gliomas: Overview and Future Directions.

    PubMed

    Hashimoto, Naoya

    2016-07-15

    Immunotherapy has been highlighted because we have obtained much evidence, which includes theoretical backborn as well as favorable results from clinical trials. As immunotherapy gives an apparently different cytotoxic mechanism and a little adverse event, the promising results are getting a lot of attention. In this article, cancer immunotherapy for gliomas is reviewed thoroughly from the literature, focusing on the clinical trial results.

  10. Development of Novel Immunotherapies for Multiple Myeloma

    PubMed Central

    Al-Hujaily, Ensaf M.; Oldham, Robyn A. A.; Hari, Parameswaran; Medin, Jeffrey A.

    2016-01-01

    Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. PMID:27618026

  11. Immunotherapy advances in uro-genital malignancies.

    PubMed

    Ratta, Raffaele; Zappasodi, Roberta; Raggi, Daniele; Grassi, Paolo; Verzoni, Elena; Necchi, Andrea; Di Nicola, Massimo; Salvioni, Roberto; de Braud, Filippo; Procopio, Giuseppe

    2016-09-01

    Immunotherapy for the treatment of cancer has made significant progresses over the last 20 years. Multiple efforts have been attempted to restore immune-mediated tumor elimination, leading to the development of several targeted immunotherapies. Data from recent clinical trials suggest that these agents might improve the prognosis of patients with advanced genito-urinary (GU) malignancies. Nivolumab has been the first immune checkpoint-inhibitor approved for pre-treated patients with metastatic renal cell carcinoma. Pembrolizumab and atezolizumab have shown promising results in both phase I and II trials in urothelial carcinoma. Brentuximab vedotin has demonstrated early signals of clinical activity and immunomodulatory effects in highly pre-treated patients with testicular germ cell tumors. In this review, we have summarized the major clinical achievements of immunotherapy in GU cancers, focusing on immune checkpoint blockade as well as the new immunomodulatory monoclonal antibodies (mAbs) under clinical evaluation for these malignancies.

  12. Development of Novel Immunotherapies for Multiple Myeloma.

    PubMed

    Al-Hujaily, Ensaf M; Oldham, Robyn A A; Hari, Parameswaran; Medin, Jeffrey A

    2016-01-01

    Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. PMID:27618026

  13. Immunotherapy in prostate cancer: challenges and opportunities.

    PubMed

    Noguchi, Masanori; Koga, Noriko; Moriya, Fukuko; Itoh, Kyogo

    2016-01-01

    Although treatment options for castration-resistant prostate cancer (CRPC) have increased over the last decade, there remains a need for strategies that can provide durable disease control and long-term benefit. Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of CRPC. To date, there are multiple strategies to target the immune system, and several approaches including therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in clinical trials. With regard to this, we report the results of the most recent clinical trials investigating immunotherapy in CRPC and discuss the future development of immunotherapy for CRPC, as well as the potential importance of biomarkers in the future progress of this field.

  14. Immunotherapy in acute arsenic poisoning.

    PubMed

    Leikin, J B; Goldman-Leikin, R E; Evans, M A; Wiener, S; Hryhorczuk, D O

    1991-01-01

    We investigated the use of immunotherapy on the treatment of sodium arsenite toxicity. Female balb/c mice injected with arsanilic acid conjugated to a carrier protein (ovalbumin) were shown to produce antibodies (arsenic reactive serum, ARS) reactive with arsanilic acid and sodium arsenite. Serum was tested for anti-ARS antibodies using a solid phase radioimmunoassay. The antisera bound to ARS conjugated to the synthetic copolymer glutamic acid60 tyrosine30 when diluted as high as 1:4096. Following multiple injections of 100 micrograms of arsanilic acid--ovalbumin compound, mortality on injection with sodium arsenite 0.87 mg/kg i.p. one week later decreased to 0 deaths in 22 pretreated mice vs 9 deaths in 29 untreated mice (31% mortality; p less than .005). No decrease in mortality was noted at higher challenges (1.15 mg/kg) of sodium arsenite. Antisera from pretreated mice was injected 0.1 cc i.p. into 12 week old female balb/c mice followed by an injection of sodium arsenite 0.87 mg/kg i.p. at 10 minutes. Again a protective effect was observed with 0 deaths in 18 mice vs eight deaths in 21 mice (38%; p less than .005). Seventeen additional mice were given an injection of 0.87 mg/kg i.p. of sodium arsenite. After 30 minutes, all mice became symptomatic whereupon antisera 0.1 cc i.p. was given. The one day mortality (2/17, 12%) was possibly lower than the combined control mortality (17/50, 34%; p less than 0.07). There was no change in mortality noted when antisera was administered to mice acutely exposed to 5 mg/kg HgCl2.

  15. Immunotherapies: The Blockade of Inhibitory Signals

    PubMed Central

    Wu, Yan-Ling; Liang, Jing; Zhang, Wen; Tanaka, Yoshimasa; Sugiyama, Hiroshi

    2012-01-01

    T lymphocytes require signaling by the T cell receptor and by nonclonotypic cosignaling receptors. The costimulatory and inhibitory signals profoundly influence the course of immune responses by amplifying or reducing the transcriptional effects of T cell receptor triggering. The inhibitory receptors such as CTLA-4, PD-1, and BTLA have recently drawn much attention as potential targets for immunotherapies. This review focuses on the progress that has been made with the mentioned receptors in the field of immunotherapies for autoimmune diseases, malignancies, infectious diseases, and transplantation. PMID:23197939

  16. Immunotherapy for advanced melanoma: future directions.

    PubMed

    Valpione, Sara; Campana, Luca G

    2016-02-01

    As calculated by the meta-analysis of Korn et al., the prognosis of metastatic melanoma in the pretarget and immunological therapy era was poor, with a median survival of 6.2 and a 1-year life expectancy of 25.5%. Nowadays, significant advances in melanoma treatment have been gained, and immunotherapy is one of the promising approaches to get to durable responses and survival improvement. The aim of the present review is to highlight the recent innovations in melanoma immunotherapy and to propose a critical perspective of the future directions of this enthralling oncology subspecialty.

  17. Sublingual versus Vaginal Misoprostol for the Induction of Labor at Term: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial

    PubMed Central

    Jahromi, Bahia Namavar; Poorgholam, Foroogh; Yousefi, Gholamhossein; Salarian, Leila

    2016-01-01

    Background: We sought to compare the effectiveness and safety of sublingual versus vaginal misoprostol for the termination of pregnancy with a live full-term fetus. Methods: This randomized, triple-blind, placebo-controlled clinical trial was performed on 200 primiparous women with normal, singleton, full-term pregnancies candidated for the induction of labor. Sublingual and vaginal tablets containing misoprostol (25 mcg) or placebo in similar shapes were administered every 4 hours until the Bishop score reached above 8. Maternal and neonatal complications and outcomes were compared. Results: There were 100 parturient women in each group. The mean maternal age, gestational age, and Bishop score at the commencement of misoprostol had no statistical differences between the sublingual and vaginal groups. The mean time interval between misoprostol commencement and delivery was 497.10±291.49 and 511.67±08.46 minutes for the sublingual and vaginal groups, correspondingly. Twenty-two women had Cesarean deliveries in the sublingual group versus 14 in the vaginal group. Meconium-stained amniotic fluid was seen in 12 women in the sublingual group and 4 in the vaginal group (P=0.03). Late fetal heart rate deceleration was observed in 8 women in the sublingual group and 4 in the vaginal group (P=0.22). The mean neonatal birth weight, blood gas value at birth, Apgar score, and length of admission time in the neonatal intensive care unit were not different between the 2 groups. Conclusion: Sublingual and vaginal misoprostol had similar effectiveness; however, meconium-stained liquor was observed considerably more frequently with sublingual misoprostol than with vaginal misoprostol. Trial Registration Number: IRCT201402096541N3 PMID:26989277

  18. CHANGES IN SUBLINGUAL MICROCIRCULATION IS CLOSELY RELATED WITH THAT OF BULBAR CONJUNCTIVAL MICROCIRCULATION IN A RAT MODEL OF CARDIAC ARREST.

    PubMed

    Yin, Lu; Yang, Zhengfei; Yu, Haifang; Qian, Jie; Zhao, Shen; Wang, Jiangang; Wu, Xiaobo; Cahoon, Jena; Tang, Wanchun

    2016-04-01

    Following successful resuscitation, a significantly impaired microcirculation has been identified. The severity of the impairment of microcirculation is closely related to that of vital organ dysfunction. Sublingual microcirculation is a traditional site for the measurement of tissue perfusion. In the present study, we investigated the bulbar conjunctival microcirculatory alterations following CPR and its relationship with the changes of sublingual microcirculation in a rat model of cardiac arrest.Male Sprague-Dawley rats (450-550 g) were utilized. Ventricular fibrillation was induced and untreated for 8 min followed by 8 min of CPR. Sublingual and bulbar conjunctival microcirculatory blood flow was visualized by a sidestream dark-field imaging device at baseline, 30 min, 1, 2, 4, and 8 h post-resuscitation. Both perfused vessel density (PVD) and microcirculatory flow index (MFI) were recorded.The post-resuscitation PVD and MFI were significantly decreased in both sublingual and bulbar conjunctival sites. Sublingual PVD decreased from baseline of 5.9 ± 0.3 to 3.1 ± 0.4 n/mm at 30 min post-resuscitation and MFI from 3.0 ± 0.0 to 1.5 ± 0.3 (both P < 0.05 vs. baseline). Bulbar conjunctival PVD was significantly reduced from baseline of 6.5 ± 0.6 to 3.9 ± 0.5 n/mm at 30 min post-resuscitation and MFI from 3.0 ± 0.0 to 1.2 ± 0.4 (both P < 0.05 vs. baseline). PVD, MFI, and cardiac function did not change significantly from the 30-min measurements in the surviving rats throughout the remainder of the study (both P > 0.05 vs. 30-min post-resuscitation). The decreases in sublingual microcirculatory blood flow were closely correlated with the reductions of bulbar conjunctival microcirculatory blood flow (PVD: r = 0.87, P < 0.05; MFI: r = 0.92, P < 0.05). Myocardial function was significantly impaired in all animals after resuscitation when compared with baseline values (P < 0.05). The impairments of both sublingual and bulbar conjunctival microcirculation were

  19. Sublingual injection of microparticles containing glycolipid ligands for NKT cells and subunit vaccines induces antibody responses in oral cavity

    PubMed Central

    DeLyria, Elizabeth S; Zhou, Dapeng; Lee, Jun Soo; Singh, Shailbala; Song, Wei; Li, Fenge; Sun, Qing; Lu, Hongzhou; Wu, Jinhui; Qiao, Qian; Hu, Yiqiao; Zhang, Guodong; Li, Chun; Sastry, K. Jagannadha; Shen, Haifa

    2014-01-01

    Natural Killer T (NKT) cells are a unique type of innate immune cells which exert paradoxical roles in animal models through producing either Th1 or Th2 cytokines and activating dendritic cells. Alpha-galactosylceramide (αGalCer), a synthetic antigen for NKT cells, was found to be safe and immune stimulatory in cancer and hepatitis patients. We recently developed microparticle-formulated αGalCer, which is selectively presented by dendritic cells and macrophages, but not B cells, and thus can avoid the anergy of NKT cells. In this study, we have examined the immunogenicity of microparticles containing αGalCer and protein vaccine components through sublingual injection in mice. The results showed that sublingual injection of microparticles containing αGalCer and ovalbumin triggered IgG responses in serum (titer >1:100,000), which persisted for more than 3 months. Microparticles containing ovalbumin alone also induced comparable level of IgG responses. However, immunoglobulin subclass analysis showed that sublingually injected microparticles containing αGalCer and ovalbumin induced 20 fold higher Th1 biased antibody (IgG2c) than microparticles containing OVA alone (1:20,000 as compared to 1:1000 titer). Sublingual injection of microparticles containing αGalCer and ovalbumin induced secretion of both IgG (titer >1:1000) and IgA (titer =1:80) in saliva secretion, while microparticles containing ovalbumin alone only induced secretion of IgG in saliva. Our results suggest that sublingual injection of microparticles and their subsequent trafficking to draining lymph nodes may induce adaptive immune responses in mucosal compartments. Ongoing studies are focused on the mechanism of antigen presentation and lymphocyte biology in the oral cavity, as well as the toxicity and efficacy of these candidate microparticles for future applications. PMID:25555750

  20. Sublingual injection of microparticles containing glycolipid ligands for NKT cells and subunit vaccines induces antibody responses in oral cavity.

    PubMed

    DeLyria, Elizabeth S; Zhou, Dapeng; Lee, Jun Soo; Singh, Shailbala; Song, Wei; Li, Fenge; Sun, Qing; Lu, Hongzhou; Wu, Jinhui; Qiao, Qian; Hu, Yiqiao; Zhang, Guodong; Li, Chun; Sastry, K Jagannadha; Shen, Haifa

    2015-03-20

    Natural Killer T (NKT) cells are a unique type of innate immune cells which exert paradoxical roles in animal models through producing either Th1 or Th2 cytokines and activating dendritic cells. Alpha-galactosylceramide (αGalCer), a synthetic antigen for NKT cells, was found to be safe and immune stimulatory in cancer and hepatitis patients. We recently developed microparticle-formulated αGalCer, which is selectively presented by dendritic cells and macrophages, but not B cells, and thus can avoid the anergy of NKT cells. In this study, we have examined the immunogenicity of microparticles containing αGalCer and protein vaccine components through sublingual injection in mice. The results showed that sublingual injection of microparticles containing αGalCer and ovalbumin triggered IgG responses in serum (titer >1:100,000), which persisted for more than 3months. Microparticles containing ovalbumin alone also induced comparable level of IgG responses. However, immunoglobulin subclass analysis showed that sublingually injected microparticles containing αGalCer and ovalbumin induced 20 fold higher Th1 biased antibody (IgG2c) than microparticles containing OVA alone (1:20,000 as compared to 1:1000 titer). Sublingual injection of microparticles containing αGalCer and ovalbumin induced secretion of both IgG (titer >1:1000) and IgA (titer=1:80) in saliva secretion, while microparticles containing ovalbumin alone only induced secretion of IgG in saliva. Our results suggest that sublingual injection of microparticles and their subsequent trafficking to draining lymph nodes may induce adaptive immune responses in mucosal compartments. Ongoing studies are focused on the mechanism of antigen presentation and lymphocyte biology in the oral cavity, as well as the toxicity and efficacy of these candidate microparticles for future applications.

  1. Biomarkers for glioma immunotherapy: the next generation

    PubMed Central

    Ung, Timothy H.; Neira, Justin A.; Canoll, Peter; Bruce, Jeffrey N.

    2015-01-01

    The term “biomarker” historically refers to a single parameter, such as the expression level of a gene or a radiographic pattern, used to indicate a broader biological state. Molecular indicators have been applied to several aspects of cancer therapy: to describe the genotypic and phenotypic state of neoplastic tissue for prognosis, to predict susceptibility to anti-proliferative agents, to validate the presence of specific drug targets, and to evaluate responsiveness to therapy. For glioblastoma (GBM), immunohistochemical and radiographic biomarkers accessible to the clinical lab have informed traditional regimens, but while immunotherapies have emerged as potentially disruptive weapons against this diffusely infiltrating, heterogeneous tumor, biomarkers with strong predictive power have not been fully established. The cancer immunotherapy field, through the recently accelerated expansion of trials, is currently leveraging this wealth of clinical and biological data to define and revise the use of biomarkers for improving prognostic accuracy, personalization of therapy, and evaluation of responses across the wide variety of tumors. Technological advancements in DNA sequencing, cytometry, and microscopy have facilitated the exploration of more integrated, high-dimensional profiling of the disease system—incorporating both immune and tumor parameters—rather than single metrics, as biomarkers for therapeutic sensitivity. Here we discuss the utility of traditional GBM biomarkers in immunotherapy and how the impending transformation of the biomarker paradigm—from single markers to integrated profiles—may offer the key to bringing predictive, personalized immunotherapy to GBM patients. PMID:25724916

  2. Targeting dendritic cells in allergen immunotherapy.

    PubMed

    Novak, Natalija

    2006-05-01

    Allergen immunotherapy is a well-established strategy for treating allergic diseases with the goal of inducing allergen-specific tolerance. Identified mechanisms contributing to the therapeutic effect of immunotherapy include a shift of T helper 2 (Th2)-type immune responses to a modified Th2 immune response, a change of the balance of IgE-producing B cells to the production of IgG subtypes, in addition to increased IL-10 and TGF-beta secretion and activation of the suppressive functions of regulatory T-cells. Dendritic cells (DCs), which as outposts of the immune system are capable of T-cell priming through efficient allergen uptake by IgE receptors expressed on their cell surface. Most of the hypotheses concerning the function of DCs as facilitators of allergen-specific tolerance in allergen immunotherapy remain speculative. Therefore, studies must focus on the functional changes of DCs under immunotherapy to close the gap of knowledge about their exact role. These experimental data should help confirm the hypothesis of DCs as efficient silencers and potential target cells and take advantage of the bivalent character and tolerogenic properties of DCs. PMID:16701146

  3. Role of IL-2 in cancer immunotherapy.

    PubMed

    Jiang, Tao; Zhou, Caicun; Ren, Shengxiang

    2016-06-01

    Interleukin-2 (IL-2) is one of the key cytokines with pleiotropic effects on immune system. It has been approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Recent progress has been made in our understanding of IL-2 in regulating lymphocytes that has led to exciting new directions for cancer immunotherapy. While improved IL-2 formulations might be used as monotherapies, their combination with other anticancer immunotherapies, such as adoptive cell transfer regimens, antigen-specific vaccination, and blockade of immune checkpoint inhibitory molecules, for example cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) mono-antibodies, would held the promise of treating metastatic cancer. Despite the comprehensive studies of IL-2 on immune system have established the application of IL-2 for cancer immunotherapy, a number of poignant obstacles remain for future research. In the present review, we will focus on the key biological features of IL-2, current applications, limitations, and future directions of IL-2 in cancer immunotherapy.

  4. Current progress in immunotherapy for pancreatic cancer.

    PubMed

    Foley, Kelly; Kim, Victoria; Jaffee, Elizabeth; Zheng, Lei

    2016-10-10

    Pancreatic cancer remains one of the most lethal cancers with few treatment options. Immune-based strategies to treat pancreatic cancer, such as immune checkpoint inhibitors, therapeutic vaccines, and combination immunotherapies, are showing promise where other approaches have failed. Immune checkpoint inhibitors, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies, are effective as single agents in immune sensitive cancers like melanoma, but lack efficacy in immune insensitive cancers including pancreatic cancer. However, these inhibitors are showing clinical activity, even in traditionally non-immunogenic cancers, when combined with other interventions, including chemotherapy, radiation therapy, and therapeutic vaccines. Therapeutic vaccines given together with immune modulating agents are of particular interest because vaccines are the most efficient way to induce effective anti-tumor T cell responses, which is required for immunotherapies to be effective. In pancreatic cancer, early studies suggest that vaccines can induce T cells that have the potential to recognize and kill pancreatic cancer cells, but the tumor microenvironment inhibits effective T cell trafficking and function. While progress has been made in the development of immunotherapies for pancreatic cancer over the last several years, additional trials are needed to better understand the signals within the tumor microenvironment that are formidable barriers to T cell infiltration and function. Additionally, as more pancreatic specific antigens are identified, immunotherapies will continue to be refined to provide the most significant clinical benefit.

  5. Targeted immunotherapy for pediatric solid tumors

    PubMed Central

    Kopp, Lisa M.; Katsanis, Emmanuel

    2016-01-01

    ABSTRACT Metastatic and refractory pediatric solid tumor malignancies continue to have a poor outcome despite the > 80% cure rates appreciated in many pediatric cancers. Targeted immunotherapy is impacting treatment and survival in these aggressive tumors. We review current promising immunotherapeutic approaches in the pediatric oncology solid tumor setting. PMID:27141344

  6. Bioinformatics for cancer immunology and immunotherapy.

    PubMed

    Charoentong, Pornpimol; Angelova, Mihaela; Efremova, Mirjana; Gallasch, Ralf; Hackl, Hubert; Galon, Jerome; Trajanoski, Zlatko

    2012-11-01

    Recent mechanistic insights obtained from preclinical studies and the approval of the first immunotherapies has motivated increasing number of academic investigators and pharmaceutical/biotech companies to further elucidate the role of immunity in tumor pathogenesis and to reconsider the role of immunotherapy. Additionally, technological advances (e.g., next-generation sequencing) are providing unprecedented opportunities to draw a comprehensive picture of the tumor genomics landscape and ultimately enable individualized treatment. However, the increasing complexity of the generated data and the plethora of bioinformatics methods and tools pose considerable challenges to both tumor immunologists and clinical oncologists. In this review, we describe current concepts and future challenges for the management and analysis of data for cancer immunology and immunotherapy. We first highlight publicly available databases with specific focus on cancer immunology including databases for somatic mutations and epitope databases. We then give an overview of the bioinformatics methods for the analysis of next-generation sequencing data (whole-genome and exome sequencing), epitope prediction tools as well as methods for integrative data analysis and network modeling. Mathematical models are powerful tools that can predict and explain important patterns in the genetic and clinical progression of cancer. Therefore, a survey of mathematical models for tumor evolution and tumor-immune cell interaction is included. Finally, we discuss future challenges for individualized immunotherapy and suggest how a combined computational/experimental approaches can lead to new insights into the molecular mechanisms of cancer, improved diagnosis, and prognosis of the disease and pinpoint novel therapeutic targets.

  7. Immunity to TB and targets for immunotherapy.

    PubMed

    Gonzalez-Juarrero, Mercedes

    2012-02-01

    For centuries the treatment of TB has presented an enormous challenge to global health. In the 20th century, the treatment of TB patients with long-term multidrug therapy gave hope that TB could be controlled and cured; however, contrary to these expectations and coinciding with the emergence of AIDS, the world has witnessed a rampant increase in hard-to-treat cases of TB, along with the emergence of highly virulent and multidrug-resistant Mycobacterium tuberculosis strains. Unfortunately, these bacteria are now circulating around the world, and there are few effective drugs to treat them. As a result, the prospects for improved treatment and control of TB in the 21st century have worsened and we urgently need to identify new therapies that deal with this problem. The potential use of immunotherapy for TB is now of greater consideration than ever before, as immunotherapy could potentially overcome the problem of drug resistance. TB immunotherapy targets the already existing host anti-TB immune response and aims to enhance killing of the bacilli. For this purpose, several approaches have been used: the use of anti-Mycobacteria antibodies; enhancing the Th1 protective responses by using mycobacterial antigens or increasing Th1 cytokines; interfering with the inflammatory process and targeting of immunosuppressive pathways and targeting the cell activation/proliferation pathways. This article reviews our current understanding of TB immunity and targets for immunotherapy that could be used in combination with current TB chemotherapy.

  8. Nitroglycerin Sublingual

    MedlinePlus

    ... Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for ...

  9. Emerging Opportunities and Challenges in Cancer Immunotherapy.

    PubMed

    Whiteside, Theresa L; Demaria, Sandra; Rodriguez-Ruiz, Maria E; Zarour, Hassane M; Melero, Ignacio

    2016-04-15

    Immunotherapy strategies against cancer are emerging as powerful weapons for treatment of this disease. The success of checkpoint inhibitors against metastatic melanoma and adoptive T-cell therapy with chimeric antigen receptor T cells against B-cell-derived leukemias and lymphomas are only two examples of developments that are changing the paradigms of clinical cancer management. These changes are a result of many years of intense research into complex and interrelated cellular and molecular mechanisms controling immune responses. Promising advances come from the discovery of cancer mutation-encoded neoantigens, improvements in vaccine development, progress in delivery of cellular therapies, and impressive achievements in biotechnology. As a result, radical transformation of cancer treatment is taking place in which conventional cancer treatments are being integrated with immunotherapeutic agents. Many clinical trials are in progress testing potential synergistic effects of treatments combining immunotherapy with other therapies. Much remains to be learned about the selection, delivery, and off-target effects of immunotherapy used alone or in combination. The existence of numerous escape mechanisms from the host immune system that human tumors have evolved still is a barrier to success. Efforts to understand the rules of immune cell dysfunction and of cancer-associated local and systemic immune suppression are providing new insights and fuel the enthusiasm for new therapeutic strategies. In the future, it might be possible to tailor immune therapy for each cancer patient. The use of new immune biomarkers and the ability to assess responses to therapy by noninvasive monitoring promise to improve early cancer diagnosis and prognosis. Personalized immunotherapy based on individual genetic, molecular, and immune profiling is a potentially achievable future goal. The current excitement for immunotherapy is justified in view of many existing opportunities for harnessing

  10. Amyloid beta peptide immunotherapy in Alzheimer disease.

    PubMed

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation.

  11. [The impact of periodontal disease treatment on endothelium of sublingual microvessels].

    PubMed

    Grudyanov, A I; Tkacheva, O N; Khatagov, A T; Mustafina, F N; Gorshkov, A Yu

    2016-01-01

    The intactness degree of glycocalyx and the thickness of endothelium layer in sublingual microvessels was determined by means of darkfield microscopy and GlycoCheck RI software in 35 patients (19 men and 16 women, aged 35 to 65 years) with chronic generalized severe periodontitis before and after anti-inflammatory and surgical treatment. The patients were divided into two groups. The first group recieved only local anti-inflammatory therapy while patients of group 2 underwent surgical intervention on the periodontium in addition to local anti-inflammatory therapy. In both groups the changes of parameters of endothelial glycocalyx (EGC) in the early stages of treatment were not significant. In long terms the changes were not revealed in group 1, but in group 2 6 months after surgical treatment in all patients the decrease in the thickness of the permeable glycocalyx decreased and increase of the volume of red blood cells filling was observed. PMID:27636753

  12. [The impact of periodontal disease treatment on endothelium of sublingual microvessels].

    PubMed

    Grudyanov, A I; Tkacheva, O N; Khatagov, A T; Mustafina, F N; Gorshkov, A Yu

    2016-01-01

    The intactness degree of glycocalyx and the thickness of endothelium layer in sublingual microvessels was determined by means of darkfield microscopy and GlycoCheck RI software in 35 patients (19 men and 16 women, aged 35 to 65 years) with chronic generalized severe periodontitis before and after anti-inflammatory and surgical treatment. The patients were divided into two groups. The first group recieved only local anti-inflammatory therapy while patients of group 2 underwent surgical intervention on the periodontium in addition to local anti-inflammatory therapy. In both groups the changes of parameters of endothelial glycocalyx (EGC) in the early stages of treatment were not significant. In long terms the changes were not revealed in group 1, but in group 2 6 months after surgical treatment in all patients the decrease in the thickness of the permeable glycocalyx decreased and increase of the volume of red blood cells filling was observed.

  13. Accidental Displacement of Third Molar into the Sublingual Space: a Case Report

    PubMed Central

    Garcia, Robson Rodrigues; Botelho, Tessa Lucena; Franco, Ademir; Silva, Rhonan Ferreira

    2014-01-01

    ABSTRACT Background Successful extraction of third molars depends on preoperative diagnosis and planning. Gold standard preoperative examinations are performed through computed tomography, decreasing risks and avoiding potential accidents. The present report highlights the value of preoperative examinations in face of accidentally displaced third molars. Methods An 18-years-old female patient underwent a third mandibular molar extraction with a general dentist. Accidentally, the mandibular left third molar was displaced into the sublingual space, making necessary a second surgical step. The surgery was interrupted and the patient was referred to an expert in maxillofacial surgery. Results After 21 days awaiting an asymptomatic health status, the second surgical step was successfully performed using multislice computed tomography as preoperative imaging guide. Conclusions The present case report highlights the clinical usefulness of imaging planning and informed consents in face of legal and ethic potential complaints. PMID:25386232

  14. Rizatriptan wafer--sublingual vs. placebo at the onset of acute migraine.

    PubMed

    Klapper, J A; O'Connor, S

    2000-07-01

    Rizatriptan wafer is a 5HT1B/1D agonist for use in the acute treatment of migraine. It is a freeze-fried formulation, approved for oral administration, which dissolves on the tongue and is swallowed with saliva. In this study the efficacy of sublingually administered rizatriptan 10-mg wafer was evaluated in a randomized, double-blind, placebo-controlled, out-patient study involving 39 migraineurs. Patients were instructed to treat a migraine at the onset of pain in order to evaluate time of onset of pain relief and pain relief at 1 h. The average time to onset of relief was 25 min for patients treated with rizatriptan wafer and 27 min for patients treated with placebo. At 1 h, 50% of the patients receiving rizatriptan wafer and 50% of the patients receiving placebo experienced significant relief. Implications and potential reasons for a high placebo response are discussed.

  15. A new preparation of nifedipine for sublingual application in hypertensive urgencies.

    PubMed

    Kürkciyan, I; Sterz, F; Roden, M; Heinz, G; Hirschl, M M; Müllner, M; Laggner, A N

    1994-07-01

    A new preparation of nifedipine for sublingual application in hypertensive urgencies was investigated in a prospective study. Patients admitted to the Emergency Department with a persistent elevation of systolic blood pressure (SBP) greater than 190 mmHg and/or a diastolic blood pressure (DBP) greater than 100 mmHg received nifedipine 10 mg sublingual with a sprayer. A second dose was administrated fifteen minutes later if an adequate response defined as a stable reduction of SBP below 180 mmHg and DBP below 100 mmHg had not occurred. Of 30 patients, 21 (70%) responded to the first nifedipine application, 7 responded to the second dose, and 2 nonresponders had to be treated with urapidil. Overall mean SBP was 206 +/- 19 mmHg and mean DBP was 113 +/- 15 mmHg before treatment, and a significant antihypertensive effect was noted within fifteen minutes after nifedipine spray (p < 0.05). The maximum antihypertensive effect was for SBP in sixty minutes (146 +/- 19 mmHg) and for DBP after one hundred twenty minutes (78 +/- 18 mmHg). The average reduction in SBP was 29% and in DBP 31%. In first-dose responders (n = 21) a significant antihypertensive effect was noted within fifteen minutes. SBP declined from 205 +/- 21 to a minimum of 142 +/- 15 mmHg (22.3%) after sixty minutes and DBP from 113 +/- 13 to a minimum of 77 +/- 11 mmHg (22.2%) after one hundred twenty minutes. In second-dose responders (n = 7) a significant antihypertensive effect was noted within thirty minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections

    PubMed Central

    Lorenzo-Gómez, María F.; Padilla-Fernández, Bárbara; García-Cenador, María B.; Virseda-Rodríguez, Álvaro J.; Martín-García, Isidoro; Sánchez-Escudero, Alfonso; Vicente-Arroyo, Manuel J.; Mirón-Canelo, José A.

    2015-01-01

    Objective: To compare the clinical impact of a prophylactic treatment with sublingual immunostimulation in the prevention of recurrent urinary tract infections (rUTIs) with the use of antibiotics. Material and Methods: Retrospective cohort study evaluating the medical records of 669 women with rUTIs; 339 had a 6-month prophylaxis with antibiotics and 360 a 3-month prophylaxis with a sublingual bacterial preparation (MV 140-Uromune®). The time frame after the prophylaxis-period until the appearance of a new infection (assessed by uroculture) was scored and followed during 1 year. The absolute risk reduction (ARR) and number needed to treat (NNT) were also calculated. Results: All patients treated with antibiotics experienced a new UTI during the scoring period of 12 months, being 19 days the median number of days free of UTIs (range 5–300). In the group treated with the bacterial preparation, 35 (9.7%) patients experienced an UTI in the same period. Kaplan-Meier curves comparing the accumulated survival (disease-free time) between both groups were significant different (P < 0.0001). The absolute risk reduction (ARR) was 90.28% (87.18–93.38) and the number needed to treat (NNT) 1.1 (1.1–1.1). Conclusions: These results suggest that the treatment with this bacterial preparation significantly reduces the incidence of rUTIs, arising as an effective strategy to reduce the frequency of rUTIs. It reduces antibiotic consumption, matching the current recommendations due to the raise of antimicrobial resistance. Randomized, double-blind and placebo-controlled, clinical trials are needed to establish, more accurately, the clinical impact of this bacterial preparation in patients with rUTIs. PMID:26090341

  17. Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

    PubMed Central

    2012-01-01

    Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace

  18. A randomized trial of immunotherapy for persistent genital warts

    PubMed Central

    Jardine, David; Lu, Jieqiang; Pang, James; Palmer, Cheryn; Tu, Quanmei; Chuah, John; Frazer, Ian H.

    2012-01-01

    Aim To determine whether immunotherapy with HPV6 L1 virus like particles (VLPs) without adjuvant (VLP immunotherapy) reduces recurrence of genital warts following destructive therapy. Trial design A randomized placebo controlled blinded study of treatment of recurrent genital warts amenable to destructive therapy, conducted independently in Australia and China. Methods Patients received conventional destructive therapy of all evident warts together with intramuscular administration of 1, 5 or 25 µg of VLP immunotherapy, or of placebo immunotherapy (0.9% NaCl), as immunotherapy at week 0 and week 4. Primary outcome, assessed at week 8, was recurrence of visible warts. Results Of 33 protocol compliant Brisbane recipients of placebo immunotherapy, 11 were disease free at two months, and a further 9 demonstrated reduction of > 50% in total wart area. Wart area reduction following destructive treatment correlated with prior duration of disease. Among 102 protocol compliant Brisbane recipients of VLP immunotherapy, disease reduction was significantly greater than among the placebo immunotherapy (50% ± s.e.m. 7%) recipients for subjects receiving 5 µg or 25 µg of VLP immunotherapy/dose (71% ± s.e.m.7%) but not for those receiving 1 µg VLP immunotherapy/dose (42% ± 7%). Of 52 protocol compliant placebo immunotherapy recipients in Wenzhou, 37 were disease free at two months, and a further 8 had > 50% disease reduction. Prior disease duration was much shorter in Wenzhou subject (8.1 ± 1.1 mo) than in Brisbane subjects (53.7 ± 5.5 mo). No significant reduction in mean wart area was observed for the 168 Wenzhou protocol compliant subjects who also received VLP immunotherapy. Conclusions This study confirms the findings in a previous open label trial that administration of VLP immunotherapy may assist in clearance of recurrent genital warts in patients for whom destructive therapy is unsuccessful and that unsuccessful destructive therapy is more common with increasing

  19. Prospects for immunotherapy and vaccines against Cryptosporidium

    PubMed Central

    Mead, Jan R

    2014-01-01

    Cryptosporidium spp is a ubiquitous parasite that has long been recognized as a frequent cause of protozoal diarrhea in humans. While infections in immunocompetent hosts are usually self-limiting, immunocompromised individuals can develop severe, chronic, and life-threatening illness. Vaccine development or immunotherapy that prevents disease or reduces the severity of infection is a relevant option since efficacious drug treatments are lacking. In particular, children in developing countries might benefit the most from a vaccine since cryptosporidiosis in early childhood has been reported to be associated with subsequent impairment in growth, physical fitness, and intellectual capacity. In this review, immunotherapies that have been used clinically are described as well as experimental vaccines and their evaluation in vivo. PMID:24638018

  20. [Transcutaneous applications for vaccination and immunotherapy].

    PubMed

    Krämer, Isabel; Zabel, Franziska; Kündig, Thomas M; Johansen, Pål

    2014-10-15

    Although Edward Jenner applied the first vaccines by scratching cow pox material into the skin, the profound immunological properties of the skin have become evident through research and discoveries only in the last 20 years. The immunological cells in the epidermis and the dermis are suitable targets for transcutaneous vaccination and immunotherapy. However, as the skin represents a natural barrier for topically administered large molecules, novel methods to overcome this barrier function have been described. There are chemical, biochemical and physical methods, many of which are pain-free and therefore especially suitable for children. Also for adults non-invasive methods of vaccination and immunotherapy are attractive as self-administration is feasible. Future products are currently undergoing clinical tests which provide promising results.

  1. Immunotherapy for neuroblastoma: turning promise into reality.

    PubMed

    Gray, Juliet C; Kohler, Janice A

    2009-12-01

    Neuroblastoma is one of the commonest and most aggressive paediatric malignancies. The majority of children present with metastatic disease for which long-term survival remains poor despite intensive multi-modal therapies. Toxicity from current treatment regimes is already significant, and there is little room to further intensify therapy. Alternative treatment strategies are therefore needed in order to improve survival. Immunotherapy is an attractive therapeutic option for these children as it potentially offers a much more specific and less toxic treatment than conventional therapies. This review discusses the different immunotherapy strategies that may be useful in neuroblastoma, their advantages and disadvantages and the challenges that need to be overcome to successfully use them clinically.

  2. RNA-Based Vaccines in Cancer Immunotherapy.

    PubMed

    McNamara, Megan A; Nair, Smita K; Holl, Eda K

    2015-01-01

    RNA vaccines traditionally consist of messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and template DNA that encodes the antigen(s) of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm and then the resulting antigens are presented to antigen presenting cells to stimulate an immune response. Alternatively, dendritic cells can be loaded with either tumor associated antigen mRNA or total tumor RNA and delivered to the host to elicit a specific immune response. In this review, we will explain why RNA vaccines represent an attractive platform for cancer immunotherapy, discuss modifications to RNA structure that have been developed to optimize mRNA vaccine stability and translational efficiency, and describe strategies for nonviral delivery of mRNA vaccines, highlighting key preclinical and clinical data related to cancer immunotherapy.

  3. Era of cancer immunotherapy has come.

    PubMed

    Nakatsura, Tetsuya

    2016-01-01

      The dramatic and long durable anti-tumor effect of immune checkpoint blockade, such as anti-CTLA-4 Ab, anti-PD-1 Ab, and anti-PD-L1 Ab was surprised the world. In addition, CAR-T cell therapy that target the CD19 indicates a very high response rate to the CD19-positive hematologic malignancies. Now, no one doubts the presence of immunity against cancer.  Further, accordingly, tumor-specific neoantigen are attention now, the clinical trials of individualized peptide vaccination that target patient individual neoantigens has begun in the Western. On the other hand, the peptide vaccine therapy that target common self-antigen is not yet been approved in Japan, the development is struggling.  In this paper, I overview the cancer immunotherapy and neoantigen and introduce some development of cancer immunotherapy in Japan.

  4. Development of PROSTVAC immunotherapy in prostate cancer

    PubMed Central

    Singh, Parminder; Pal, Sumanta K; Alex, Anitha; Agarwal, Neeraj

    2015-01-01

    PROSTVAC immunotherapy is a heterologous prime-boost regimen of two different recombinant pox-virus vectors; vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against prostate-specific antigen. Both vectors contain transgenes for prostate-specific antigen and a triad of T-cell costimulatory molecules (TRICOM). In a placebo-controlled Phase II trial of men with minimally symptomatic, chemotherapy-naive metastatic castration-resistant prostate cancer, PROSTVAC was well tolerated and associated with a 44% reduction in death. With a novel mechanism of action, and excellent tolerability, PROSTVAC has the potential to dramatically alter the treatment landscape of prostate cancer, not only as a monotherapy, but also in combination with other novel agents, such as immune check point inhibitors and novel androgen receptor blockers. A Phase III trial recently completed accrual. PMID:26235179

  5. RNA-Based Vaccines in Cancer Immunotherapy

    PubMed Central

    McNamara, Megan A.; Nair, Smita K.; Holl, Eda K.

    2015-01-01

    RNA vaccines traditionally consist of messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and template DNA that encodes the antigen(s) of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm and then the resulting antigens are presented to antigen presenting cells to stimulate an immune response. Alternatively, dendritic cells can be loaded with either tumor associated antigen mRNA or total tumor RNA and delivered to the host to elicit a specific immune response. In this review, we will explain why RNA vaccines represent an attractive platform for cancer immunotherapy, discuss modifications to RNA structure that have been developed to optimize mRNA vaccine stability and translational efficiency, and describe strategies for nonviral delivery of mRNA vaccines, highlighting key preclinical and clinical data related to cancer immunotherapy. PMID:26665011

  6. Evolving Immunotherapy Strategies in Urothelial Cancer

    PubMed Central

    Brancato, Sam J.; Lewi, Keidren; Agarwal, Piyush K.

    2016-01-01

    The treatment of nonmuscle-invasive urothelial carcinoma with bacillus Calmette-Guérin (BCG) represents the importance of immunotherapy in the treatment of cancer. Despite its clinical efficacy, up to 30% of patients will ultimately experience progression to muscle-invasive disease. This, along with an improved understanding of the biologic pathways involved, has led to efforts to improve, enhance, or alter the immune response in the treatment of urothelial carcinoma. A number of novel therapeutic approaches currently are being pursued, including recombinant BCG to induce T helper type 1 (Th1) immune responses, nonlive Mycobacterium agents, targeted agents toward cancer-associated antigens, immune-modulating vaccines, and adoptive T-cell therapies. Here, we review the current and future immunotherapy treatment options for patients with urothelial cancer. PMID:25993187

  7. Molecular biomarkers for grass pollen immunotherapy

    PubMed Central

    Popescu, Florin-Dan

    2014-01-01

    Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines. PMID:25237628

  8. Molecular biomarkers for grass pollen immunotherapy.

    PubMed

    Popescu, Florin-Dan

    2014-03-26

    Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines.

  9. [Transcutaneous applications for vaccination and immunotherapy].

    PubMed

    Krämer, Isabel; Zabel, Franziska; Kündig, Thomas M; Johansen, Pål

    2014-10-15

    Although Edward Jenner applied the first vaccines by scratching cow pox material into the skin, the profound immunological properties of the skin have become evident through research and discoveries only in the last 20 years. The immunological cells in the epidermis and the dermis are suitable targets for transcutaneous vaccination and immunotherapy. However, as the skin represents a natural barrier for topically administered large molecules, novel methods to overcome this barrier function have been described. There are chemical, biochemical and physical methods, many of which are pain-free and therefore especially suitable for children. Also for adults non-invasive methods of vaccination and immunotherapy are attractive as self-administration is feasible. Future products are currently undergoing clinical tests which provide promising results. PMID:25305116

  10. The sweet side of tumor immunotherapy.

    PubMed

    Freire, Teresa; Osinaga, Eduardo

    2012-07-01

    Carbohydrate signatures on tumor cells have functional implications in tumor growth and metastasis and constitute valuable tools in cancer diagnosis and immunotherapy. Increasing data regarding the mechanisms by which they are recognized by the immune system are facilitating the design of more efficient immunotherapeutic protocols based on cancer-associated glycan structures. Recent molecular and proteomic studies revealed that carbohydrates are recognized, not only by B cells and antibodies, but also by cells from the innate arm of immunity, as well as by T cells, and are able to induce specific T-cell immunity and cytotoxicity. In this review, we discuss and update the different strategies targeting tumor-associated carbohydrate antigens that are being evaluated for antitumor immunotherapy, an approach that will be highly relevant, especially when combined with other strategies, in the future fight against cancer.

  11. Dendritic cell-based immunotherapy in mesothelioma.

    PubMed

    Cornelissen, Robin; Lievense, Lysanne A; Heuvers, Marlies E; Maat, Alexander P; Hendriks, Rudi W; Hoogsteden, Henk C; Hegmans, Joost P; Aerts, Joachim G

    2012-10-01

    Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several studies have investigated immunotherapeutic strategies to improve the prognosis of patients with mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an update and provides a future perspective in which immunotherapy may improve the outcome of mesothelioma therapy.

  12. Immunotherapy for gastric premalignant lesions and cancer.

    PubMed

    Zorzetto, Valerio; Maddalo, Gemma; Basso, Daniela; Farinati, Fabio

    2012-06-01

    Chronic atrophic gastritis, a precancerous change for gastric cancer, shows a loss of appropriate glands, Helicobacter pylori infection and autoimmune gastritis being the two main etiologic factors. While H. pylori eradication is the mandatory treatment for the former, no etiologic treatment is available for the latter, in which a Th1-type response, modulated by Tregs and Th17 cells, is involved. H. pylori-related atrophic gastritis is a risk factor for gastric adenocarcinoma, while autoimmune atrophic gastritis is also linked to a substantial risk of gastric type I carcinoid, related to the chronic stimulus exerted by hypergastrinemia on enterochromaffin-like cells. Several studies have been published on gastric cancer treatment through an active specific immunotherapy, aimed at improving the immunoregulatory response and increasing the circulating tumor-specific T cells. No study on immunotherapy of carcinoids is available but, in our experience, the administration of an antigastrin 17 vaccine induced carcinoid regression in two out of three patients treated.

  13. Prospects for immunotherapy and vaccines against Cryptosporidium.

    PubMed

    Mead, Jan R

    2014-01-01

    Cryptosporidium spp is a ubiquitous parasite that has long been recognized as a frequent cause of protozoal diarrhea in humans. While infections in immunocompetent hosts are usually self-limiting, immunocompromised individuals can develop severe, chronic, and life-threatening illness. Vaccine development or immunotherapy that prevents disease or reduces the severity of infection is a relevant option since efficacious drug treatments are lacking. In particular, children in developing countries might benefit the most from a vaccine since cryptosporidiosis in early childhood has been reported to be associated with subsequent impairment in growth, physical fitness, and intellectual capacity. In this review, immunotherapies that have been used clinically are described as well as experimental vaccines and their evaluation in vivo.

  14. Cancer Immunotherapy for Gliomas: Overview and Future Directions

    PubMed Central

    HASHIMOTO, Naoya

    2016-01-01

    Immunotherapy has been highlighted because we have obtained much evidence, which includes theoretical backborn as well as favorable results from clinical trials. As immunotherapy gives an apparently different cytotoxic mechanism and a little adverse event, the promising results are getting a lot of attention. In this article, cancer immunotherapy for gliomas is reviewed thoroughly from the literature, focusing on the clinical trial results. PMID:27087194

  15. Treatment of peanut allergy with rush immunotherapy.

    PubMed

    Oppenheimer, J J; Nelson, H S; Bock, S A; Christensen, F; Leung, D Y

    1992-08-01

    Peanut and peanut products are a common food in the diet. Peanuts are also one of the most common foods responsible for food-induced anaphylaxis. Patients rarely lose sensitivity to peanuts. Although the ideal treatment is avoidance, this is often not possible because of hidden exposures; therefore, a more effective treatment is needed. Subjects with confirmed peanut allergy were treated in a double-blind, placebo-controlled study with peanut immunotherapy or placebo. Objective measures of efficacy included changes in symptom score during double-blind placebo-controlled peanut challenge (DBPCPC) and titrated end point prick skin tests (PST). Three subjects treated with peanut immunotherapy completed the study. These subjects displayed a 67% to 100% decrease in symptoms induced by DBPCPC. Subjects also had a 2- to 5-log reduction in end point PST reactivity to peanut extract. One placebo-treated subject completed the study. This subject had essentially no change in DBPCPC symptom scores or PST sensitivity to peanut. Two other placebo-treated subjects underwent a second PST session. These subjects had a 1- to 2-log increase in skin test sensitivity to peanut. All peanut-treated subjects were able to reach maintenance dose, and in no case did an anaphylactic reaction occur secondary to the peanut immunotherapy. The current study provides preliminary data demonstrating the efficacy of injection therapy with peanut extract and provides a future line of clinical investigation for the treatment of this potentially lethal disease. It should be noted, however, that the rate of systemic reactions with rush immunotherapy was 13.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Immunotherapy of neuroblastoma: present, past and future.

    PubMed

    Raffaghello, Lizzia; Pistoia, Vito

    2006-04-01

    Neuroblastoma is a neuroectodermal tumor of childhood with poor prognosis and low survival in patients with advanced-stage disease who respond to conventional therapies but unfortunately, often present relapse. Therefore, the search for novel therapeutic strategies is warranted and represents the objective of many investigators. Among the new, innovative approaches, immunotherapy has attracted much interest. However, until recently, little information was available about the immunogenicity of human neuroblastoma.

  17. ATMPs for Cancer Immunotherapy: A Regulatory Overview.

    PubMed

    Galli, Maria Cristina

    2016-01-01

    This chapter discusses European regulatory requirements for development of advanced therapy medicinal products (ATMP) for cancer immunotherapy approaches, describing the framework for clinical trials and for marketing authorization.Regulatory critical issues and challenges for developing ATMP are also discussed, with focus on potency determination, long-term follow-up, comparability, and insertional mutagenesis issues. Some of the most critical features of GMP application to ATMP are also described.

  18. Soy polysaccharide as a novel superdisintegrant in sildenafil citrate sublingual tablets: preparation, characterization, and in vivo evaluation

    PubMed Central

    Hosny, Khaled Mohamed; Mosli, Hisham Ahmed; Hassan, Ali Habiballah

    2015-01-01

    Sildenafil citrate (SC), a drug used to treat erectile dysfunction, is available in tablet form but has three major problems. First, the drug displays inadequate aqueous solubility, which delays the onset of its action. Second, the drug undergoes extensive first-pass metabolism, resulting in a low (40%) bioavailability. Third, the gastrointestinal effects of SC include dyspepsia and a burning sensation. The aim of this research was to prepare SC as a sublingual tablet utilizing soy polysaccharide as novel superdisintegrant to mitigate the abovementioned problems. The solubility of SC in various hydrophilic carrier solutions was estimated in order to prepare the drug as a coprecipitate. Sublingual tablets were prepared and evaluated for hardness, friability, drug content, wetting time, water absorption ratio, in vitro dispersion time, dissolution rate, and stability study. The pharmacokinetic study of the tablets was carried out on healthy volunteers. The results indicated that the co-precipitation of SC with polyvinylpyrollidone K30 enhanced the solubility of SC by more than eight folds. The tablet contained 8% soy polysaccharide as a superdisintegrant and provided a wetting time of 25 seconds, and in vitro dispersion times of 55 seconds. The drug release was found to be 95.6%. The prepared SC sublingual tablet also exhibited a rapid onset of action, and its bioavailability was enhanced 1.68-fold compared with that of the marketed tablets. It can be concluded that SC sublingual tablet is a promising formulation that results in higher solubility, faster dispersion and onset of action, higher release rate, and higher systemic bioavailability. PMID:25624751

  19. Immunotherapy for lung cancer: advances and prospects.

    PubMed

    Yang, Li; Wang, Liping; Zhang, Yi

    2016-01-01

    Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer-related deaths worldwide. To date, surgery is the first choice treatment, but most clinically diagnosed cases are inoperable. While chemotherapy and/or radiotherapy are the next considered options for such cases, these treatment modalities have adverse effects and are sometimes lethal to patients. Thus, new effective strategies with minimal side effects are urgently needed. Cancer immunotherapy provides either active or passive immunity to target tumors. Multiple immunotherapy agents have been proposed and tested for potential therapeutic benefit against lung cancer, and some pose fewer side effects as compared to conventional chemotherapy and radiotherapy. In this article, we discuss studies focusing on interactions between lung cancer and the immune system, and we place an emphasis on outcome evidence in order to create a knowledge base well-grounded in clinical reality. Overall, this review highlights the need for new lung cancer treatment options, with much ground to be paved for future advances in the field. We believe that immunotherapy agents alone or with other forms of treatment can be recognized as next modality of lung cancer treatment. PMID:27168951

  20. Immunotherapy for lung cancer: advances and prospects

    PubMed Central

    Yang, Li; Wang, Liping; Zhang, Yi

    2016-01-01

    Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer-related deaths worldwide. To date, surgery is the first choice treatment, but most clinically diagnosed cases are inoperable. While chemotherapy and/or radiotherapy are the next considered options for such cases, these treatment modalities have adverse effects and are sometimes lethal to patients. Thus, new effective strategies with minimal side effects are urgently needed. Cancer immunotherapy provides either active or passive immunity to target tumors. Multiple immunotherapy agents have been proposed and tested for potential therapeutic benefit against lung cancer, and some pose fewer side effects as compared to conventional chemotherapy and radiotherapy. In this article, we discuss studies focusing on interactions between lung cancer and the immune system, and we place an emphasis on outcome evidence in order to create a knowledge base well-grounded in clinical reality. Overall, this review highlights the need for new lung cancer treatment options, with much ground to be paved for future advances in the field. We believe that immunotherapy agents alone or with other forms of treatment can be recognized as next modality of lung cancer treatment. PMID:27168951

  1. Laser immunotherapy of canine and feline neoplasia

    NASA Astrophysics Data System (ADS)

    Woods, J. P.; Bartels, Kenneth E.; Davidson, Ellen B.; Ritchey, Jerry W.; Lehenbauer, Terry W.; Nordquist, Robert E.; Chen, Wei R.

    1998-07-01

    The major cause of treatment failure in human and veterinary cancer patients is tumor invasion and metastasis. The inability of local therapy (surgery, radiation, photodynamic therapy) to eradicate a metastatic cancer presents a challenge in the therapy of residual or micrometastatic disease. Because of its local therapy limitations, chromophore-enhanced selective photothermal laser treatment has been augmented with a superimposed laser-induced systemic photobiological reaction, laser immunotherapy. Laser immunotherapy is a novel cancer treatment consisting of: (1) a laser in the infrared wavelength range (i.e. 805 nm solid state laser); (2) a photosensitizer of the corresponding absorption peak [i.e. indocyanine green (ICG)]; and (3) an immunoadjuvant [i.e. glycated chitosan gel (GCG)]. The intratumor injection of the photosensitizer (ICG) and immunoadjuvant (GCG) solution is followed by noninvasive laser irradiation. The laser energy causes tumor cell destruction by photothermal interaction to reduce the tumor burden and at the same time exposes tumor antigens. The immunoadjuvant concomitantly stimulates the host to mount a systemic anti-tumor immune response against the remaining cells of the tumor and to induce a long-term, tumor-specific immunity. This study investigates the feasibility of utilizing laser immunotherapy as an adjunctive therapy for the control of feline fibrosarcoma in future.

  2. Immunotherapy with the storage mite lepidoglyphus destructor.

    PubMed

    Armentia-Medina, A; Tapias, J A; Martín, J F; Ventas, P; Fernández, A

    1995-01-01

    We carried out a double-blind clinical trial of immunotherapy on 35 patients sensitized to the storage mite Lepidoglyphus destructor (Ld). Before and after 12 months of specific hyposensitization (Abelló Lab., Spain) we performed in vivo (skin tests with Ld, methacholine and challenge tests), and in vitro tests (specific IgE, IgG, IgG1 and IgG4 to Ld and specific IgE, IgG, IgG1 and IgG4 to their major allergen Lep dI). We also monitored the efficacy and safety of the immunotherapy with clinical and analytical controls (symptoms and medication score, detection of immune complexes). After therapy we found a significant decrease in specific skin reactivity, dose of positive challenge tests, and hyperresponsiveness to methacholine. Sputum eosinophilia decreased. Specific IgE to Ld was increased and we also observed an increase in specific IgG1 and IgG4 to Ld and Lep DI. The placebo group showed no changes in these variables. There were no severe secondary reactions after treatment with the extract. Patients-self-evaluation was favourable and their labour absence decreased. No development of circulating immune complexes was associated with this immunotherapy. PMID:8526179

  3. Oral immunotherapy in birch pollen hay fever.

    PubMed

    Taudorf, E; Laursen, L C; Lanner, A; Björksten, B; Dreborg, S; Søborg, M; Weeke, B

    1987-08-01

    Previous controlled trials with oral administration of allergen have not demonstrated any treatment effect in patients with allergic rhinoconjunctivitis or asthma. In the present double-blind, placebo-controlled trial, we have tested the effect of oral immunotherapy in adult patients with birch pollinosis. Thirty-nine patients completed this 18-month study comprising two birch pollen seasons. The patients received enterosoluble capsules daily, and the actively treated patients reached a cumulated dose of 280 times 10(6) biologic units of birch pollen extract, which is about 200 times higher than the dose used in conventional subcutaneous immunotherapy. We found a significant decrease in eye symptom scores and conjunctival sensitivity to birch pollen, as determined by conjunctival provocation test, as well as a numerical but nonsignificant decrease in nasal symptom scores, nasal sensitivity as determined by nasal provocation test, and antiallergic medication. The treatment was safe, and only a few slight side effects were observed. We thus conclude that our study demonstrates a clinical effect of oral immunotherapy in birch pollinosis.

  4. Current Status and Perspective of Immunotherapy in Gastrointestinal Cancers

    PubMed Central

    Kim, Jung Hoon; Kim, Bum Jun; Kim, Hyeong Su; Kim, Jung Han

    2016-01-01

    Cancer immunotherapy is at dawn of the Renaissance after the Medieval Dark Ages. Recent advances of understanding tumor immunology and molecular drug development are leading us to the epoch of cancer immunotherapy. Some types of immunotherapy have shown to provide survival benefit for patients with solid tumors such as malignant melanoma, renal cell carcinoma, or non-small cell lung cancer. Several studies have suggested that immune checkpoint inhibition might be effective in some patients with gastrointestinal cancers. However, the era of cancer immunotherapy in gastrointestinal cancers is still in an inchoate stage. Here we briefly review the current status and perspective of immunotherapeutic approaches in patients with gastrointestinal cancers. PMID:27698896

  5. Current Status and Perspective of Immunotherapy in Gastrointestinal Cancers

    PubMed Central

    Kim, Jung Hoon; Kim, Bum Jun; Kim, Hyeong Su; Kim, Jung Han

    2016-01-01

    Cancer immunotherapy is at dawn of the Renaissance after the Medieval Dark Ages. Recent advances of understanding tumor immunology and molecular drug development are leading us to the epoch of cancer immunotherapy. Some types of immunotherapy have shown to provide survival benefit for patients with solid tumors such as malignant melanoma, renal cell carcinoma, or non-small cell lung cancer. Several studies have suggested that immune checkpoint inhibition might be effective in some patients with gastrointestinal cancers. However, the era of cancer immunotherapy in gastrointestinal cancers is still in an inchoate stage. Here we briefly review the current status and perspective of immunotherapeutic approaches in patients with gastrointestinal cancers.

  6. Allergen immunotherapy, routes of administration and cytokine networks: an update.

    PubMed

    Cuppari, Caterina; Leonardi, Salvatore; Manti, Sara; Filippelli, Martina; Alterio, Tommaso; Spicuzza, Lucia; Rigoli, Luciana; Arrigo, Teresa; Lougaris, Vassilios; Salpietro, Carmelo

    2014-01-01

    Allergen immunotherapy is a disease-modifying therapy, effective for the treatment of allergic rhinitis, allergic asthma, conjunctivitis or stinging insect allergy. Allergen immunotherapy involves the administration of increasing doses of allergens with the aim of ameliorating the allergic response. Although precise underlying mechanisms of the induction of immune tolerance remain unclear, immunotherapy has been associated with the induction of distinct subsets of Tregs that eventually lead to peripheral tolerance by inducing a deviation from Th2 to Th1 immune responses. This review focuses on the current knowledge of the mechanisms of immunotherapy in relationship to different routes of administration and also provides a unifying view.

  7. EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

    PubMed Central

    2012-01-01

    Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy. Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies. Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases. Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as

  8. EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy.

    PubMed

    Calderon, Moises A; Demoly, Pascal; Gerth van Wijk, Roy; Bousquet, Jean; Sheikh, Aziz; Frew, Anthony; Scadding, Glenis; Bachert, Claus; Malling, Hans J; Valenta, Rudolph; Bilo, Beatrice; Nieto, Antonio; Akdis, Cezmi; Just, Jocelyne; Vidal, Carmen; Varga, Eva M; Alvarez-Cuesta, Emilio; Bohle, Barbara; Bufe, Albrecht; Canonica, Walter G; Cardona, Victoria; Dahl, Ronald; Didier, Alain; Durham, Stephen R; Eng, Peter; Fernandez-Rivas, Montserrat; Jacobsen, Lars; Jutel, Marek; Kleine-Tebbe, Jörg; Klimek, Ludger; Lötvall, Jan; Moreno, Carmen; Mosges, Ralph; Muraro, Antonella; Niggemann, Bodo; Pajno, Giovanni; Passalacqua, Giovanni; Pfaar, Oliver; Rak, Sabina; Senna, Gianenrico; Senti, Gabriela; Valovirta, Erkka; van Hage, Marianne; Virchow, Johannes C; Wahn, Ulrich; Papadopoulos, Nikolaos

    2012-01-01

    Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a

  9. Confocal and electron microscopy to characterize sialoglycoconjugates in mouse sublingual gland acinar cells.

    PubMed

    Menghi, G; Bondi, A M; Marchetti, L; Ballarini, P; Materazzi, G

    1998-08-01

    Double lectin labeling for confocal microscopy and lectin-protein A-gold binding for electron microscopy were applied to the mouse sublingual gland in order to study surface and cytoplasmic sialoglycoconjugates. For this purpose, serially cut sections were submitted to sialidase followed by incubation with lectins recognizing usually acceptor sugars for terminal sialic acids. At the electron microscope level, the residues subtended to sialic acid were individually identified on adjacent sections by an indirect technique of labeling, whereas with confocal microscopy the above sugars were simultaneously visualized on the same section by a double staining method using fluorescein isothiocyanate (FITC)- and tetramethylrhodamine isothiocyanate (TRITC)-conjugated lectins. Acinar cells were found to contain the terminal sequence sialic acid-beta-galactose in abundance while the sequence sialic acid-alpha-N-acetylgalactosamine appeared to be present in modest amounts. Both sialoglycoconjugates were homogeneously codistributed inside acinar cells. The combination with a saponification method also allowed the occurrence of C4 acetylated sialic acids linked to beta-galactose to be discovered, at the electron microscope level, on acinar cell secretory products.

  10. Methylglycol chitosan and a synthetic TLR4 agonist enhance immune responses to influenza vaccine administered sublingually.

    PubMed

    Spinner, Justin L; Oberoi, Hardeep S; Yorgensen, Yvonne M; Poirier, Danielle S; Burkhart, David J; Plante, Martin; Evans, Jay T

    2015-10-26

    Influenza is a vaccine-preventable contagious respiratory illness caused by influenza (flu) viruses which can lead to hospitalization and sometimes even death. Current flu vaccines delivered intramuscularly (IM) or intradermally (ID) are less effective at eliciting protective mucosal immune responses and vaccines delivered intranasally (IN) possess potential safety concerns. Sublingual (SL) vaccination is a promising alternative route for vaccine delivery which has been indicated as safe and effective at inducing protective immune responses in both systemic and mucosal compartments. We evaluated the efficacy of methylglycol chitosan (MGC) and a synthetic toll-like receptor 4 agonist (CRX-601), alone or in combination, for improving systemic and mucosal immune responses to a monovalent detergent-split flu virus vaccine delivered SL. SL vaccination of mice with split-flu vaccine formulated with either MGC or CRX-601 resulted in specific serum IgG and mucosal IgA titers that were significantly greater than titers from non-adjuvanted vaccination and equivalent to or greater than titers in mice vaccinated IM. Our results demonstrate that SL vaccination utilizing MGC or CRX-601 as adjuvants is a viable alternative route of vaccination for flu which can elicit systemic immune responses equivalent to or greater than IM vaccination with the added benefit of stimulating a robust specific mucosal immune response.

  11. New developments in the management of opioid dependence: focus on sublingual buprenorphine–naloxone

    PubMed Central

    Soyka, Michael

    2015-01-01

    Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. Buprenorphine, a partial opioid agonist, has been found by numerous studies to be an effective and safe medication in the treatment of opioid dependence. At present, buprenorphine is available as a monodrug or in a fixed 4:1 ratio combination with naloxone. A diminished risk of diversion and abuse for the buprenorphine–naloxone combination is likely but not firmly established. Conventional formulations are given sublingually to avoid the hepatic first-pass effect. A novel film tablet is available only in the US and Australia. Other novel, sustained-release formulations (implant, depot) are currently being developed and tested. Recent studies, including a Cochrane meta-analysis, suggest that the retention with buprenorphine is lower than for methadone, but that buprenorphine may be associated with less drug use. Higher doses of buprenorphine are associated with better retention rates. Buprenorphine has a ceiling effect at the opioid receptor with regard to respiratory depression, and may cause fewer fatal intoxications than methadone. Possible antidepressant effects of buprenorphine and its use in comorbid psychiatric patients has not been studied in much detail. Clinical implications are discussed. PMID:25610012

  12. Fast-Acting Sublingual Zolpidem for Middle-of-the-Night Wakefulness

    PubMed Central

    Pergolizzi, Joseph V.; Taylor, Robert; Raffa, Robert B.; Chopra, Maninder

    2014-01-01

    Sleep disorders (somnipathies) are conditions characterized by disruptions of sleep quality or of sleep pattern. They can involve difficulty falling asleep (prolonged sleep onset latency), difficulty staying asleep (disturbance of sleep maintenance), sleep of poor quality (unrefreshing), or combinations of these and can lead to poor health and quality of life problems. A subtype of sleep-maintenance insomnia is middle-of-the-night wakefulness, a relatively common occurrence. Zolpidem, a nonbenzodiazepine benzodiazepine receptor agonist, allosterically modulates an ion channel and increases the influx of Cl−, thereby dampening the effect of excitatory (sleep disrupting) input. Recently, product label changes to some zolpidem containing products have been implemented by the FDA in order to reduce the risk associated with their morning after residual side effects. A new formulation of zolpidem tartrate (Intermezzo) sublingual tablet, an approved product indicated exclusively for the treatment of middle-of-the-night wakefulness and difficulty returning to sleep, did not have its label changed. We present a short summary of its basic science and clinical attributes in light of the recent regulatory changes for zolpidem products. PMID:24649369

  13. Low-dose, sublingual AZT-monophosphate therapy for HIV+ patients?

    PubMed

    Johnson, S

    2001-03-01

    AZT concentrations as low as 0.001 mg/l inhibit viral replication, while concentrations above 0.3 mg/l cause considerable damage to erythroid, myeloid progenitor cells and inhibit blastogenesis in mononuclear cells. Furthermore, AZT must be converted first to monophosphate and then to diphosphate and finally to triphosphate by the same enzyme: thymidine kinase (TK). Therefore, large doses of AZT overwhelm TK, causing massive production of monophosphate and reducing the production of di and triphosphate. Yet the recommended dosage of 100 mg AZT every 4 hours results in a peak concentration of 0.5 mg/l and a trough concentration of 0.1 mg/l (harmful to human cells and resulting in reduced production of triphosphate). On the other hand, sublingual administration of 1 mg AZT monophosphate every 8 hours (since the intracellular half life of AZT triphosphate is 3 hours) would be desirable, resulting in more damage to the virus and less harm to the patient. Finally, the small dose of monophosphate ensures that most of the AZT be converted to triphosphate, greatly increasing the efficiency and reducing the likelihood of the virus developing resistance due to reverse transcriptase binding to the similar but non inhibiting mono and diphosphate. PMID:11359372

  14. Methylglycol chitosan and a synthetic TLR4 agonist enhance immune responses to influenza vaccine administered sublingually.

    PubMed

    Spinner, Justin L; Oberoi, Hardeep S; Yorgensen, Yvonne M; Poirier, Danielle S; Burkhart, David J; Plante, Martin; Evans, Jay T

    2015-10-26

    Influenza is a vaccine-preventable contagious respiratory illness caused by influenza (flu) viruses which can lead to hospitalization and sometimes even death. Current flu vaccines delivered intramuscularly (IM) or intradermally (ID) are less effective at eliciting protective mucosal immune responses and vaccines delivered intranasally (IN) possess potential safety concerns. Sublingual (SL) vaccination is a promising alternative route for vaccine delivery which has been indicated as safe and effective at inducing protective immune responses in both systemic and mucosal compartments. We evaluated the efficacy of methylglycol chitosan (MGC) and a synthetic toll-like receptor 4 agonist (CRX-601), alone or in combination, for improving systemic and mucosal immune responses to a monovalent detergent-split flu virus vaccine delivered SL. SL vaccination of mice with split-flu vaccine formulated with either MGC or CRX-601 resulted in specific serum IgG and mucosal IgA titers that were significantly greater than titers from non-adjuvanted vaccination and equivalent to or greater than titers in mice vaccinated IM. Our results demonstrate that SL vaccination utilizing MGC or CRX-601 as adjuvants is a viable alternative route of vaccination for flu which can elicit systemic immune responses equivalent to or greater than IM vaccination with the added benefit of stimulating a robust specific mucosal immune response. PMID:26392012

  15. New developments in the management of opioid dependence: focus on sublingual buprenorphine-naloxone.

    PubMed

    Soyka, Michael

    2015-01-01

    Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. Buprenorphine, a partial opioid agonist, has been found by numerous studies to be an effective and safe medication in the treatment of opioid dependence. At present, buprenorphine is available as a monodrug or in a fixed 4:1 ratio combination with naloxone. A diminished risk of diversion and abuse for the buprenorphine-naloxone combination is likely but not firmly established. Conventional formulations are given sublingually to avoid the hepatic first-pass effect. A novel film tablet is available only in the US and Australia. Other novel, sustained-release formulations (implant, depot) are currently being developed and tested. Recent studies, including a Cochrane meta-analysis, suggest that the retention with buprenorphine is lower than for methadone, but that buprenorphine may be associated with less drug use. Higher doses of buprenorphine are associated with better retention rates. Buprenorphine has a ceiling effect at the opioid receptor with regard to respiratory depression, and may cause fewer fatal intoxications than methadone. Possible antidepressant effects of buprenorphine and its use in comorbid psychiatric patients has not been studied in much detail. Clinical implications are discussed. PMID:25610012

  16. The Proteomes of Human Parotid and Submandibular/Sublingual Gland Salivas Collected as the Ductal Secretions

    PubMed Central

    Denny, Paul; Hagen, Fred K.; Hardt, Markus; Liao, Lujian; Yan, Weihong; Arellanno, Martha; Bassilian, Sara; Bedi, Gurrinder S.; Boontheung, Pinmannee; Cociorva, Daniel; Delahunty, Claire M.; Denny, Trish; Dunsmore, Jason; Faull, Kym F.; Gilligan, Joyce; Gonzalez-Begne, Mireya; Halgand, Frédéric; Hall, Steven C.; Han, Xuemei; Henson, Bradley; Hewel, Johannes; Hu, Shen; Jeffrey, Sherry; Jiang, Jiang; Loo, Joseph A.; Ogorzalek Loo, Rachel R.; Malamud, Daniel; Melvin, James E.; Miroshnychenko, Olga; Navazesh, Mahvash; Niles, Richard; Park, Sung Kyu; Prakobphol, Akraporn; Ramachandran, Prasanna; Richert, Megan; Robinson, Sarah; Sondej, Melissa; Souda, Puneet; Sullivan, Mark A.; Takashima, Jona; Than, Shawn; Wang, Jianghua; Whitelegge, Julian P.; Witkowska, H. Ewa; Wolinsky, Lawrence; Xie, Yongming; Xu, Tao; Yu, Weixia; Ytterberg, Jimmy; Wong, David T.; Yates, John R.; Fisher, Susan J.

    2009-01-01

    Saliva is a body fluid with important functions in oral and general health. A consortium of three research groups catalogued the proteins in human saliva collected as the ductal secretions: 1166 identifications—914 in parotid and 917 in submandibular/sublingual saliva—were made. The results showed that a high proportion of proteins that are found in plasma and/or tears are also present in saliva along with unique components. The proteins identified are involved in numerous molecular processes ranging from structural functions to enzymatic/catalytic activities. As expected, the majority mapped to the extracellular and secretory compartments. An immunoblot approach was used to validate the presence in saliva of a subset of the proteins identified by mass spectrometric approaches. These experiments focused on novel constituents and proteins for which the peptide evidence was relatively weak. Ultimately, information derived from the work reported here and related published studies can be used to translate blood-based clinical laboratory tests into a format that utilizes saliva. Additionally, a catalogue of the salivary proteome of healthy individuals allows future analyses of salivary samples from individuals with oral and systemic diseases, with the goal of identifying biomarkers with diagnostic and/or prognostic value for these conditions; another possibility is the discovery of therapeutic targets. PMID:18361515

  17. The proteomes of human parotid and submandibular/sublingual gland salivas collected as the ductal secretions.

    PubMed

    Denny, Paul; Hagen, Fred K; Hardt, Markus; Liao, Lujian; Yan, Weihong; Arellanno, Martha; Bassilian, Sara; Bedi, Gurrinder S; Boontheung, Pinmannee; Cociorva, Daniel; Delahunty, Claire M; Denny, Trish; Dunsmore, Jason; Faull, Kym F; Gilligan, Joyce; Gonzalez-Begne, Mireya; Halgand, Frédéric; Hall, Steven C; Han, Xuemei; Henson, Bradley; Hewel, Johannes; Hu, Shen; Jeffrey, Sherry; Jiang, Jiang; Loo, Joseph A; Ogorzalek Loo, Rachel R; Malamud, Daniel; Melvin, James E; Miroshnychenko, Olga; Navazesh, Mahvash; Niles, Richard; Park, Sung Kyu; Prakobphol, Akraporn; Ramachandran, Prasanna; Richert, Megan; Robinson, Sarah; Sondej, Melissa; Souda, Puneet; Sullivan, Mark A; Takashima, Jona; Than, Shawn; Wang, Jianghua; Whitelegge, Julian P; Witkowska, H Ewa; Wolinsky, Lawrence; Xie, Yongming; Xu, Tao; Yu, Weixia; Ytterberg, Jimmy; Wong, David T; Yates, John R; Fisher, Susan J

    2008-05-01

    Saliva is a body fluid with important functions in oral and general health. A consortium of three research groups catalogued the proteins in human saliva collected as the ductal secretions: 1166 identifications--914 in parotid and 917 in submandibular/sublingual saliva--were made. The results showed that a high proportion of proteins that are found in plasma and/or tears are also present in saliva along with unique components. The proteins identified are involved in numerous molecular processes ranging from structural functions to enzymatic/catalytic activities. As expected, the majority mapped to the extracellular and secretory compartments. An immunoblot approach was used to validate the presence in saliva of a subset of the proteins identified by mass spectrometric approaches. These experiments focused on novel constituents and proteins for which the peptide evidence was relatively weak. Ultimately, information derived from the work reported here and related published studies can be used to translate blood-based clinical laboratory tests into a format that utilizes saliva. Additionally, a catalogue of the salivary proteome of healthy individuals allows future analyses of salivary samples from individuals with oral and systemic diseases, with the goal of identifying biomarkers with diagnostic and/or prognostic value for these conditions; another possibility is the discovery of therapeutic targets.

  18. Recombinant allergens for allergen-specific immunotherapy: 10 years anniversary of immunotherapy with recombinant allergens.

    PubMed

    Valenta, Rudolf; Linhart, B; Swoboda, I; Niederberger, V

    2011-06-01

    The broad applicability of allergen-specific immunotherapy for the treatment and eventually prevention of IgE-mediated allergy is limited by the poor quality and allergenic activity of natural allergen extracts that are used for the production of current allergy vaccines. Today, the genetic code of the most important allergens has been deciphered; recombinant allergens equalling their natural counterparts have been produced for diagnosis and immunotherapy, and a large panel of genetically modified allergens with reduced allergenic activity has been characterized to improve safety of immunotherapy and explore allergen-specific prevention strategies. Successful immunotherapy studies have been performed with recombinant allergens and hypoallergenic allergen derivatives and will lead to the registration of the first recombinant allergen-based vaccines in the near future. There is no doubt that recombinant allergen-based vaccination strategies will be generally applicable to most allergen sources, including respiratory, food and venom allergens and allow to produce safe allergy vaccines for the treatment of the most common forms of IgE-mediated allergies.

  19. Immunotherapy in urothelial carcinoma: fade or future standard?

    PubMed Central

    Breyer, Johannes; Burger, Maximilian

    2016-01-01

    Immunotherapy of non-muscle-invasive bladder carcinoma by Bacillus-Calmette-Guérin (BCG) instillation is a well-established treatment option since decades. Despite this fact, the immunocellular basis was first studied in recent years. New aspects of immunotherapy, also for progressed bladder carcinoma, might follow promising research on immunological targets. PMID:27785423

  20. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    PubMed Central

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

  1. Immunotherapy for Melanoma: Current Status and Perspectives

    PubMed Central

    Alexandrescu, Doru T.; Ichim, Thomas E.; Riordan, Neil H.; Marincola, Francesco M.; Nardo, Anna Di; Kabigting, Filamer D.; Dasanu, Constantin A.

    2012-01-01

    Summary Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease. PMID:20551839

  2. Immunobiology and immunotherapy in genitourinary malignancies

    PubMed Central

    Grivas, Petros

    2016-01-01

    Immunotherapy has traditionally been a critical component of the cancer treatment armamentarium in genitourinary (GU) cancers. It has an established role in the management of carefully selected patients with metastatic renal cell carcinoma (RCC) [e.g., high dose interleukin-2 (IL-2)] and non-muscle invasive bladder cancer (NMIBC) [e.g., intravesical Bacillus Calmette-Guérin (BCG)]. In 2010, the sipuleucel-T vaccine was approved by the FDA for the management of metastatic castration-resistant prostate cancer (mCRPC), based on a phase III trial showing overall survival (OS) benefit compared to placebo. The immune checkpoint inhibitor nivolumab (anti-PD-1) recently received FDA approval for the management of patients with advanced RCC patients previously treated with anti-angiogenic therapy, based on OS benefit compared to everolimus. Recently, large clinical trials demonstrated meaningful clinical benefit, including durable responses, as well as a good tolerability/safety profile with the use of immune checkpoint inhibitors in advanced RCC and chemotherapy-resistant advanced urothelial carcinoma (UC), while FDA just approved atezolizumab for platinum-treated advanced UC. Numerous interesting trials in different cancers are ongoing. Several combinations of immune checkpoint blockade with chemotherapeutics, vaccines, targeted tyrosine kinase inhibitors & monoclonal antibodies, epigenetic modifiers, anti-angiogenic agents, tumor microenvironment & myeloid cell targeting therapies, metabolic modification strategies, radiation, and others, are being tested in clinical trials. Comprehensive understanding of the factors underlying antitumor immune responses in physiologically relevant animal models and humans will refine further the clinical benefit of immunotherapy. Discovery and validation of appropriate molecular biomarkers via coordinated translational research efforts, rational clinical trial designs with suitable endpoints and well-defined eligibility criteria

  3. Immunobiology and immunotherapy in genitourinary malignancies.

    PubMed

    Tsiatas, Marinos; Grivas, Petros

    2016-07-01

    Immunotherapy has traditionally been a critical component of the cancer treatment armamentarium in genitourinary (GU) cancers. It has an established role in the management of carefully selected patients with metastatic renal cell carcinoma (RCC) [e.g., high dose interleukin-2 (IL-2)] and non-muscle invasive bladder cancer (NMIBC) [e.g., intravesical Bacillus Calmette-Guérin (BCG)]. In 2010, the sipuleucel-T vaccine was approved by the FDA for the management of metastatic castration-resistant prostate cancer (mCRPC), based on a phase III trial showing overall survival (OS) benefit compared to placebo. The immune checkpoint inhibitor nivolumab (anti-PD-1) recently received FDA approval for the management of patients with advanced RCC patients previously treated with anti-angiogenic therapy, based on OS benefit compared to everolimus. Recently, large clinical trials demonstrated meaningful clinical benefit, including durable responses, as well as a good tolerability/safety profile with the use of immune checkpoint inhibitors in advanced RCC and chemotherapy-resistant advanced urothelial carcinoma (UC), while FDA just approved atezolizumab for platinum-treated advanced UC. Numerous interesting trials in different cancers are ongoing. Several combinations of immune checkpoint blockade with chemotherapeutics, vaccines, targeted tyrosine kinase inhibitors & monoclonal antibodies, epigenetic modifiers, anti-angiogenic agents, tumor microenvironment & myeloid cell targeting therapies, metabolic modification strategies, radiation, and others, are being tested in clinical trials. Comprehensive understanding of the factors underlying antitumor immune responses in physiologically relevant animal models and humans will refine further the clinical benefit of immunotherapy. Discovery and validation of appropriate molecular biomarkers via coordinated translational research efforts, rational clinical trial designs with suitable endpoints and well-defined eligibility criteria

  4. Postoperative immunotherapy of murine C1300-neuroblastoma.

    PubMed

    Fowler, C L; Brooks, S P; Rossman, J E; Cooney, D R

    1990-02-01

    Low-dose cyclophosphamide (CY) is an immunomodulating agent that down-regulates T suppressor cell function. This study investigates postoperative immunotherapy with CY as an alternate treatment for advanced immunogenic tumors such as neuroblastoma that typically respond poorly to traditional high-dose chemotherapy. A/J mice with 1.5-cm subcutaneous C1300-neuroblastoma (C1300-NB) tumors were divided into the following treatment groups: I, untreated (n = 14); II, 85% tumor resection (n = 18); III, sham-operated (n = 18); IV, multiple-dose CY (n = 6); V, 85% resection and single-dose CY (n = 14); VI, 85% resection and multiple-dose CY (n = 14). CY (100 mg/kg, intraperitoneally) was given initially 24 hours post-operatively to groups IV, V, and VI. Groups IV and VI also received weekly maintenance doses of 25 mg/kg CY. Results showed significantly increased survival (log-rank test) in CY-treated groups (IV, V, VI) compared with control groups (I,II,III). Cures were observed only in groups receiving partial resection plus CY (V, 7%; VI, 29%). Although surgical debulking of tumor alone (II) did not enhance survival, the procedure normalized depressed total lymphocyte counts and the subpopulation of Lyt 2,3+ (T suppressor/cytolytic cells) in the immediate postoperative period during which immunotherapy with CY was instigated. This may have contributed to the success of CY immunotherapy. To characterize the tumor-host immune interaction, additional studies were performed. Results showed the following. (1) Mice cured by debulking plus CY (from groups V and VI) could not be successfully reimplanted with C1300-NB, demonstrating immunologic mediation by CY.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Specific immunotherapy in ovarian cancer: a systematic review.

    PubMed

    Alipour, Soroush; Zoghi, Samaneh; Khalili, Nastaran; Hirbod-Mobarakeh, Armin; Emens, Leisha A; Rezaei, Nima

    2016-10-01

    Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Several approaches of active and passive immunotherapy for EOC have been studied. The aim of this systematic review was to assess the clinical efficacy of specific immunotherapy in patients with EOC. We found 4524 references in seven databases and we included ten controlled clinical trials with 2285 patients with EOC reporting five active immunotherapeutic agents and three passive immunotherapies. Meta-analysis of six studies showed that overall there was not any significant difference in overall survival and recurrence-free survival between patients undergoing specific immunotherapy and those in control group. Most of the studies we evaluated reported a positive outcome from treatment with specific immunotherapy, although this was not significant. PMID:27605068

  6. Specific immunotherapy in ovarian cancer: a systematic review.

    PubMed

    Alipour, Soroush; Zoghi, Samaneh; Khalili, Nastaran; Hirbod-Mobarakeh, Armin; Emens, Leisha A; Rezaei, Nima

    2016-10-01

    Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Several approaches of active and passive immunotherapy for EOC have been studied. The aim of this systematic review was to assess the clinical efficacy of specific immunotherapy in patients with EOC. We found 4524 references in seven databases and we included ten controlled clinical trials with 2285 patients with EOC reporting five active immunotherapeutic agents and three passive immunotherapies. Meta-analysis of six studies showed that overall there was not any significant difference in overall survival and recurrence-free survival between patients undergoing specific immunotherapy and those in control group. Most of the studies we evaluated reported a positive outcome from treatment with specific immunotherapy, although this was not significant.

  7. Harnessing the Microbiome to Enhance Cancer Immunotherapy

    PubMed Central

    Nelson, Michelle H.; Diven, Marshall A.; Huff, Logan W.; Paulos, Chrystal M.

    2015-01-01

    The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies. PMID:26101781

  8. Immunotherapy strategies for spinal cord injury.

    PubMed

    Wang, Yong-Tang; Lu, Xiu-Min; Chen, Kai-Ting; Shu, Ya-Hai; Qiu, Chun-Hong

    2015-01-01

    Regeneration in the central nervous system (CNS) of adult mammalian after traumatic injury is limited, which often causes permanent functional motor and sensory loss. After spinal cord injury (SCI), the lack of regeneration is mainly attributed to the presence of a hostile microenvironment, glial scarring, and cavitation. Besides, inflammation has also been proved to play a crucial role in secondary degeneration following SCI. The more prominent treatment strategies in experimental models focus mainly on drugs and cell therapies, however, only a few strategies applied in clinical studies and therapies still have only limited effects on the repair of SCI. Recently, the interests in immunotherapy strategies for CNS are increasing in number and breadth. Immunotherapy strategies have made good progresses in treating many CNS degenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and multiple sclerosis (MS). However, the strategies begin to be considered to the treatment of SCI and other neurological disorders in recent years. Besides anti-inflamatory therapy, immunization with protein vaccines and DNA vaccines has emerged as a novel therapy strategy because of the simplicity of preparation and application. An inflammatory response followed by spinal cord injury, and is controled by specific signaling molecules, such as some cytokines playing a crucial role. As a result, appropriate immunoregulation, the expression of pro-inflammatory cytokines and anti-inflammatory cytokines may be an effective therapy strategy for earlier injury of spinal cord. In addition, myelinassociated inhibitors (MAIs) in the injured spinal cord, such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte- myelin glycoprotein (OMgp) are known to prevent axonal regeneration through their co-receptors, and to trigger demyelinating autoimmunity through T cell-mediated harmful autoimmune response. The antagonism of the MAIs through vaccinating with

  9. Fighting cancer with magnetic nanoparticles and immunotherapy

    NASA Astrophysics Data System (ADS)

    Gutiérrez, L.; Mejías, R.; Barber, D. F.; Veintemillas-Verdaguer, S.; Serna, C. J.; Lázaro, F. J.; Morales, M. P.

    2012-03-01

    IFN-γ-adsorbed DMSA-coated magnetite nanoparticles can be used as an efficient in vivo drug delivery system for tumor immunotherapy. Magnetic nanoparticles, with adsorbed interferon-γ, were targeted to the tumor site by application of an external magnetic field. A relevant therapeutic dosage of interferon in the tumor was detected and led to a notable reduction in tumor size. In general, only 10% of the total injected nanoparticles after multiple exposures were found in tissues by AC susceptibility measurements of the corresponding resected tissues. Magnetic nanoparticle biodistribution is affected by the application of an external magnetic field.

  10. Solving the Problem of Nonadherence to Immunotherapy.

    PubMed

    Bender, Bruce G; Lockey, Richard F

    2016-02-01

    Allergen immunotherapy (AIT) can improve allergic response by modifying the underlying disease. Many patients are nonadherent, and do not achieve full benefit. Numerous studies reveal that fewer than 10% of patients complete a full course and that most abandon treatment in the first year. The development and testing of interventions to improve AIT are emerging. Data from adherence interventions in other chronic conditions provide guidance to allergists/immunologists. Evidence-based communication strategies-patient-centered care, motivational interviewing, and shared-decision making-underscore the importance of taking time to establish trust, understand patient concerns and priorities, and involve the patient in decisions regarding AIT.

  11. A stochastic model for immunotherapy of cancer

    PubMed Central

    Baar, Martina; Coquille, Loren; Mayer, Hannah; Hölzel, Michael; Rogava, Meri; Tüting, Thomas; Bovier, Anton

    2016-01-01

    We propose an extension of a standard stochastic individual-based model in population dynamics which broadens the range of biological applications. Our primary motivation is modelling of immunotherapy of malignant tumours. In this context the different actors, T-cells, cytokines or cancer cells, are modelled as single particles (individuals) in the stochastic system. The main expansions of the model are distinguishing cancer cells by phenotype and genotype, including environment-dependent phenotypic plasticity that does not affect the genotype, taking into account the effects of therapy and introducing a competition term which lowers the reproduction rate of an individual in addition to the usual term that increases its death rate. We illustrate the new setup by using it to model various phenomena arising in immunotherapy. Our aim is twofold: on the one hand, we show that the interplay of genetic mutations and phenotypic switches on different timescales as well as the occurrence of metastability phenomena raise new mathematical challenges. On the other hand, we argue why understanding purely stochastic events (which cannot be obtained with deterministic models) may help to understand the resistance of tumours to therapeutic approaches and may have non-trivial consequences on tumour treatment protocols. This is supported through numerical simulations. PMID:27063839

  12. Personalized cancer immunotherapy using Systems Medicine approaches.

    PubMed

    Gupta, Shailendra K; Jaitly, Tanushree; Schmitz, Ulf; Schuler, Gerold; Wolkenhauer, Olaf; Vera, Julio

    2016-05-01

    The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma.

  13. Melanoma immunotherapy: past, present, and future.

    PubMed

    Saleh, Farid; Renno, Waleed; Klepacek, Ivo; Ibrahim, Ghada; Asfar, Sami; Dashti, Hussein; Romero, Pedro; Dashti, Ali; Behbehani, Abdullah

    2005-01-01

    The incidence of cancer and its related morbidity and mortality remain on the increase in both developing and developed countries. Cancer remains a huge burden on the health and social welfare sectors worldwide and its prevention and cure remain two golden goals that science strives to achieve. Among the treatment options for cancer that have emerged in the past 100 years, cancer vaccine immunotherapy seems to present a promising and relatively safer approach as compared to chemotherapy and radiotherapy. The identification of different tumour antigens in the last fifteen years using a variety of techniques, together with the molecular cloning of cytotoxic T lymphocytes (CTLs)- and tumour infiltrating lymphocytes (TILs)-defined tumour antigens allowed more refining of the cancer vaccines that are currently used in different clinical trials. In a proportion of treated patients, some of these vaccines have resulted in partial or complete tumour regression, while they have increased the disease-free survival rate in others. These outcomes are more evident now in patients suffering from melanoma. This review provides an update on melanoma vaccine immunotherapy. Different cancer antigens are reviewed with a detailed description of the melanoma antigens discovered so far. The review also summarises clinical trials and individual clinical cases in which some of the old and current methods to vaccinate against or treat melanoma were used. These include vaccines made of autologous or allogenic melanoma tumour cells, melanoma peptides, recombinant bacterial or viral vectors, or dendritic cells. PMID:16248801

  14. Personalized cancer immunotherapy using Systems Medicine approaches.

    PubMed

    Gupta, Shailendra K; Jaitly, Tanushree; Schmitz, Ulf; Schuler, Gerold; Wolkenhauer, Olaf; Vera, Julio

    2016-05-01

    The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma. PMID:26174229

  15. Tecemotide: An antigen-specific cancer immunotherapy

    PubMed Central

    Wurz, Gregory T; Kao, Chiao-Jung; Wolf, Michael; DeGregorio, Michael W

    2015-01-01

    The identification of tumor-associated antigens (TAA) has made possible the development of antigen-specific cancer immunotherapies such as tecemotide. One of those is mucin 1 (MUC1), a cell membrane glycoprotein expressed on some epithelial tissues such as breast and lung. In cancer, MUC1 becomes overexpressed and aberrantly glycosylated, exposing the immunogenic tandem repeat units in the extracellular domain of MUC1. Designed to target tumor associated MUC1, tecemotide is being evaluated in Phase III clinical trials for treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC) as maintenance therapy following chemoradiotherapy. Additional Phase II studies in other indications are ongoing. This review discusses the preclinical and clinical development of tecemotide, ongoing preclinical studies of tecemotide in human MUC1 transgenic mouse models of breast and lung cancer, and the potential application of these models for optimizing the timing of chemoradiotherapy and tecemotide immunotherapy to achieve the best treatment outcome for patients. PMID:25483673

  16. Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies.

    PubMed

    Gastaldi, Matteo; Thouin, Anaïs; Vincent, Angela

    2016-01-01

    Over the last 15 years it has become clear that rare but highly recognizable diseases of the central nervous system (CNS), including newly identified forms of limbic encephalitis and other encephalopathies, are likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated 1 protein and contactin-associated protein like 2, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Most importantly, the new antibody-associated diseases almost invariably respond to immunotherapies with considerable and sometimes complete recovery, and there is convincing evidence of their pathogenicity in the relatively limited studies performed so far. Treatments include first-line steroids, intravenous immunoglobulins, and plasma exchange, and second-line rituximab and cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term. This review focuses mainly on N-methyl D-aspartate receptor- and voltage-gated potassium channel complex-related Abs in adults, the clinical phenotypes, and treatment responses. Pediatric cases are referred to but not reviewed in detail. As there have been very few prospective studies, the conclusions regarding immunotherapies are based on retrospective studies. PMID:26692392

  17. Algenpantucel-L immunotherapy in pancreatic adenocarcinoma.

    PubMed

    Coveler, Andrew L; Rossi, Gabriela R; Vahanian, Nicholas N; Link, Charles; Chiorean, E Gabriela

    2016-02-01

    Pancreatic adenocarcinoma is the 4th leading cause of cancer death in the USA and the EU. A minority of patients presents with surgically resectable and potentially curable disease, but among these, 80% are destined to relapse and overall survival rates with adjuvant chemotherapy average 24 months. Immunotherapy is a promising therapeutic option and a potential paradigm shift in the treatment of patients with pancreatic cancer, and may be particularly effective when used early in the disease course to prevent metastatic spread. Algenpantucel-L (HyperAcute Pancreas, NewLink Genetics, Ames, IA, USA) is a whole-cell immunotherapy consisting of irradiated allogeneic pancreatic cancer cells genetically engineered to express the murine enzyme α-GT, which results in hyperacute rejection of the tumor cells with complement- and antibody-dependent cytotoxicity. Phase II clinical trial data has been encouraging, particularly for patients who demonstrated humoral immunologic responses. Here, we report preliminary results and biomarkers correlations with clinical activity of algenpantucel-L in pancreatic cancer.

  18. Combination immunotherapies for type 1 diabetes mellitus.

    PubMed

    Pozzilli, Paolo; Maddaloni, Ernesto; Buzzetti, Raffaella

    2015-05-01

    Immunotherapies for type 1 diabetes mellitus (T1DM) have been the focus of intense basic and clinical research over the past few decades. Restoring β-cell function is the ultimate goal of intervention trials that target the immune system in T1DM. In an attempt to achieve this aim, different combination therapies have been proposed over the past few years that are based on treatments tackling the various mechanisms involved in the destruction of β cells. The results of clinical trials have not matched expectations based on the positive results from preclinical studies. The heterogeneity of T1DM might explain the negative results obtained, but previous trials have not addressed this issue. However, novel promising combination therapies are being developed, including those that couple immunomodulators with drugs that stimulate β-cell regeneration in order to restore normoglycaemia. This strategy is an encouraging one to pursue the goal of finding a cure for T1DM. This Review summarizes the available data about combination immunotherapies in T1DM, particularly addressing their clinical importance. The available data supporting the use of registered drugs, such as proton pump inhibitors and incretin-based agents, that have been shown to induce β-cell regeneration will also be discussed.

  19. Tecemotide: an antigen-specific cancer immunotherapy.

    PubMed

    Wurz, Gregory T; Kao, Chiao-Jung; Wolf, Michael; DeGregorio, Michael W

    2014-01-01

    The identification of tumor-associated antigens (TAA) has made possible the development of antigen-specific cancer immunotherapies such as tecemotide. One of those is mucin 1 (MUC1), a cell membrane glycoprotein expressed on some epithelial tissues such as breast and lung. In cancer, MUC1 becomes overexpressed and aberrantly glycosylated, exposing the immunogenic tandem repeat units in the extracellular domain of MUC1. Designed to target tumor associated MUC1, tecemotide is being evaluated in Phase III clinical trials for treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC) as maintenance therapy following chemoradiotherapy. Additional Phase II studies in other indications are ongoing. This review discusses the preclinical and clinical development of tecemotide, ongoing preclinical studies of tecemotide in human MUC1 transgenic mouse models of breast and lung cancer, and the potential application of these models for optimizing the timing of chemoradiotherapy and tecemotide immunotherapy to achieve the best treatment outcome for patients. PMID:25483673

  20. Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets.

    PubMed

    Greenblatt, David J; Harmatz, Jerold S; Singh, Nikhilesh N; Roth, Thomas; Harris, Stephen C; Kapil, Ram P

    2013-11-01

    Ingesting food can impact the pharmacokinetics of sedative-hypnotic drugs. A buffered zolpidem sublingual tablet (ZST) recently became available for the treatment of middle-of-the-night awakening. In this randomized, open-label, single-site study, the pharmacokinetic profile of ZST was evaluated when administered while fasting and following a standard high-fat meal (fed state). Healthy adults aged 18-64 years received a single morning dose of 3.5 mg ZST in the fed or fasting state. From 20 min to 3 h post-dose, zolpidem plasma levels were lower in the fed state compared to the fasting state. After 4 h post-dose (corresponding to "morning wake time"), higher zolpidem plasma levels were evident in the fed state. Area under the concentration-time curve (AUC) values for the 0-8 h interval were 160 ng/mL h in the fed state and 203 ng/mL h in the fasting state (P < .001). In the fed versus fasting states, Cmax was 32.0 ng/mL versus 57.3 ng/mL (P < .001), respectively, and Tmax was 3.0 h versus 0.92 h (P < .001), respectively. Together these data suggest that administration of ZST in the fed state is not optimal for maximizing the likelihood of therapeutic benefit and minimizing the probability of residual sedation.

  1. Cancer immunotherapy: Strategies for personalization and combinatorial approaches.

    PubMed

    Sathyanarayanan, Vishwanath; Neelapu, Sattva S

    2015-12-01

    The results of recent clinical trials using novel immunotherapy strategies such as immune checkpoint blockade and adoptive T-cell therapy approaches including CAR T-cell therapy have clearly established immunotherapy as an important modality for the treatment of cancer besides the traditional approaches of surgery, radiotherapy, and chemotherapy or targeted therapy. However, to date immunotherapy has been shown to induce durable clinical benefit in only a fraction of the patients. The use of combination strategies is likely to increase the number of patients that might benefit from immunotherapy. Indeed, over the last decade, the characterization of multiple immune resistance mechanisms used by the tumor to evade the immune system and the development of agents that target those mechanisms has generated a lot of enthusiasm for cancer immunotherapy. But a critical issue is to determine how best to combine such agents. This review will focus on novel immunotherapy agents currently in development and discuss strategies to develop and personalize combination cancer immunotherapy strategies.

  2. Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria.

    PubMed

    Salman, Sam; Bendel, Daryl; Lee, Toong C; Templeton, David; Davis, Timothy M E

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197-3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick

  3. Solitary fibrous tumor with pseudo-lipoblasts involving the sublingual gland: report of a case and review of the literature.

    PubMed

    Ayad, Tareck; Ghannoum, Julien

    2007-01-01

    Solitary fibrous tumors (SFTs) are mesenchymal neoplasms uncommonly occurring in the salivary glands. In rare instances, SFTs can contain mature fat, atrophic fat, or vacuolated cells previously termed 'pseudo-lipoblasts', which may be misinterpreted as a feature of malignancy. We report an unusual tumor with pseudo-lipoblasts occurring in the sublingual gland. The tumor exhibited a prominent hemangiopericytic pattern, bland cytology, and immunohistochemical and morphologic features consistent with that of an SFT. A review of 15 cases of SFTs of the salivary glands is presented. Emphasis is laid upon the histologic differential diagnosis and the clinical features of these tumors.

  4. Intraoral management of iatrogenically displaced lower third molar roots in the sublingual space: a report of 2 cases

    PubMed Central

    Zhao, Sufeng; Huang, Zheng; Geng, Tengyu; Huang, Lanzhu

    2015-01-01

    Surgical removal of the mandibular third molars is one of the most common procedures performed by dentists, as well as by oral and maxillofacial surgeons. Accidental displacement of teeth or roots into the fascial spaces, during surgical removal of the mandibular third molars, is a rare, but serious complication. Herein, we present 2 cases of iatrogenically displaced mandibular third molar roots into the sublingual space, which were successfully removed under local anesthesia intraorally. In addition to methods to minimize the risk of accidental tooth or root displacement, the importance of recognizing this complication and the methods of retrieval are also discussed. PMID:26770616

  5. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

    PubMed Central

    Soltani, Ghasem; Khorsand, Mahmood; Shamloo, Alireza Sepehri; Jarahi, Lida; Zirak, Nahid

    2015-01-01

    Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA) with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5µg/kg sublingually) and morphine (0.2mg/kg intravenously). Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes), and in the ward (at 3, 6 and 12 hours). SPSS version 19 software was used for data analysis and the significance level was set at P<0.05. Results: Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics. Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P<0.001). Postoperative mean heart rate in the buprenorphine group was four beats lower than the morphine group (P<0.001). Also, in the buprenorphine 48.6% and in the morphine group 86.7% of cases were conscious in recovery (P=0.001) with a higher rate of pruritus in the latter group (P=0.001). Conclusion: Sublingual buprenorphine administration before anesthesia induction in closed reduction surgery can lead to better postoperative pain control in comparison to intravenous morphine. Due to simple usage and longer postoperative sedation, sublingual buprenorphine is recommended as a suitable drug in closed reduction surgery

  6. Immunotherapy coming of age: What will it take to make it standard of care for glioblastoma?

    PubMed Central

    Heimberger, Amy B.; Sampson, John H.

    2011-01-01

    With the recent approval by the FDA of an immunotherapy for prostate cancer and another positive immunotherapy trial in melanoma, immunotherapy may finally be coming of age. So what will it take for it to become part of the standard treatment for glioblastoma? To put this question into perspective, we summarize critical background information in neuro-immunology, address immunotherapy clinical trial design, and discuss a number of extrinsic factors that will impact the development of immunotherapy in neuro-oncology. PMID:21149252

  7. Immunoproteasomes and immunotherapy-a smoking gun for lung cancer?

    PubMed

    Spits, Menno; Neefjes, Jacques

    2016-07-01

    Lung cancer is the second most prevalent cancer in both women and men with some 221,200 new cases and 158,040 deaths reported in 2015. Almost 90% of these are non-small cell lung cancer (NSCLC) and these patients have a very poor prognosis. Recently a new treatment option for NSCLC appeared that strongly improved treatment responses-immunotherapy. Here we review the various forms of immunotherapy and how immune modification of proteasomes in lung cancer may support the immune system in controlling NSCLC. These immunoproteasomes then support recognition of NSCLC and may act as a biomarker for selecting responding patients to immunotherapy. PMID:27501321

  8. Improving cancer immunotherapy by targeting the STATe of MDSCs

    PubMed Central

    de Haas, Nienke; de Koning, Coco; Spilgies, Lisanne; de Vries, I. Jolanda M.; Hato, Stanleyson V.

    2016-01-01

    ABSTRACT Cancer immunotherapy is a promising therapeutic avenue; however, in practice its efficacy is hampered by an immunosuppressive tumor microenvironment that consists of suppressive cell types like myeloid-derived suppressor cells (MDSCs). Eradication or reprogramming of MDSCs could therefore enhance clinical responses to immunotherapy. Here, we review clinically available drugs that target MDSCs, often through inhibition of STAT signaling, which is essential for MDSC accumulation and suppressive functions. Interestingly, several drugs used for non-cancerous indications and natural compounds similarly inhibit MDSCs by STAT inhibition, but have fewer side effects than anticancer drugs. Therefore, they show great potential for combination strategies with immunotherapy. PMID:27622051

  9. Malignant melanoma-The cradle of anti-neoplastic immunotherapy.

    PubMed

    Koller, Kristian M; Wang, Wenge; Schell, Todd D; Cozza, Eugene M; Kokolus, Kathleen M; Neves, Rogerio I; Mackley, Heath B; Pameijer, Colette; Leung, Anna; Anderson, Bryan; Mallon, Carol A; Robertson, Gavin; Drabick, Joseph J

    2016-10-01

    One of the defining characteristics of the malignant phenotype is the ability to evade the host immune system. Immunotherapy as a treatment modality represents a new dawn in the way we think about the treatment of a variety of malignancies. The story of immunotherapy traces its roots to its relationship with malignant melanoma. In this article, we review the intertwined history of immunotherapy and melanoma, including the early significant history, a discussion on immune mechanisms, resistance, local and systemic immunotherapeutic modalities, and speculate on possible novel future treatment options. PMID:27637351

  10. Improving cancer immunotherapy by targeting the STATe of MDSCs

    PubMed Central

    de Haas, Nienke; de Koning, Coco; Spilgies, Lisanne; de Vries, I. Jolanda M.; Hato, Stanleyson V.

    2016-01-01

    ABSTRACT Cancer immunotherapy is a promising therapeutic avenue; however, in practice its efficacy is hampered by an immunosuppressive tumor microenvironment that consists of suppressive cell types like myeloid-derived suppressor cells (MDSCs). Eradication or reprogramming of MDSCs could therefore enhance clinical responses to immunotherapy. Here, we review clinically available drugs that target MDSCs, often through inhibition of STAT signaling, which is essential for MDSC accumulation and suppressive functions. Interestingly, several drugs used for non-cancerous indications and natural compounds similarly inhibit MDSCs by STAT inhibition, but have fewer side effects than anticancer drugs. Therefore, they show great potential for combination strategies with immunotherapy.

  11. Evolving synergistic combinations of targeted immunotherapies to combat cancer.

    PubMed

    Melero, Ignacio; Berman, David M; Aznar, M Angela; Korman, Alan J; Pérez Gracia, José Luis; Haanen, John

    2015-08-01

    Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients. PMID:26205340

  12. Immunotherapy for Infectious Diseases: Past, Present, and Future.

    PubMed

    Manohar, Akshay; Ahuja, Jasmine; Crane, John K

    2015-01-01

    Passive immunotherapy for established infections, as opposed to active immunization to prevent disease, remains a tiny niche in the world of antimicrobial therapies. Many of the passive immunotherapies currently available are directed against bacterial toxins, such as botulism, or are intended for agents of bioterrorism such as anthrax, which fortunately has remained rare. The emergence of Ebola virus and multi-drug resistant pathogens, however, may breathe new life into the immunotherapy field as researchers seek non-antibiotic interventions for infectious diseases. PMID:26575462

  13. GD2-targeted immunotherapy and radioimmunotherapy.

    PubMed

    Dobrenkov, Konstantin; Cheung, Nai-Kong V

    2014-10-01

    Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high-risk metastatic neuroblastoma. Building on this experience, novel combinations of antibodies, cytokines, cells, and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In this review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions.

  14. MYCN as a target for cancer immunotherapy.

    PubMed

    Himoudi, Nourredine; Yan, Mengyong; Papanastasiou, Antigoni; Anderson, John

    2008-05-01

    MYCN is a potential target for cancer immunotherapy by virtue of its overexpression in numerous human malignancies and its functional role in tumour progression. Here we show limited expression of MYCN in normal human tissues indicating that anti-MYCN immune responses are unlikely to cross react with self tissues. An HLA-A2 restricted ten amino acid peptide epitope from MYCN, VILKKATEYV, was used to stimulate cytotoxic T cell lines from the peripheral blood of normal blood donors, and from a patient with MYCN amplified neuroblastoma. Strong and specific activity was seen against each MYCN overexpressing cell line and against autologous tumour cells. We generated two CTL clones capable of killing cells pulsed with as low as 0.5 nM of VIL peptide. Therefore strong and specific immune responses against MYCN expressing tumours are possible in patients with the most common HLA class 1 type in the Caucasian population.

  15. Targeting natural killer cells in cancer immunotherapy.

    PubMed

    Guillerey, Camille; Huntington, Nicholas D; Smyth, Mark J

    2016-08-19

    Alteration in the expression of cell-surface proteins is a common consequence of malignant transformation. Natural killer (NK) cells use an array of germline-encoded activating and inhibitory receptors that scan for altered protein-expression patterns, but tumor evasion of detection by the immune system is now recognized as one of the hallmarks of cancer. NK cells display rapid and potent immunity to metastasis or hematological cancers, and major efforts are now being undertaken to fully exploit NK cell anti-tumor properties in the clinic. Diverse approaches encompass the development of large-scale NK cell-expansion protocols for adoptive transfer, the establishment of a microenvironment favorable to NK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function. In this Review we detail recent advances in NK cell-based immunotherapies and discuss the advantages and limitations of these strategies. PMID:27540992

  16. Biological Response Modifier in Cancer Immunotherapy.

    PubMed

    Liu, Ronghua; Luo, Feifei; Liu, Xiaoming; Wang, Luman; Yang, Jiao; Deng, Yuting; Huang, Enyu; Qian, Jiawen; Lu, Zhou; Jiang, Xuechao; Zhang, Dan; Chu, Yiwei

    2016-01-01

    Biological response modifiers (BRMs) emerge as a lay of new compounds or approaches used in improving cancer immunotherapy. Evidences highlight that cytokines, Toll-like receptor (TLR) signaling, and noncoding RNAs are of crucial roles in modulating antitumor immune response and cancer-related chronic inflammation, and BRMs based on them have been explored. In particular, besides some cytokines like IFN-α and IL-2, several Toll-like receptor (TLR) agonists like BCG, MPL, and imiquimod are also licensed to be used in patients with several malignancies nowadays, and the first artificial small noncoding RNA (microRNA) mimic, MXR34, has entered phase I clinical study against liver cancer, implying their potential application in cancer therapy. According to amounts of original data, this chapter will review the regulatory roles of TLR signaling, some noncoding RNAs, and several key cytokines in cancer and cancer-related immune response, as well as the clinical cases in cancer therapy based on them.

  17. Development of Passive Immunotherapies for Synucleinopathies.

    PubMed

    Bergström, Ann-Louise; Kallunki, Pekka; Fog, Karina

    2016-02-01

    Immunotherapy using antibodies targeting alpha-synuclein has proven to be an effective strategy for ameliorating pathological and behavioral deficits induced by excess pathogenic alpha-synuclein in various animal and/or cellular models. However, the process of selecting the anti-alpha-synuclein antibody with the best potential to treat synucleinopathies in humans is not trivial. Critical to this process is a better understanding of the pathological processes involved in the synucleinopathies and how antibodies are able to influence these. We will give an overview of the first proof-of-concept studies in rodent disease models and discuss challenges associated with developing antibodies against alpha-synuclein resulting from the distribution and structural characteristics of the protein. We will also provide a status on the passive immunization approaches targeting alpha-synuclein that have entered, or are expected to enter, clinical evaluation.

  18. The Role of Immunotherapy in Multiple Myeloma

    PubMed Central

    Kocoglu, Mehmet; Badros, Ashraf

    2016-01-01

    Multiple myeloma is the second most common hematologic malignancy. The treatment of this disease has changed considerably over the last two decades with the introduction to the clinical practice of novel agents such as proteasome inhibitors and immunomodulatory drugs. Basic research efforts towards better understanding of normal and missing immune surveillence in myeloma have led to development of new strategies and therapies that require the engagement of the immune system. Many of these treatments are under clinical development and have already started providing encouraging results. We, for the second time in the last two decades, are about to witness another shift of the paradigm in the management of this ailment. This review will summarize the major approaches in myeloma immunotherapies. PMID:26784207

  19. Honeybee venom immunotherapy: certainties and pitfalls.

    PubMed

    Bilò, M Beatrice; Antonicelli, Leonardo; Bonifazi, Floriano

    2012-11-01

    The honeybee is an interesting insect because of the fundamental agricultural role it plays, together with the composition of its venom, which presents new diagnostic and immunotherapeutic challenges. This article examines various aspects of honeybee venom allergy from epidemiology to diagnosis and treatment, with special emphasis on venom immunotherapy (VIT). Honeybee venom allergy represents a risk factor for severe systemic reaction in challenged allergic patients, for the diminished effectiveness of VIT, for more frequent side effects during VIT and relapse after cessation of treatment. Some strategies are available for reducing the risk of honeybee VIT-induced side effects; however, there is considerable room for further improvement in these all-important areas. At the same time, sensitized and allergic beekeepers represent unique populations for epidemiological, venom allergy immunopathogenesis and VIT mechanism studies.

  20. Aluminium in Allergies and Allergen immunotherapy.

    PubMed

    Jensen-Jarolim, Erika

    2015-01-01

    Aluminium is a hot topic in the current debate. Exposure occurs due to environmental, dietary and intentional exposure to aluminium, such as in vaccines where it was introduced in 1926. In spite of the fact that it is a typical Th2 adjuvant, aluminium redirects the immune response in systemic allergen immunotherapy (SIT) upon prolonged immunization. SIT in the US, and SLIT in general, are at present non-adjuvanted therapies, but in Europe aluminium is used as adjuvant in most SIT preparations. It enhances the safety of SIT by local deposition of the allergen. Undesired properties of aluminium adjuvants comprise acute and chronic inflammation at the injection site, its Th2 immune stimulatory capacity, its accumulation besides biodistribution in the body. The adjuvant and safety profile of aluminium adjuvants in allergy vaccines are discussed, as well as the need for putting modern delivery systems and adjuvants on the fast track.

  1. GD2-targeted immunotherapy and radioimmunotherapy

    PubMed Central

    Dobrenkov, Konstantin; Cheung, Nai-Kong

    2014-01-01

    Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high risk metastatic neuroblastoma. Building on this experience, novel combinations of antibody, cytokines, cells and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In the review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions. PMID:25440605

  2. Nanoparticle based-immunotherapy against allergy.

    PubMed

    Gamazo, Carlos; Gastaminza, Gabriel; Ferrer, Marta; Sanz, María L; Irache, Juan M

    2014-01-01

    Allergic diseases are one of the most prevalent diseases, reaching epidemic proportions in developed countries. An allergic reaction occurs after contact with an environmental protein, such as inhalants allergens (pollen, animal dander, house dust mites), or food proteins. This response is known as part of the type 2 immunity that is counterbalanced by Type 1 immunity and Tregs. Widely used allergen-specific immunotherapy (IT) is a long term treatment to induce such switch from Th2 to Th1 response. However, conventional IT requires multiple allergen injections over a long period of time and is not free of risk of producing allergic reactions. As a consequence, new safer and faster immunotherapeutic methods are required. This review deals with allergen IT using nanoparticles as allergen delivery system that will allow a different way of administration, reduce dose and diminish allergen exposure to IgE bound to mast cells or basophils.

  3. Toxicities of Immunotherapy for the Practitioner

    PubMed Central

    Weber, Jeffrey S.; Yang, James C.; Atkins, Michael B.; Disis, Mary L.

    2015-01-01

    The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune nature and the T-cell–mediated adverse events seen. The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy. Cytokines seem to generate diffuse and nonspecific T-cell reactivity, whereas checkpoint protein inhibition, vaccines, and adoptive cell therapy seem to activate more specific T cells that interact directly with normal tissues, potentially causing specific organ damage. In this review, we summarize the toxicities that are unique to immunotherapies, emphasizing the need to familiarize the oncology practitioner with the spectrum of adverse events seen with newly approved and emerging modalities. PMID:25918278

  4. Brain tumor immunotherapy: an immunologist's perspective.

    PubMed

    Lampson, Lois A

    2003-01-01

    Key concepts in brain tumor immunotherapy are reviewed. "Immunotherapy" can refer to a fully-developed, tumor-specific immune response, or to its individual cellular or molecular mediators. The immune response is initiated most efficiently in organized lymphoid tissue. After initiation, antigen-specific T lymphocytes (T cells) survey the tissues--including the brain. If the T cells re-encounter their antigen at a tumor site, they can be triggered to carry out their effector functions. T cells can attack tumor in many ways, directly and indirectly, through cell-cell contact, secreted factors, and attraction and activation of other cells, endogenous or blood-borne. Recent work expands the list of candidate tumor antigens: they are not limited to cell surface proteins and need not be absolutely tumor-specific. Once identified, tumor antigens can be targeted immunologically, or in novel ways. The immune response is under complex regulatory control. Most current work aims to enhance initiation of the response (for example, with tumor vaccines), rather than enhancing the effector phase at the tumor site. The effector phase includes a rich, interactive set of cells and mediators; some that are not usually stressed are of particular interest against tumor in the brain. Within the brain, immune regulation varies from site to site, and local neurochemicals (such as substance P or glutamate) can contribute to local control. Given the complexity of a tumor, the brain, and the immune response, animal models are essential, but more emphasis should be given to their limitations and to step-by-step analysis, rather than animal "cures".

  5. Nanochemistry-based immunotherapy for HIV-1.

    PubMed

    Lori, F; Calarota, S A; Lisziewicz, J

    2007-01-01

    Highly active antiretroviral treatment (HAART), i.e. the combination of three or more drugs against human immunodeficiency virus type 1 (HIV-1), has greatly improved the clinical outcome of HIV-1-infected individuals. However, HAART is unable to reconstitute HIV-specific immunity and eradicate the virus. Several observations in primate models and in humans support the notion that cell-mediated immunity can control viral replication and slow disease progression. Thus, besides drugs, an immunotherapy that induces long-lasting HIV-specific T-cell responses could play a role in the treatment of HIV/AIDS. To induce such immune responses, DermaVir Patch has been developed. DermaVir consists of an HIV-1 antigen-encoding plasmid DNA that is chemically formulated in a nanoparticle. DermaVir is administered under a patch after a skin preparation that supports the delivery of the nanoparticle to Langerhans cells (LC). Epidermal LC trap and transport the nanomedicine to draining lymph nodes. While in transit, LC mature into dendritic cells (DC), which can efficiently present the DNA-encoded antigens to naïve T-cells for the induction of cellular immunity. Pre-clinical studies and Phase I clinical testing of DermaVir in HIV-1-infected individuals have demonstrated the safety and tolerability of DermaVir Patch. To further modulate cellular immunity, molecular adjuvants might be added into the nanoparticle. DermaVir Patch represents a new nanomedicine platform for immunotherapy of HIV/AIDS. In this review, the antiviral activity of DermaVir-induced cellular immunity is discussed. Furthermore, the action of some cytokines currently being tested as adjuvants are highlighted and the adjuvant effect of cytokine plasmid DNA included in the DermaVir nanoparticle is reviewed.

  6. The effect of dietary consistency and water content on the parotid glands of submandibular and sublingual duct-ligated rats.

    PubMed

    Kurahashi, M

    2002-05-01

    The aim here was to estimate the significance of oral sensation and mastication on functional changes in the parotid glands of partially desalivated rats. Submandibular and sublingual duct-ligated and sham-operated control rats were fed three diets of similar chemical composition but different physical presentations. Two were solid, either pellets or powder, and one was liquid. Water and food intakes were similar for both the duct-ligated rats and sham-operated control rats when they ate the pelleted or powdered-diet, though more food was wasted by the duct-ligated rats in the powdered-diet group than in the pelleted-diet group. No food was wasted in the rats fed the liquid-diet. Parotid gland weight and amylase activity were greatest with the submandibular and sublingual duct-ligated rats fed the powdered-diet and smallest with the duct-ligated and sham-operated control rats fed the liquid-diet. The amount of food wasted correlated positively with the parotid gland weight and parotid amylase activity of the rats. These findings support the view that it is the contact of dry food with the oral mucosa rather than the jaw movements involved in mastication that increases parotid gland weight and amylase activity in partial desalivated rats.

  7. Characterization of the human submandibular/sublingual saliva glycoproteome using lectin affinity chromatography coupled to Multidimensional Protein Identification Technology

    PubMed Central

    Gonzalez-Begne, Mireya; Lu, Bingwen; Liao, Lujian; Xu, Tao; Bedi, Gurrinder; Melvin, James E.; Yates, John R.

    2011-01-01

    In-depth analysis of the salivary proteome is fundamental to understanding the functions of salivary proteins in the oral cavity and to reveal disease biomarkers involved in different pathophysiological conditions, with the ultimate goal of improving patient diagnosis and prognosis. Submandibular and sublingual glands contribute saliva rich in glycoproteins to the total saliva output, making them valuable sources for glycoproteomic analysis. Lectin-affinity chromatography coupled to mass spectrometry-based shotgun proteomics was used to explore the submandibular/sublingual (SM/SL) saliva glycoproteome. A total of 262 N- and O-linked glycoproteins were identified by multidimensional protein identification technology (MudPIT). Only 38 were previously described in SM and SL salivas from the human salivary N-linked glycoproteome, while 224 were unique. Further comparison analysis with SM/SL saliva of the human saliva proteome, revealed 125 glycoproteins not formerly reported in this secretion. KEGG pathway analyses demonstrated that many of these glycoproteins are involved in processes such as complement and coagulation cascades, cell communication, glycosphingolipid biosynthesis neo-lactoseries, O-glycan biosynthesis, glycan structures-biosynthesis 2, starch and sucrose metabolism, peptidoglycan biosynthesis or others pathways. In summary, lectin-affinity chromatography coupled to MudPIT mass spectrometry identified many novel glycoproteins in SM/SL saliva. These new additions to the salivary proteome may prove to be a critical step for providing reliable biomarkers in the diagnosis of a myriad of oral and systemic diseases. PMID:21936497

  8. Brain Tumor Immunotherapy: What have We Learned so Far?

    PubMed Central

    Van Gool, Stefaan Willy

    2015-01-01

    High grade glioma is a rare brain cancer, incurable in spite of modern neurosurgery, radiotherapy, and chemotherapy. Novel approaches are in research, and immunotherapy emerges as a promising strategy. Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, we developed an immunotherapy schedule and we categorized patients into clinically defined risk profiles. We learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, we developed a mode of care within academic centers to organize cell-based therapies for experimental clinical trials in a large number of patients. PMID:26137448

  9. Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy

    PubMed Central

    Datta, Jashodeep; Terhune, Julia H.; Lowenfeld, Lea; Cintolo, Jessica A.; Xu, Shuwen; Roses, Robert E.; Czerniecki, Brian J.

    2014-01-01

    Dendritic cells (DC) are professional antigen-presenting cells uniquely suited for cancer immunotherapy. They induce primary immune responses, potentiate the effector functions of previously primed T-lymphocytes, and orchestrate communication between innate and adaptive immunity. The remarkable diversity of cytokine activation regimens, DC maturation states, and antigen-loading strategies employed in current DC-based vaccine design reflect an evolving, but incomplete, understanding of optimal DC immunobiology. In the clinical realm, existing DC-based cancer immunotherapy efforts have yielded encouraging but inconsistent results. Despite recent U.S. Federal and Drug Administration (FDA) approval of DC-based sipuleucel-T for metastatic castration-resistant prostate cancer, clinically effective DC immunotherapy as monotherapy for a majority of tumors remains a distant goal. Recent work has identified strategies that may allow for more potent “next-generation” DC vaccines. Additionally, multimodality approaches incorporating DC-based immunotherapy may improve clinical outcomes. PMID:25506283

  10. Advances in strategies and methodologies in cancer immunotherapy.

    PubMed

    Lam, Samuel S K; Zhou, Feifan; Hode, Tomas; Nordquist, Robert E; Alleruzzo, Luciano; Raker, Joseph; Chen, Wei R

    2015-04-01

    Since the invention of Coley's toxin by William Coley in early 1900s, the path for cancer immunotherapy has been a convoluted one. Although still not considered standard of care, with the FDA approval of trastuzumab, Provenge and ipilimumab, the medical and scientific community has started to embrace the possibility that immunotherapy could be a new hope for cancer patients with otherwise untreatable metastatic diseases. This review aims to summarize the development of some major strategies in cancer immunotherapy, from the earliest peptide vaccine and transfer of tumor specific antibodies/T cells to the more recent dendritic cell (DC) vaccines, whole cell tumor vaccines, and checkpoint blockade therapy. Discussion of some major milestones and obstacles in the shaping of the field and the future perspectives is included. Photoimmunotherapy is also reviewed as an example of emerging new therapies combining phototherapy and immunotherapy.

  11. Immunotherapy: A useful strategy to help combat multidrug resistance

    PubMed Central

    Curiel, Tyler J.

    2012-01-01

    Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic agents, capitalization on other immune properties of MDR positive cells, or conditional immunotoxins expressed under MDR control. Additional insights into the immunogenic potential of some cytotoxic agents can also be brought to bear on these strategies. This review will highlight key concepts in cancer immunotherapy and illustrate immune principles and strategies that have been or could be used to help destroy MDR positive tumor cells, either alone or in rational combinations. PMID:22483359

  12. Development of immunoglobulins to venoms during specific immunotherapy.

    PubMed

    Palma-Carlos, M L; Santos, M C; Pedro, E; Branco-Ferreira, M; Spínola, A; Palma-Carlos, A G

    1999-03-01

    Immunotherapy against venoms (itv) is an efficacious treatment for most subjects who are allergic to hymnenoptera venoms. The authors studied 8 patients: 7 who were allergic to honey been venom and 1 who was allergic to wasp venom, followed for two years during immunotherapy with an aqueous extract of pure venoms from ALBAY Dome Hollister Stier. Specific IgE and IgG4 were evaluated by the Elisa Cap Technique of Pharmacia at different times: T0 before immunotherapy, T1 (one year after) and T2 (2 years after). A significant fall of specific IgE (p < 0.02) and a significant increase in specific IgG4 (p < 0.008) were seen during the two years in all patients. Four of the patients were re-stung and none had systemic reactions. These results suggest that increase in specific IgG4 is correlated with the protective effect of immunotherapy. PMID:10226679

  13. Cancer immunotherapy: harnessing the immune system to battle cancer.

    PubMed

    Yang, Yiping

    2015-09-01

    The recent clinical successes of immune checkpoint blockade and chimeric antigen receptor T cell therapies represent a turning point in cancer immunotherapy. These successes also underscore the importance of understanding basic tumor immunology for successful clinical translation in treating patients with cancer. The Reviews in this Review Series focus on current developments in cancer immunotherapy, highlight recent advances in our understanding of basic aspects of tumor immunology, and suggest how these insights can lead to the development of new immunotherapeutic strategies.

  14. Cancer immunotherapy: harnessing the immune system to battle cancer

    PubMed Central

    Yang, Yiping

    2015-01-01

    The recent clinical successes of immune checkpoint blockade and chimeric antigen receptor T cell therapies represent a turning point in cancer immunotherapy. These successes also underscore the importance of understanding basic tumor immunology for successful clinical translation in treating patients with cancer. The Reviews in this Review Series focus on current developments in cancer immunotherapy, highlight recent advances in our understanding of basic aspects of tumor immunology, and suggest how these insights can lead to the development of new immunotherapeutic strategies. PMID:26325031

  15. [FDDF (fast dissolving dosage form) piroxicam for sublingual administration in the treatment of rheumatoid arthritis].

    PubMed

    Montecucco, C; Caporali, R; Ronchetti, A; Rossi, S; Comaschi, E

    1994-12-01

    Open non-comparative study for the evaluation of the efficacy and tolerance of piroxicam FDDF for sublingual administration in the treatment of rheumatoid arthritis. Thirty patients (6 males and 24 females) suffering from rheumatoid arthritis in the active phase have been treated. All the patients had to fulfil the criteria for the rheumatoid arthritis classification proposed by the American Rheumatism Association (ARA). The efficacy of therapy has been evaluated, after 2, 4 and 6 week of treatment, through the changes in: the number of painful or tender joints on motion, the number of swollen joints, grip strength, ESR. Also day pain, night pain, duration of morning stiffness and functional index have been evaluated. As regards the functional index, activities as dressing, arising, eating, walking, taking care of hygiene, bending, standing and sitting have been considered. The study sample was composed by 30 patients, with a mean age of 59.73 years, suffering from rheumatoid arthritis from 4.76 years. As regards efficacy parameters, day pain, which is recorded on a 21 compartment visual analogue scale, was initially of 8.13 (+/- 3.73), and after 2 weeks of therapy decreased of about 1 point and after 4 weeks was of 6.57 (+/- 3.73). This improvement was already statistically significant at the first control (p = 0.01). At the first control also morning stiffness resulted improved in a statistically significant way (p < 0.0001). As regards functional index a statistically significant improvement was observed in the disability of walking and of picking up objects after 2 weeks; after 4 weeks a significant improvement was observed in the disability of arising and of bending. These changes in functional ability probably depend upon the kind of joint involved and the duration of these lesions. Also the grip strength resulted statistically improved at the 2 control. As regards objective values, there was a statistically significant improvement in tender and swollen

  16. Intestinal and sublingual microcirculation are more severely compromised in hemodilution than in hemorrhage.

    PubMed

    Ferrara, Gonzalo; Kanoore Edul, Vanina Siham; Martins, Enrique; Canales, Héctor Saúl; Canullán, Carlos; Murias, Gastón; Pozo, Mario Omar; Estenssoro, Elisa; Ince, Can; Dubin, Arnaldo

    2016-05-15

    The alterations in O2 extraction in hemodilution have been linked to fast red blood cell (RBC) velocity, which might affect the complete release of O2 from Hb. Fast RBC velocity might also explain the normal mucosal-arterial Pco2 (ΔPco2). Yet sublingual and intestinal microcirculation have not been completely characterized in extreme hemodilution. Our hypothesis was that the unchanged ΔPco2 in hemodilution depends on the preservation of villi microcirculation. For this purpose, pentobarbital-anesthetized and mechanically ventilated sheep were submitted to stepwise hemodilution (n = 8), hemorrhage (n = 8), or no intervention (sham, n = 8). In both hypoxic groups, equivalent reductions in O2 consumption (V̇o2) were targeted. Microcirculation was assessed by videomicroscopy, intestinal ΔPco2 by air tonometry, and V̇o2 by expired gases analysis. Although cardiac output and superior mesenteric flow increased in hemodilution, from the very first step (Hb = 5.0 g/dl), villi functional vascular density and RBC velocity decreased (21.7 ± 0.9 vs. 15.9 ± 1.0 mm/mm(2) and 1,033 ± 75 vs. 850 ± 79 μm/s, P < 0.01). In the last stage (Hb = 1.2 g/dl), these variables were lower in hemodiution than in hemorrhage (11.1 ± 0.5 vs. 15.4 ± 0.9 mm/mm(2) and 544 ± 26 vs. 686 ± 70 μm/s, P < 0.01), and were associated with lower intestinal fractional O2 extraction (0.61 ± 0.04 vs. 0.79 ± 0.02, P < 0.01) but preserved ΔPco2 (5 ± 2 vs. 25 ± 4 mmHg, P < 0.01). Therefore, alterations in O2 extraction in hemodilution seemed related to microvascular shunting, not to fast RBC velocity. The severe microvascular abnormalities suggest that normal ΔPco2 was not dependent on CO2 washout by the villi microcirculation. Increased perfusion in deeper intestinal layers might be an alternative explanation. PMID:26989219

  17. Cancer immunotherapy: accomplishments to date and future promise.

    PubMed

    Helmy, Karim Y; Patel, Shyam A; Nahas, George R; Rameshwar, Pranela

    2013-10-01

    Cancer remains a devastating disease as existing therapies are too often ineffective and toxicities remain unacceptably high. Immunotherapies for cancer offer the promise of the specificity and memory of the immune system against malignant cells to achieve durable cure with minimal toxicity. Beginning with the success of bone marrow transplantation for blood-borne cancers, and the more recent development of monoclonal antibody therapeutics for a variety of tumors, immunotherapies are already among the most successful class of treatments for cancer. Greater understanding of immunoregulatory mechanisms and improved techniques for immune cell manipulation and engineering have led to new immunomodulatory approaches and cell-based therapies for cancer that have generated great excitement within the biomedical community. As these technologies continue to improve, and as new approaches for harnessing the power and specificity of the immune system are developed, immunotherapies will play an increasingly important role in the treatment of cancer. Here, we review the history of immunotherapies for cancer and discuss existing and emerging immunotherapy technologies that hope to translate the promise of immunotherapy into clinical reality.

  18. Immunotherapy of Childhood Cancer: From Biologic Understanding to Clinical Application

    PubMed Central

    Wayne, Alan S.; Capitini, Christian M.; Mackall, Crystal L.

    2010-01-01

    Purpose of review Most children with cancer can be cured with combination regimens of chemotherapy, radiation, and/or surgery. However, standard therapies are toxic to normal tissues, cancer cells commonly develop resistance to chemotherapy, and relapsed malignancy is a leading cause of mortality in pediatrics. Elucidation of the principles of the normal immune response and tumor biology, coupled with technological developments, have led to important advances in the field of cancer immunotherapy. This review summarizes the biologic basis of cancer immunotherapy and highlights recent examples of progress in the application of novel humoral and cellular immunotherapies to children and adolescents with malignancy. Recent Findings Clinical trials of immunotherapy for pediatric cancer have recently been initiated. To date, most immune-based therapies have been well tolerated and some have shown clinically significant activity against specific refractory high-risk malignancies. Summary Recent clinical trial results provide proof-of-principle that cancer immunotherapy has the capacity to overcome chemotherapy resistance without the usual toxicities associated with cytotoxic regimens. Immunotherapy holds promise in the treatment of children and adolescents with cancer and has the potential to improve both survival and quality of life. PMID:19952749

  19. Study Design of the Microcirculatory Shock Occurrence in Acutely Ill Patients (microSOAP): an International Multicenter Observational Study of Sublingual Microcirculatory Alterations in Intensive Care Patients

    PubMed Central

    Vellinga, Namkje A. R.; Boerma, E. Christiaan; Koopmans, Matty; Donati, Abele; Dubin, Arnaldo; Shapiro, Nathan I.; Pearse, Rupert M.; Bakker, Jan; Ince, Can

    2012-01-01

    Objective. Sublingual microcirculatory alterations are associated with an adverse prognosis in several critical illness subgroups. Up to now, single-center studies have reported on sublingual microcirculatory alterations in ICU patient subgroups, but an extensive evaluation of the prevalence of these alterations is lacking. We present the study design of an international multicenter observational study to investigate the prevalence of microcirculatory alterations in critically ill: the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Methods. 36 ICU's worldwide have participated in this study aiming for inclusion of over 500 evaluable patients. To enable communication and data collection, a website, an Open Clinica 3.0 database, and image uploading software have been designed. A one-session assessment of the sublingual microcirculation using Sidestream Dark Field imaging and data collection on patient characteristics has been performed in every ICU patient >18 years, regardless of underlying disease. Statistical analysis will provide insight in the prevalence and severity of sublingual alterations, its relation to systemic hemodynamic variables, disease, therapy, and outcome. Conclusion. This study will be the largest microcirculation study ever performed. It is expected that this study will also establish a basis for future studies related to the microcirculation in critically ill. PMID:22666566

  20. Preparation and In Vitro/In Vivo Characterization of Porous Sublingual Tablets Containing Ternary Kneaded Solid System of Vinpocetine with β-Cyclodextrin and Hydroxy Acid

    PubMed Central

    Aburahma, Mona H.; El-Laithy, Hanan M.; Hamza, Yassin El-Said

    2010-01-01

    The demand for sublingual tablets has been growing during the previous decades especially for drugs with extensive hepatic first-pass metabolism. Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor aqueous solubility and marked first-pass metabolism. Accordingly, the aim of this work was to develop tablets for the sublingual delivery of vinpocetine. Initially, the feasibility of improving vinpocetine’s poor aqueous solubility by preparing kneaded solid systems of the drug with β-Cyclodextrin and hydroxy acids (citric acid and tartaric acid) was assessed. The solid system with improved solubility and dissolution properties was incorporated into porous tablets that rapidly disintegrate permitting fast release of vinpocetine into the sublingual cavity. The pores were induced into these tablets by directly compressing the tablets’ excipients with a sublimable material, either camphor or menthol, which was eventually sublimated leaving pores. The obtained results demonstrated that the tablets prepared using camphor attained sufficient mechanical strength for practical use together with rapid disintegration and dissolution. In vivo absorption study performed in rabbits indicated that the sublingual administration of the proposed porous tablets containing vinpocetine solid system with β-Cyclodextrin and tartaric acid could be useful for therapeutic application. PMID:21179352

  1. Comparison of N-linked Glycoproteins in Human Whole Saliva, Parotid, Submandibular, and Sublingual Glandular Secretions Identified using Hydrazide Chemistry and Mass Spectrometry.

    PubMed

    Ramachandran, Prasanna; Boontheung, Pinmanee; Pang, Eric; Yan, Weihong; Wong, David T; Loo, Joseph A

    2008-12-01

    INTRODUCTION: Saliva is a body fluid that holds promise for use as a diagnostic fluid for detecting diseases. Salivary proteins are known to be heavily glycosylated and are known to play functional roles in the oral cavity. We identified N-linked glycoproteins in human whole saliva, as well as the N-glycoproteins in parotid, submandibular, and sublingual glandular fluids. MATERIALS AND METHODS: We employed hydrazide chemistry to affinity enrich for N-linked glycoproteins and glycopeptides. PNGase F releases the N-peptides/proteins from the agarose-hydrazide resin, and liquid chromatography-tandem mass spectrometry was used to identify the salivary N-glycoproteins. RESULTS: A total of 156 formerly N-glycosylated peptides representing 77 unique N-glycoproteins were identified in salivary fluids. The total number of N-glycoproteins identified in the individual fluids was: 62, 34, 44, and 53 in whole saliva, parotid fluid, submandibular fluid, and sublingual fluid, respectively. The majority of the N-glycoproteins were annotated as extracellular proteins (40%), and several of the N-glycoproteins were annotated as membrane proteins (14%). A number of glycoproteins were differentially found in submandibular and sublingual glandular secretions. CONCLUSIONS: Mapping the N-glycoproteome of parotid, submandibular, and sublingual saliva is important for a thorough understanding of biological processes occurring in the oral cavity and to realize the role of saliva in the overall health of human individuals. Moreover, identifying glycoproteins in saliva may also be valuable for future disease biomarker studies.

  2. Immunocytokines: a promising approach to cancer immunotherapy.

    PubMed

    Lode, H N; Xiang, R; Becker, J C; Gillies, S D; Reisfeld, R A

    1998-12-01

    Recombinant antibody-cytokine fusion proteins are immunocytokines that achieve high cytokine concentrations in the tumor microenvironment and thereby effectively stimulate cellular immune responses against malignancies. The activation and expansion of immune effector cells, such as CD8+ T lymphocytes, by interleukin-2 immunocytokines resulted in the eradication of established pulmonary and hepatic metastases of murine melanoma and colorectal carcinoma in syngeneic mouse models. These immunocytokines were equally effective in eliminating established bone marrow and liver metastases of murine neuroblastoma by activating natural killer cells. The effective eradication of metastases by immunocytokines resulted in significant prolongation in life span of mice over that of controls receiving equivalent mixtures of antibody and interleukin-2, which failed to reduce the growth of disseminated metastases. Proof of concept was established, indicating that immunocytokine-induced activation and expansion of immune effector cells in the tumor microenvironment can effectively eradicate established tumor metastases. This promising new approach to cancer immunotherapy may lead to clinical applications that improve treatment of cancer patients with minimal residual disease in an adjuvant setting.

  3. [Adoptive immunotherapy with interleukin 2 in oncology].

    PubMed

    Favrot, M; Bouffet, E; Négrier, S; Combaret, V; Philip, I; Philip, T

    1990-01-01

    Forty-seven patients with renal carcinoma were included in first line or rescue protocols of immunotherapy including IL2 alone or in association with LAK cells, INF alpha or TNF. The toxicity was mild and the mortality was 2% (1 patient). The response rate was 26%. Nineteen children with neuroblastoma received IL2 either alone or in combination with LAK cells. The morbidity and mortality were higher in patients with end stage disease who had previously received high dose and prolonged chemotherapy. In contrast, the toxicity was mild and transient in patients treated in the months following autologous bone marrow transplantation. The only complete response observed was in 1 child treated with IL2, 4 months after high dose chemotherapy and ABMT. Immunological analysis showed that the immunomodulatory effect of IL2 is very different depending on whether IL2 is used alone or in combination with other cytokines; moreover, the biological effect of IL2 is dependent on the immunological status of the patients prior to IL2 therapy.

  4. Aptamers: A Feasible Technology in Cancer Immunotherapy.

    PubMed

    Soldevilla, M M; Villanueva, H; Pastor, F

    2016-01-01

    Aptamers are single-chained RNA or DNA oligonucleotides (ODNs) with three-dimensional folding structures which allow them to bind to their targets with high specificity. Aptamers normally show affinities comparable to or higher than that of antibodies. They are chemically synthesized and therefore less expensive to manufacture and produce. A variety of aptamers described to date have been shown to be reliable in modulating immune responses against cancer by either blocking or activating immune receptors. Some of them have been conjugated to other molecules to target the immune system and reduce off-target side effects. Despite the success of first-line treatments against cancer, the elevated number of relapsing cases and the tremendous side effects shown by the commonly used agents hinder conventional treatments against cancer. The advantages provided by aptamers could enhance the therapeutic index of a given strategy and therefore enhance the antitumor effect. Here we recapitulate the provided benefits of aptamers with immunomodulatory activity described to date in cancer therapy and the benefits that aptamer-based immunotherapy could provide either alone or combined with first-line treatments in cancer therapy.

  5. Role of interleukin 10 in specific immunotherapy.

    PubMed Central

    Akdis, C A; Blesken, T; Akdis, M; Wüthrich, B; Blaser, K

    1998-01-01

    The induction of allergen-specific anergy in peripheral T cells represents a key step in specific immunotherapy (SIT). Here we demonstrate that the anergic state results from increased IL-10 production. In bee venom (BV)-SIT the specific proliferative and cytokine responses against the main allergen, the phospholipase A2 (PLA), and T cell epitope-containing PLA peptides were significantly suppressed after 7 d of treatment. Simultaneously, the production of IL-10 increased during BV-SIT. After 28 d of BV-SIT the anergic state was established. Intracytoplasmic cytokine staining of PBMC combined with surface marker detection revealed that IL-10 was produced initially by activated CD4(+)CD25(+), allergen-specific T cells, and followed by B cells and monocytes. Neutralization of IL-10 in PBMC fully reconstituted the specific proliferative and cytokine responses. A similar state of IL-10-associated T cell anergy, as induced in BV-SIT, was found in hyperimmune individuals who recently had received multiple bee stings. The addition of IL-10 to soluble CD40 ligand IL-4-stimulated PBMC or purified B cells inhibited the PLA-specific and total IgE and enhanced the IgG4 formation. Accordingly, increased IL-10 production by SIT causes specific anergy in peripheral T cells, and regulates specific IgE and IgG4 production toward normal IgG4-related immunity. PMID:9649562

  6. Mechanisms of allergen-specific immunotherapy

    PubMed Central

    2012-01-01

    Allergen-specific immunotherapy (allergen-SIT) is a potentially curative treatment approach in allergic diseases. It has been used for almost 100 years as a desensitizing therapy. The induction of peripheral T cell tolerance and promotion of the formation of regulatory T-cells are key mechanisms in allergen-SIT. Both FOXP3+CD4+CD25+ regulatory T (Treg) cells and inducible IL-10- and TGF-β-producing type 1 Treg (Tr1) cells may prevent the development of allergic diseases and play a role in successful allergen-SIT and healthy immune response via several mechanisms. The mechanisms of suppression of different pro-inflammatory cells, such as eosinophils, mast cells and basophils and the development of allergen tolerance also directly or indirectly involves Treg cells. Furthermore, the formation of non-inflammatory antibodies particularly IgG4 is induced by IL-10. Knowledge of these molecular basis is crucial in the understanding the regulation of immune responses and their possible therapeutic targets in allergic diseases. PMID:22409879

  7. Aptamers: A Feasible Technology in Cancer Immunotherapy

    PubMed Central

    Villanueva, H.; Pastor, F.

    2016-01-01

    Aptamers are single-chained RNA or DNA oligonucleotides (ODNs) with three-dimensional folding structures which allow them to bind to their targets with high specificity. Aptamers normally show affinities comparable to or higher than that of antibodies. They are chemically synthesized and therefore less expensive to manufacture and produce. A variety of aptamers described to date have been shown to be reliable in modulating immune responses against cancer by either blocking or activating immune receptors. Some of them have been conjugated to other molecules to target the immune system and reduce off-target side effects. Despite the success of first-line treatments against cancer, the elevated number of relapsing cases and the tremendous side effects shown by the commonly used agents hinder conventional treatments against cancer. The advantages provided by aptamers could enhance the therapeutic index of a given strategy and therefore enhance the antitumor effect. Here we recapitulate the provided benefits of aptamers with immunomodulatory activity described to date in cancer therapy and the benefits that aptamer-based immunotherapy could provide either alone or combined with first-line treatments in cancer therapy. PMID:27413756

  8. Driving an improved CAR for cancer immunotherapy.

    PubMed

    Huang, Xiaopei; Yang, Yiping

    2016-08-01

    The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell-mediated therapy for solid tumors.

  9. Immunotherapy for advanced melanoma: fulfilling the promise.

    PubMed

    Gogas, Helen; Polyzos, Aristidis; Kirkwood, John

    2013-12-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:23725878

  10. Driving an improved CAR for cancer immunotherapy.

    PubMed

    Huang, Xiaopei; Yang, Yiping

    2016-08-01

    The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell-mediated therapy for solid tumors. PMID:27454296

  11. Toll-like Receptors in Tumor Immunotherapy

    PubMed Central

    Paulos, Chrystal M.; Kaiser, Andrew; Wrzesinski, Claudia; Hinrichs, Christian S.; Cassard, Lydie; Boni, Andrea; Muranski, Pawel; Sanchez-Perez, Luis; Palmer, Douglas C.; Yu, Zhiya; Antony, Paul A.; Gattinoni, Luca; Rosenberg, Steven A.; Restifo, Nicholas P.

    2007-01-01

    Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory Tcells (Treg) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as “sinks” for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression. PMID:17875756

  12. Multiple myeloma, immunotherapy and minimal residual disease.

    PubMed

    Kusenda, J; Kovarikova, A

    2016-01-01

    Multiple myeloma (MM) is an incurable heterogeneous hematological malignancy in which relapse is characterized by re-growth of residual tumor and immune suppression with a complex biology that affects many aspects of the disease and its response to treatment. The bone marrow microenvironment, including immune cells, plays a central role in MM pathogenesis, survival, and drug resistance. The advances in basic and translational research, introduction of novel agents, particularly combination therapies, improved indicators of quality of life and survival. Minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) has revolutionized monitoring of treatment response in MM. The importance of MFC methodology will be further strengthened by the ongoing international standardization efforts. Results of MRD testing provide unique and clinically important information and demonstrated the prognostic significance of MRD in patients, leading to regulate treatment intensity in many contemporary protocols. In this review, we will summarize the principal approaches in MM immunotherapy, focusing how new agents have potential in the treatment of MM and application of MRD detection by MFC as a surrogate endpoint would allow quicker evaluation of treatment outcomes and rapid identification of effective new therapies.

  13. Advances in cancer immunology and cancer immunotherapy.

    PubMed

    Voena, Claudia; Chiarle, Roberto

    2016-02-01

    After decades of setbacks, cancer immunology is living its Golden Age. Recent advances in cancer immunology have provided new therapeutic approaches to treat cancer. The objective clinical response observed in patients treated with antibodies that block the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) pathways, has led to their FDA approval for the treatment of melanoma in 2011 and in 2014, respectively. The anti-PD-1 antibody nivolumab has received the FDA-approval in March 2015 for squamous lung cancer treatment. In addition, antibodies targeting PD-1 or PD-L1 have demonstrated their efficacy and safety in additional tumors, including non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's lymphoma. Almost at the same time, the field of adoptive cell transfer has exploded. The chimeric antigen receptor (CAR) T technology has provided strong evidence of efficacy in the treatment of B cell malignancies, and different T cell based treatments are currently under investigation for different types of tumors. In this review we will discuss the latest advances in cancer immunology and immunotherapy as well as new treatments now under development in the clinic and potential strategies that have shown promising results in preclinical models. PMID:27011048

  14. Sarcoma Immunotherapy: Past Approaches and Future Directions

    PubMed Central

    D'Angelo, S. P.; Tap, W. D.; Schwartz, G. K.; Carvajal, R. D.

    2014-01-01

    Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. PMID:24778572

  15. Combining radiotherapy and immunotherapy: A revived partnership

    SciTech Connect

    Demaria, Sandra; Bhardwaj, Nina; McBride, William H.; Formenti, Silvia C. . E-mail: silvia.formenti@med.nyu.edu

    2005-11-01

    Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. The current rationale for its use is based largely on the ability of RT to kill the cancer cells by a direct cytotoxic effect. Nevertheless, considerable evidence indicates that RT effects extend beyond the mere elimination of the more radiosensitive fraction of cancer cells present within a tumor at the time of radiation exposure. For instance, a large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This might have far-reaching consequences regarding the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective antitumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from preclinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance antitumor effects. Conversely, RT could be a useful tool to combine with immunotherapy. This article will briefly summarize what is known about the impact of RT on tumor immunity, including tumor-associated antigens, antigen-presenting cells, and effector mechanisms. In addition, the experimental evidence supporting the contention that RT can be used as a tool to induce antitumor immunity is discussed, and a new approach to radioimmunotherapy of cancer is proposed.

  16. [Immunotherapies for multiple sclerosis : review and update].

    PubMed

    Havla, J; Kümpfel, T; Hohlfeld, R

    2015-04-01

    Multiple sclerosis (MS) is an inflammatory, presumably autoimmune disease affecting the central nervous system. Early stages of the disease are characterized by conspicuous inflammation of the white and grey matter. During later stages, presumably secondary neurodegeneration leads to physical disability progression. Over the last decade increasingly effective therapeutic options have been approved. Currently 11 immunomodulatory or immunosuppressive therapies targeting relapse rate, disease progression and paraclinical disease activity are available, mostly for relapsing forms of MS. However, the ideal of "precision medicine" is still in the distant future since biomarkers for individualized treatment are lacking. For implementation of risk-management plans to minimize the risk of severe side effects, interdisciplinary collaboration between neurologists and internists is essential. In this review article we summarize practical aspects of the implemented risk-management plans, and discuss possible side effects and special caveats of the three new immunotherapies teriflunomide, dimethyl fumarate, and alemtuzumab. This article is based on, among others, the recently updated guidelines of the German Society of Neurology. Particular attention is given to the risks of new therapies, monitoring, and on special aspects needing attention when changing treatments. Teriflunomide, dimethyl fumarate, and alemtuzumab expand treatment options for relapsing-remitting MS. Treatment selection should take into consideration the safety profile of the substance, previous and concomitant diseases, and other individual factors. This requires in-depth consultation and individual assessment of current disease activity, the potential efficacy of the therapy, and the possible risks and side effects. PMID:25720530

  17. Recent advances in immunotherapy for hepatocellular cancer.

    PubMed

    Butterfield, Lisa H

    2007-02-10

    There is a continuing need for innovative, alternative therapies for hepatocellular carcinoma (HCC). Immunotherapy of cancer is attractive because of the exquisite specificity of the immune response. Activation of an HCC-specific response can be accomplished by strategies targeting tumour-associated antigens (for example: alpha fetoprotein (AFP)) or viral antigens in those patients infected with hepatitis B or C. Uncharacterised and mutated antigens can also be targeted with whole tumour cell or tumour lysate-based immunisation strategies. Viral vectors coding for genes which make the patient's tumour immunogenic can allow the immune system to naturally evolve specificity against immunogenic target antigens. Strategies which have been tested in human clinical trials include adoptive transfer of lymphocytes, cytokine injections, autologous tumour-pulsed dendritic cells (DC) as well as AFP-derived peptides in adjuvant and pulsed onto autologous DC. These trials, testing novel immune-based interventions in HCC subjects, have resulted in immunological responses and some have impacted recurrence and survival of HCC subjects.

  18. Targeting lentiviral vectors for cancer immunotherapy

    PubMed Central

    Arce, Frederick; Breckpot, Karine; Collins, Mary; Escors, David

    2012-01-01

    Delivery of tumour-associated antigens (TAA) in a way that induces effective, specific immunity is a challenge in anti-cancer vaccine design. Circumventing tumour-induced tolerogenic mechanisms in vivo is also critical for effective immunotherapy. Effective immune responses are induced by professional antigen presenting cells, in particular dendritic cells (DC). This requires presentation of the antigen to both CD4+ and CD8+ T cells in the context of strong co-stimulatory signals. Lentiviral vectors have been tested as vehicles, for both ex vivo and in vivo delivery of TAA and/or activation signals to DC, and have been demonstrated to induce potent T cell mediated immune responses that can control tumour growth. This review will focus on the use of lentiviral vectors for in vivo gene delivery to DC, introducing strategies to target DC, either targeting cell entry or gene expression to improve safety of the lentiviral vaccine or targeting dendritic cell activation pathways to enhance performance of the lentiviral vaccine. In conclusion, this review highlights the potential of lentiviral vectors as a generally applicable ‘off-the-shelf’ anti-cancer immunotherapeutic. PMID:22983382

  19. Effects of laser immunotherapy on tumor microenvironment

    NASA Astrophysics Data System (ADS)

    Acquaviva, Joseph T.; Wood, Ethan W.; Hasanjee, Aamr; Chen, Wei R.; Vaughan, Melville B.

    2014-02-01

    The microenvironments of tumors are involved in a complex and reciprocal dialog with surrounding cancer cells. Any novel treatment must consider the impact of the therapy on the microenvironment. Recently, clinical trials with laser immunotherapy (LIT) have proven to effectively treat patients with late-stage, metastatic breast cancer and melanoma. LIT is the synergistic combination of phototherapy (laser irradiation) and immunological stimulation. One prominent cell type found in the tumor stroma is the fibroblast. Fibroblast cells can secrete different growth factors and extracellular matrix modifying molecules. Furthermore, fibroblast cells found in the tumor stroma often express alpha smooth muscle actin. These particular fibroblasts are coined cancer-associated fibroblast cells (CAFs). CAFs are known to facilitate the malignant progression of tumors. A collagen lattice assay with human fibroblast cells is used to elucidate the effects LIT has on the microenvironment of tumors. Changes in the contraction of the lattice, the differentiation of the fibroblast cells, as well as the proliferation of the fibroblast cells will be determined.

  20. Oral immunotherapy and tolerance induction in childhood.

    PubMed

    Tang, M L K; Martino, D J

    2013-09-01

    Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food-allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long-term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy.

  1. Sublingual immunization with the phosphate-binding-protein (PstS) reduces oral colonization by Streptococcus mutans.

    PubMed

    Ferreira, E L; Batista, M T; Cavalcante, R C M; Pegos, V R; Passos, H M; Silva, D A; Balan, A; Ferreira, L C S; Ferreira, R C C

    2016-10-01

    Bacterial ATP-binding cassette (ABC) transporters play a crucial role in the physiology and pathogenicity of different bacterial species. Components of ABC transporters have also been tested as target antigens for the development of vaccines against different bacterial species, such as those belonging to the Streptococcus genus. Streptococcus mutans is the etiological agent of dental caries, and previous studies have demonstrated that deletion of the gene encoding PstS, the substrate-binding component of the phosphate uptake system (Pst), reduced the adherence of the bacteria to abiotic surfaces. In the current study, we generated a recombinant form of the S. mutans PstS protein (rPstS) with preserved structural features, and we evaluated the induction of antibody responses in mice after sublingual mucosal immunization with a formulation containing the recombinant protein and an adjuvant derived from the heat-labile toxin from enterotoxigenic Escherichia coli strains. Mice immunized with rPstS exhibited systemic and secreted antibody responses, measured by the number of immunoglobulin A-secreting cells in draining lymph nodes. Serum antibodies raised in mice immunized with rPstS interfered with the adhesion of bacteria to the oral cavity of naive mice challenged with S. mutans. Similarly, mice actively immunized with rPstS were partially protected from oral colonization after challenge with the S. mutans NG8 strain. Therefore, our results indicate that S. mutans PstS is a potential target antigen capable of inducing specific and protective antibody responses after sublingual administration. Overall, these observations raise interesting perspectives for the development of vaccines to prevent dental caries. PMID:26462737

  2. Phenotype and cell proliferation activity of duct-like structures in human sublingual glands: a histological and immunohistochemical study

    PubMed Central

    TOLENTINO, Elen de Souza; TEIXEIRA, Cleverson Soares; AZEVEDO-ALANIS, Luciana Reis; HONÓRIO, Heitor Marques; DAMANTE, José Humberto

    2015-01-01

    There are several age-related microscopic changes in the salivary glands, including the increase in the number of duct-like structures (DLS). However, the true origin and the phenotype of the DLS are not known. Objective To evaluate the phenotype and the cell proliferation index of the DLS of human sublingual glands. Material and Methods Sixty sublingual glands obtained from human cadavers were divided into two groups - 0-30 and 61-90 years old. The phenotype was estimated by immunostaining for cytokeratin 19 (CK 19) and the S-100 protein as well as by the presence of mucin and glycogen. The cell proliferation index was determined by the Ki-67 antibody. The histochemical techniques used periodic acid-Schiff (PAS) and Alcian Blue. In each captured microscopic field, the DLS were counted to establish a percentage for the staining profile. The statistical analysis was accomplished using Student’s t-test, the Mann-Whitney test and Pearson’s correlation coefficient (p<0.05). Results Comparing both groups, only CK 19 showed a statistically significant difference (p=0.033), with the strongest expression in the elderly group. There was no significant difference between PAS and Alcian Blue (p=0.270). In both groups, the immunostaining for CK 19 was stronger than that for S-100 (p=0.004;p<0.001), but there was no correlation between the two immunomarkers (ρ=-0.163; p=0.315). There was no immunostaining for Ki-67. Conclusions DLS demonstrate a ductal phenotypic profile and do not present cell proliferation activity. DLS may represent a regressive process arising from acini or represent the result of metaplasia. PMID:26221919

  3. Does allergen-specific immunotherapy induce contact allergy to aluminium?

    PubMed

    Netterlid, Eva; Hindsén, Monica; Siemund, Ingrid; Björk, Jonas; Werner, Sonja; Jacobsson, Helene; Güner, Nuray; Bruze, Magnus

    2013-01-01

    Persistent, itching nodules have been reported to appear at the injection site after allergen-specific immuno-therapy with aluminium-precipitated antigen extract, occasionally in conjunction with contact allergy to aluminium. This study aimed to quantify the development of contact allergy to aluminium during allergen-specific immunotherapy. A randomized, controlled, single-blind multicentre study of children and adults entering allergen-specific immunotherapy was performed using questionnaires and patch-testing. A total of 205 individuals completed the study. In the 3 study groups all subjects tested negative to aluminium before allergen-specific immunotherapy and 4 tested positive after therapy. In the control group 4 participants tested positive to aluminium. Six out of 8 who tested positive also had atopic dermatitis. Positive test results were found in 5/78 children and 3/127 adults. Allergen-specific immunotherapy was not shown to be a risk factor for contact allergy to aluminium. Among those who did develop aluminium allergy, children and those with atopic dermatitis were more highly represented.

  4. Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy.

    PubMed

    Anguille, Sébastien; Smits, Evelien L; Bryant, Christian; Van Acker, Heleen H; Goossens, Herman; Lion, Eva; Fromm, Phillip D; Hart, Derek N; Van Tendeloo, Viggo F; Berneman, Zwi N

    2015-10-01

    Although the earliest—rudimentary—attempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy.

  5. Recent advances and future of immunotherapy for glioblastoma

    PubMed Central

    Kamran, Neha; Calinescu, Alexandra; Candolfi, Marianela; Chandran, Mayuri; Mineharu, Yohei; Assad, Antonela S; Koschmann, Carl; Nunez, Felipe; Lowenstein, Pedro; Castro, Maria

    2016-01-01

    Introduction Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. Areas covered Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. Expert opinion Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature. PMID:27411023

  6. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    PubMed Central

    Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

    2013-01-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas. PMID:24202450

  7. Immunotherapy in human colorectal cancer: Challenges and prospective

    PubMed Central

    Sun, Xuan; Suo, Jian; Yan, Jun

    2016-01-01

    Human colorectal cancer (CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy.

  8. Prostate cancer as a model for tumour immunotherapy.

    PubMed

    Drake, Charles G

    2010-08-01

    Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context.

  9. Harnessing immunosurveillance: current developments and future directions in cancer immunotherapy

    PubMed Central

    Drakes, Maureen L; Stiff, Patrick J

    2014-01-01

    Despite improved methods of cancer detection and disease management over the last few decades, cancer remains a major public health problem in many societies. Conventional therapies, such as chemotherapy, radiation, and surgery, are not usually sufficient to prevent disease recurrence. Therefore, efforts have been focused on developing novel therapies to manage metastatic disease and to prolong disease-free and overall survival, by modulating the immune system to alleviate immunosuppression, and to enhance antitumor immunity. This review discusses protumor mechanisms in patients that circumvent host immunosurveillance, and addresses current immunotherapy modalities designed to target these mechanisms. Given the complexity of cancer immunosuppressive mechanisms, we propose that identification of novel disease biomarkers will drive the development of more targeted immunotherapy. Finally, administration of different classes of immunotherapy in combination regimens, will be the ultimate route to impact low survival rates in advanced cancer patients. PMID:27471706

  10. Oral immunotherapy for food allergy: mechanisms and role in management.

    PubMed

    Nowak-Węgrzyn, A; Albin, S

    2015-02-01

    With the emergence of food allergy as an important public health problem, it has become clear that there is an unmet need in regard to treatment. In particular, IgE-mediated food allergy that is associated with risk of fatal anaphylaxis has been the subject of multiple studies in the past decade. The growing body of evidence derived from multiple centres and various study designs indicates that for IgE-mediated food allergy, immunomodulation through food immunotherapy is possible; however, the extent of protection afforded by such treatment is highly variable. At this time, the capacity for food immunotherapy to restore permanent tolerance to food has not been demonstrated conclusively. This review will discuss these topics as they apply to the most important studies of food oral immunotherapy.

  11. Strategies to genetically engineer T cells for cancer immunotherapy.

    PubMed

    Spear, Timothy T; Nagato, Kaoru; Nishimura, Michael I

    2016-06-01

    Immunotherapy is one of the most promising and innovative approaches to treat cancer, viral infections, and other immune-modulated diseases. Adoptive immunotherapy using gene-modified T cells is an exciting and rapidly evolving field. Exploiting knowledge of basic T cell biology and immune cell receptor function has fostered innovative approaches to modify immune cell function. Highly translatable clinical technologies have been developed to redirect T cell specificity by introducing designed receptors. The ability to engineer T cells to manifest desired phenotypes and functions is now a thrilling reality. In this review, we focus on outlining different varieties of genetically engineered T cells, their respective advantages and disadvantages as tools for immunotherapy, and their promise and drawbacks in the clinic. PMID:27138532

  12. Propionibacterium acnes in the pathogenesis and immunotherapy of acne vulgaris.

    PubMed

    Liu, Pei-Feng; Hsieh, Yao-Dung; Lin, Ya-Ching; Two, Aimee; Shu, Chih-Wen; Huang, Chun-Ming

    2015-01-01

    Acne vulgaris, a multi-factorial disease, is one of the most common skin diseases, affecting an estimated 80% of Americans at some point during their lives. The gram-positive and anaerobic Propionibacterium acnes (P. acnes) bacterium has been implicated in acne inflammation and pathogenesis. Therapies for acne vulgaris using antibiotics generally lack bacterial specificity, promote the generation of antibiotic-resistant bacterial strains, and cause adverse effects. Immunotherapy against P. acnes or its antigens (sialidase and CAMP factor) has been demonstrated to be effective in mice, attenuating P. acnes-induced inflammation; thus, this method may be applied to develop a potential vaccine targeting P. acnes for acne vulgaris treatment. This review summarizes reports describing the role of P. acnes in the pathogenesis of acne and various immunotherapy-based approaches targeting P. acnes, suggesting the potential effectiveness of immunotherapy for acne vulgaris as well as P. acnes-associated diseases.

  13. T-Cell-Based Immunotherapy for Osteosarcoma: Challenges and Opportunities

    PubMed Central

    Wang, Zhan; Li, Binghao; Ren, Yingqing; Ye, Zhaoming

    2016-01-01

    Even though combining surgery with chemotherapy has significantly improved the prognosis of osteosarcoma patients, advanced, metastatic, or recurrent osteosarcomas are often non-responsive to chemotherapy, making development of novel efficient therapeutic methods an urgent need. Adoptive immunotherapy has the potential to be a useful non-surgical modality for treatment of osteosarcoma. Recently, alternative strategies, including immunotherapies using naturally occurring or genetically modified T cells, have been found to hold promise in the treatment of hematologic malignancies and solid tumors. In this review, we will discuss possible T-cell-based therapies against osteosarcoma with a special emphasis on combination strategies to improve the effectiveness of adoptive T cell transfer and, thus, to provide a rationale for the clinical development of immunotherapies.

  14. Cancer Immunotherapy: Selected Targets and Small-Molecule Modulators.

    PubMed

    Weinmann, Hilmar

    2016-03-01

    There is a significant amount of excitement in the scientific community around cancer immunotherapy, as this approach has renewed hope for many cancer patients owing to some recent successes in the clinic. Currently available immuno-oncology therapeutics under clinical development and on the market are mostly biologics (antibodies, proteins, engineered cells, and oncolytic viruses). However, modulation of the immune system with small molecules offers several advantages that may be complementary and potentially synergistic to the use of large biologicals. Therefore, the discovery and development of novel small-molecule modulators is a rapidly growing research area for medicinal chemists working in cancer immunotherapy. This review provides a brief introduction into recent trends related to selected targets and pathways for cancer immunotherapy and their small-molecule pharmacological modulators.

  15. Immunotherapy in human colorectal cancer: Challenges and prospective

    PubMed Central

    Sun, Xuan; Suo, Jian; Yan, Jun

    2016-01-01

    Human colorectal cancer (CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy. PMID:27605872

  16. New insights into antigen specific immunotherapy for chronic myeloid leukemia

    PubMed Central

    2012-01-01

    Chronic myeloid leukemia (CML) is a stem cell disease in which BCR/ABL plays an important role as an oncoprotein and a molecular and immunogenic target. Despite the success of targeted therapy using tyrosine kinase inhibitors (TKIs), CML remains largely incurable, most likely due to the treatment resistance of leukemic stem cells. Several immunotherapies have been developed for CML in different stages and relapse after allogeneic stem cell transplantation. In the this review, several specific immunotherapeutic approaches for CML, including vaccination and adoptive cellular immunotherapy, are discussed along with results from clinical trials, and the value of such immunotherapies in the era of imatinib and leukemia-associated antigens (LAAs), which are capable of inducing specific T cell responses and are appropriate target structures for the immunological targeting of CML cells, are also summarized. PMID:23241263

  17. Immunotherapy in human colorectal cancer: Challenges and prospective.

    PubMed

    Sun, Xuan; Suo, Jian; Yan, Jun

    2016-07-28

    Human colorectal cancer (CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy. PMID:27605872

  18. Antigen-based immunotherapy for autoimmune disease: current status

    PubMed Central

    Hirsch, Darren Lowell; Ponda, Punita

    2015-01-01

    Autoimmune diseases are common chronic disorders that not only have a major impact on the quality of life but are also potentially life-threatening. Treatment modalities that are currently favored have conferred significant clinical benefits, but they may have considerable side effects. An optimal treatment strategy for autoimmune disease would specifically target disease-associated antigens and limit systemic side effects. Similar to allergen-specific immunotherapy for allergic rhinitis, antigen-specific immunotherapy for autoimmune disease aims to induce immune deviation and promote tolerance to specific antigens. In this review, we present the current status of studies and clinical trials in both human and animal hosts that use antigen-based immunotherapy for autoimmune disease. PMID:27471707

  19. Past, present and future targets for immunotherapy in ovarian cancer.

    PubMed

    Schwab, Carlton L; English, Diana P; Roque, Dana M; Pasternak, Monica; Santin, Alessandro D

    2014-01-01

    Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions.

  20. Melanoma immunotherapy: historical precedents, recent successes and future prospects.

    PubMed

    Raaijmakers, Marieke I G; Rozati, Sima; Goldinger, Simone M; Widmer, Daniel S; Dummer, Reinhard; Levesque, Mitchell P

    2013-02-01

    The idea of cancer immunotherapy has been around for more than a century; however, the first immunotherapeutic ipilimumab, an anti-CTLA-4 antibody, has only recently been approved by the US FDA for melanoma. With an increasing understanding of the immune response, it is expected that more therapies will follow. This review aims to provide a general overview of immunotherapy in melanoma. We first explain the development of cancer immunotherapy more than a century ago and the general opinions about it over time. This is followed by a general overview of the immune reaction in order to give insight into the possible targets for therapy. Finally, we will discuss the current therapies for melanoma, their shortcomings and why it is important to develop patient stratification criteria. We conclude with an overview of recent discoveries and possible future therapies.

  1. Immunotherapy and lung cancer: current developments and novel targeted therapies.

    PubMed

    Domingues, Duarte; Turner, Alice; Silva, Maria Dília; Marques, Dânia Sofia; Mellidez, Juan Carlos; Wannesson, Luciano; Mountzios, Giannis; de Mello, Ramon Andrade

    2014-01-01

    Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician's therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC.

  2. T-Cell-Based Immunotherapy for Osteosarcoma: Challenges and Opportunities

    PubMed Central

    Wang, Zhan; Li, Binghao; Ren, Yingqing; Ye, Zhaoming

    2016-01-01

    Even though combining surgery with chemotherapy has significantly improved the prognosis of osteosarcoma patients, advanced, metastatic, or recurrent osteosarcomas are often non-responsive to chemotherapy, making development of novel efficient therapeutic methods an urgent need. Adoptive immunotherapy has the potential to be a useful non-surgical modality for treatment of osteosarcoma. Recently, alternative strategies, including immunotherapies using naturally occurring or genetically modified T cells, have been found to hold promise in the treatment of hematologic malignancies and solid tumors. In this review, we will discuss possible T-cell-based therapies against osteosarcoma with a special emphasis on combination strategies to improve the effectiveness of adoptive T cell transfer and, thus, to provide a rationale for the clinical development of immunotherapies. PMID:27683579

  3. Propionibacterium acnes in the pathogenesis and immunotherapy of acne vulgaris.

    PubMed

    Liu, Pei-Feng; Hsieh, Yao-Dung; Lin, Ya-Ching; Two, Aimee; Shu, Chih-Wen; Huang, Chun-Ming

    2015-01-01

    Acne vulgaris, a multi-factorial disease, is one of the most common skin diseases, affecting an estimated 80% of Americans at some point during their lives. The gram-positive and anaerobic Propionibacterium acnes (P. acnes) bacterium has been implicated in acne inflammation and pathogenesis. Therapies for acne vulgaris using antibiotics generally lack bacterial specificity, promote the generation of antibiotic-resistant bacterial strains, and cause adverse effects. Immunotherapy against P. acnes or its antigens (sialidase and CAMP factor) has been demonstrated to be effective in mice, attenuating P. acnes-induced inflammation; thus, this method may be applied to develop a potential vaccine targeting P. acnes for acne vulgaris treatment. This review summarizes reports describing the role of P. acnes in the pathogenesis of acne and various immunotherapy-based approaches targeting P. acnes, suggesting the potential effectiveness of immunotherapy for acne vulgaris as well as P. acnes-associated diseases. PMID:26264195

  4. Past, present and future targets for immunotherapy in ovarian cancer

    PubMed Central

    Schwab, Carlton L; English, Diana P; Roque, Dana M; Pasternak, Monica; Santin, Alessandro D

    2015-01-01

    Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions. PMID:25524384

  5. Cellular immunotherapy for refractory hematological malignancies

    PubMed Central

    2013-01-01

    Background Acute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance. Methods/design The trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been

  6. Combined Cancer Immunotherapy Against Aurora Kinase A.

    PubMed

    Kaštánková, Iva; Poláková, Ingrid; Dušková, Martina; Šmahel, Michal

    2016-05-01

    Aurora kinase A (AURKA) is a centrosomal protein that is overexpressed in a number of human malignancies and can contribute to tumor progression. As we used this protein as a target of DNA immunization, we increased its immunogenicity by the addition of the PADRE helper epitope and decreased its potential oncogenicity by mutagenesis of the kinase domain. For in vitro analysis of induced immune responses in mice, we identified the Aurka(220-228) nonapeptide representing an H-2Kb epitope. As DNA vaccination against the Aurka self-antigen by a gene gun did not show any antitumor effect, we combined DNA immunization with anti-CD25 treatment that depletes mainly regulatory T cells. Whereas 1 anti-CD25 dose injected before DNA vaccination did not enhance the activation of Aurka-specific splenocytes, 3 doses administered on days of immunizations augmented about 10-fold immunity against Aurka. However, an opposite effect was found for antitumor immunity-only 1 anti-CD25 dose combined with DNA vaccination reduced tumor growth. Moreover, the administration of 3 doses of anti-CD25 antibody alone accelerated tumor growth. Analysis of tumor-infiltrating cells showed that 3 anti-CD25 doses not only efficiently depleted regulatory T cells but also activated helper T cells and CD3(-)CD25(+) cells. Next, we found that blockade of the PD-1 receptor initiated 1 week after the first immunization was necessary for significant inhibition of tumor growth with therapeutic DNA vaccination against Aurka combined with depletion of CD25 cells. Our results suggest that combined cancer immunotherapy should be carefully evaluated to achieve the optimal antitumor effect. PMID:27070447

  7. Amyloid-ß-directed immunotherapy for Alzheimer's disease

    PubMed Central

    Lannfelt, L; Relkin, N R; Siemers, E R

    2014-01-01

    Lannfelt L, Relkin NR, Siemers ER (Uppsala University, Uppsala, Sweden; Weill Cornell Medical College, New York, NY; and Eli Lilly and Co., Indianapolis, IN, USA). Amyloid-ß-directed immunotherapy for Alzheimer’s disease. (Key Symposium). J Intern Med 2014; 275: 284–295. Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing Aß-directed immunotherapies that have passed clinical development Phase IIa. PMID:24605809

  8. Tumor microenvironment: hypoxia and buffer capacity for immunotherapy.

    PubMed

    Liu, Chenghu; Gao, Shangxian; Qu, Zhonghua; Zhang, Lining

    2007-01-01

    In recent years, significant progress has been made in the study of tumor biology and anti-tumor immunotherapy. However, the cellular and molecular mechanisms of tumor progression still remain obscure. As we know, tumor microenvironment that can directly influence tumor development and prognosis has attracted much attention of large number of immunologists. Accumulated evidence has suggested that tumor microenvironment is in a hypoxic condition, under which immune cells may exhibit distinct functions compared to those under normal oxygen tension. The article we propose here will offer a novel point of view for understanding tumor microenvironment in order to instruct clinical immunotherapy. Just like the pH buffer system in human body, interactions of immune cells in tumor microenvironment may also constitute a buffer system, the balance of which is of great importance during immunotherapy for tumors. However, many protocols for tumor immunotherapy in clinic at present have not taken it into account, so the therapeutic outcome is often disappointing. In the present study, we have demonstrated the effect of Corynebacterium parvum, a well known immune stimulator, on malignant melanoma. Cell ingredients in tumor-infiltrating lymphocytes (TIL) and their anti-tumor effect have been altered when dosage of Corynebacterium parvum is changed. So, to obtain better therapeutic purposes, what we should do first is to detect an index to evaluate immune buffer capacity for the patient during tumor immunotherapy, then to choose appropriate drug doses to augment buffer capacity for their immune buffer system. Taken together, the hypothesis proposed here may help understand the pathogenesis of tumor progression and design more effective strategy for clinical immunotherapy for tumors. PMID:17360127

  9. Dendritic cell-based cancer immunotherapy for colorectal cancer.

    PubMed

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-05-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients. PMID:27158196

  10. Dendritic cell-based cancer immunotherapy for colorectal cancer.

    PubMed

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-05-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients.

  11. Vaccines versus immunotherapy: Overview of approaches in deciding between options

    PubMed Central

    Dalgleish, Angus G

    2015-01-01

    This review compares the optimal use of vaccines vs. other forms of immunotherapy, which includes cytokines, such as IL-2, monoclonal antibodies, such as the ‘checkpoint inhibitors’, against CTLA-4 and PD-1. The review includes both prophylactic and therapeutic vaccines using a variety of technologies. It is already established that vaccines can be enhanced by other immunotherapies, such as cytokines (IL-2) and there is scope for combining both of these with the ‘checkpoint’ antibodies. Moreover, both can be enhanced with other modalities, such as radiotherapy, ablative therapy and both high and low dose chemotherapies. PMID:25625932

  12. Current Immunotherapies for Sarcoma: Clinical Trials and Rationale

    PubMed Central

    Mitsis, Demytra; Francescutti, Valerie

    2016-01-01

    Sarcoma tumors are rare and heterogeneous, yet they possess many characteristics that may facilitate immunotherapeutic responses. Both active strategies including vaccines and passive strategies involving cellular adoptive immunotherapy have been applied clinically. Results of these clinical trials indicate a distinct benefit for select patients. The recent breakthrough of immunologic checkpoint inhibition is being rapidly introduced to a variety of tumor types including sarcoma. It is anticipated that these emerging immunotherapies will exhibit clinical efficacy for a variety of sarcomas. The increasing ability to tailor immunologic therapies to sarcoma patients will undoubtedly generate further enthusiasm and clinical research for this treatment modality. PMID:27703409

  13. MUC1 as a target antigen for cancer immunotherapy.

    PubMed

    Acres, Bruce; Limacher, Jean-Marc

    2005-08-01

    The cancer-associated antigen MUC1 is overexpressed and modified by tumor cells in over half of all cancer cases. Despite various complexities associated with this antigen, it is well worth pursuing as a vaccine for the immunotherapy of cancer. In this review, the authors describe the discovery of MUC1 and its association with cancer, recent observations showing that the immunology of MUC1 is complicated, animal data showing that it can be a target for immune-mediated tumor rejection, and finally, preliminary clinical results to show that vaccine-based immunotherapy with MUC1 does have an impact on the therapy of cancer. PMID:16117706

  14. Dendritic cell-based cancer immunotherapy for colorectal cancer

    PubMed Central

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-01-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients. PMID:27158196

  15. Gene-modified hematopoietic stem cells for cancer immunotherapy.

    PubMed

    Larson, Sarah; De Oliveira, Satiro N

    2014-01-01

    The rapid expansion of available cancer immunotherapies has resulted in favorable early outcomes. Specifically the use of gene therapy to introduce chimeric antigen receptors (CARs) and T cell receptors (TCRs) in T cells creates new immunotherapy options for patients. While showing early success with these approaches, limitations remain that can be overcome by the use of modification of hematopoietic stem cells (HSCs) to express CARs and TCRs. With modern gene therapy technologies, increased safety and control of the modification of the HSCs can be achieved through the use of a suicide gene.

  16. Porous silicon advances in drug delivery and immunotherapy

    PubMed Central

    Savage, D; Liu, X; Curley, S; Ferrari, M; Serda, RE

    2013-01-01

    Biomedical applications of porous silicon include drug delivery, imaging, diagnostics and immunotherapy. This review summarizes new silicon particle fabrication techniques, dynamics of cellular transport, advances in the multistage vector approach to drug delivery, and the use of porous silicon as immune adjuvants. Recent findings support superior therapeutic efficacy of the multistage vector approach over single particle drug delivery systems in mouse models of ovarian and breast cancer. With respect to vaccine development, multivalent presentation of pathogen-associated molecular patterns on the particle surface creates powerful platforms for immunotherapy, with the porous matrix able to carry both antigens and immune modulators. PMID:23845260

  17. A synthetic triacylated pseudo-dipeptide molecule promotes Th1/TReg immune responses and enhances tolerance induction via the sublingual route.

    PubMed

    Mascarell, Laurent; Van Overtvelt, Laurence; Lombardi, Vincent; Razafindratsita, Alain; Moussu, Hélène; Horiot, Stéphane; Chabre, Henri; Limal, David; Moutel, Stéphane; Bauer, Jacques; Chiavaroli, Carlo; Moingeon, Philippe

    2007-12-21

    In this study, we tested two triacylated pseudo-dipeptidic molecules, OM-197-MP-AC and OM-294-BA-MP as candidate adjuvants for allergy vaccines. Both molecules induce human dendritic cell (h-DC) maturation and polarize naïve T cells toward the Th1 type with IFNgamma production. Only OM-294-BA-MP induces IL10 gene expression both in monocyte-derived DCs and CD4+ naïve T cells. Sublingual administration of OM-294-BA-MP plus the antigen enhances tolerance induction in BALB/c mice with established asthma to ovalbumin with an impact on both airways hyperresponsiveness and lung inflammation. Given its Th1/Treg polarizing properties, OM-294-BA-MP is a valid candidate for sublingual allergy vaccines.

  18. Ipsilateral removal of sublingual gland after excision of submandibular gland for benign disease: 10-year prospective study and comprehensive review 1978-2008.

    PubMed

    O'Regan, Barry; Mather, Craig I

    2011-04-01

    The removal of the submandibular salivary gland for non-neoplastic disease is a common procedure that has well documented risks and postoperative complications. Persistent symptoms of pain and swelling in the floor of the mouth that can occur after excision of the submandibular gland may require removal of the sublingual gland, but a causative association between the two has not, to our knowledge, been comprehensively established. We prospectively studied 77 patients who had had excision of the submandibular gland for benign disease, six of whom (8%) returned to theatre for ipsilateral sublingual sialadenectomy within a 5-year period after the initial operation (mean 24 months). These findings suggest that the association is under-reported, and may need to be considered during the consent process for excision of the submandibular salivary gland.

  19. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome

    PubMed Central

    Yoshizawa, Kunio; Moroi, Akinori; Kawashiri, Shuichi; Ueki, Koichiro

    2016-01-01

    A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS) is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS) with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis. PMID:27144039

  20. A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway

    PubMed Central

    Kiyotoh, Eiji; Okazaki, Arimichi; Gomi, Yasuyuki; Tanimoto, Takeshi; Takeuchi, Osamu; Akira, Shizuo; Hori, Mitsuhiko

    2015-01-01

    A lipopolysaccharide from Pantoea agglomerans (LPSpa) has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine) with LPSpa induced both HA-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens. PMID:25978818

  1. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome.

    PubMed

    Yoshizawa, Kunio; Moroi, Akinori; Kawashiri, Shuichi; Ueki, Koichiro

    2016-01-01

    A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS) is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS) with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis.

  2. Cancer immunotherapy: are we there yet?

    PubMed Central

    2013-01-01

    The immune system is the built-in host defense mechanism against infectious agents as well as cancer. Protective immunity against cancer was convincingly demonstrated in the 1940s with syngeneic animal models (JNCI 18:769-778, 1976; Cancer Immun 1:6, 2001). Since then, the last century’s dream has been to effectively prevent and cure cancers by immunological means. This dream has slowly but surely become a reality (Nature 480:480-489, 2011). The successful examples of immunoprophylaxis and therapy against cancers include: (i) targeted therapy using monoclonal antibodies (Nat Rev Cancer 12:278-287, 2012); (ii) allogeneic hematopoietic stem cell transplantion to elicit graft-versus-cancer effect against a variety of hematopoietic malignancies (Blood 112:4371-4383, 2008); (iii) vaccination for preventing cancers with clear viral etiology such as hepatocellular carcinoma and cervical cancer (Cancer J Clin 57:7-28, 2007; NEJM 336:1855-1859, 1997); (iv) T cell checkpoint blockade against inhibitory pathways including targeting CTLA-4 and PD-1 inhibitory molecules for the treatment of melanoma and other solid tumors (NEJM 363:711-723, 2010; NEJM 366:2443-2454, 2012; NEJM 369:122-133, 2013; NEJM 366:2455-2465, 2012); (v) antigen-pulsed autologous dendritic cell vaccination against prostate cancer (NEJM 363:411-422, 2010); and (vi) the transfer of T cells including those genetically engineered with chimeric antigen receptors allowing targeting of B cell neoplasms (NEJM 365:725-733, 2011; NEJM 368:1509-1518, 2013; Blood 118:4817-4828, 2013; Sci Transl Med 5:177ra138, 2013). This article provides an overview on the exciting and expanding immunological arsenals against cancer, and discusses critical remaining unanswered questions of cancer immunology. The inherent specificity and memory of the adaptive immune response towards cancer will undoubtedly propel cancer immunotherapy to the forefront of cancer treatment in the immediate near future. Study of the fundamental

  3. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    PubMed Central

    Swift, Stephanie L.; Stojdl, David F.

    2016-01-01

    Large-scale assays, such as microarrays, next-generation sequencing and various “omics” technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy—from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse—has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system. PMID:26861383

  4. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy.

    PubMed

    Swift, Stephanie L; Stojdl, David F

    2016-02-01

    Large-scale assays, such as microarrays, next-generation sequencing and various "omics" technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy-from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse-has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system. PMID:26861383

  5. Novel technologies and emerging biomarkers for personalized cancer immunotherapy.

    PubMed

    Yuan, Jianda; Hegde, Priti S; Clynes, Raphael; Foukas, Periklis G; Harari, Alexandre; Kleen, Thomas O; Kvistborg, Pia; Maccalli, Cristina; Maecker, Holden T; Page, David B; Robins, Harlan; Song, Wenru; Stack, Edward C; Wang, Ena; Whiteside, Theresa L; Zhao, Yingdong; Zwierzina, Heinz; Butterfield, Lisa H; Fox, Bernard A

    2016-01-01

    The culmination of over a century's work to understand the role of the immune system in tumor control has led to the recent advances in cancer immunotherapies that have resulted in durable clinical responses in patients with a variety of malignancies. Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, not all patients respond to immunotherapy and even those that do often experience toxicities. Thus, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of the mechanisms underlying the complex interactions between the immune system and cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) reconvened an Immune Biomarkers Task Force to review state of the art technologies, identify current hurdlers, and make recommendations for the field. As a product of this task force, Working Group 2 (WG2), consisting of international experts from academia and industry, assembled to identify and discuss promising technologies for biomarker discovery and validation. Thus, this WG2 consensus paper will focus on the current status of emerging biomarkers for immune checkpoint blockade therapy and discuss novel technologies as well as high dimensional data analysis platforms that will be pivotal for future biomarker research. In addition, this paper will include a brief overview of the current challenges with recommendations for future biomarker discovery.

  6. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    PubMed

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy.

  7. Cancer immunotherapy: the beginning of the end of cancer?

    PubMed

    Farkona, Sofia; Diamandis, Eleftherios P; Blasutig, Ivan M

    2016-05-05

    These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.

  8. Dendritic-tumor fusion cells in cancer immunotherapy.

    PubMed

    Takakura, Kazuki; Kajihara, Mikio; Ito, Zensho; Ohkusa, Toshifumi; Gong, Jianlin; Koido, Shigeo

    2015-03-01

    A promising area of clinical investigation is the use of cancer immunotherapy to treat cancer patients. Dendritic cells (DCs) operate as professional antigen-presenting cells (APCs) and play a critical role in the induction of antitumor immune responses. Thus, DC-based cancer immunotherapy represents a powerful strategy. One DC-based cancer immunotherapy strategy that has been investigated is the administration of fusion cells generated with DCs and whole tumor cells (DC-tumor fusion cells). The DC-tumor fusion cells can process a broad array of tumor-associated antigens (TAAs), including unidentified molecules, and present them through major histocompatibility complex (MHC) class I and II pathways in the context of co-stimulatory signals. Improving the therapeutic efficacy of DC-tumor fusion cell-based cancer immunotherapy requires increased immunogenicity of DCs and whole tumor cells. We discuss the potential ability of DC-tumor fusion cells to activate antigen-specific T cells and strategies to improve the immunogenicity of DC-tumor fusion cells as anticancer vaccines.

  9. Improving the clinical impact of biomaterials in cancer immunotherapy.

    PubMed

    Gammon, Joshua M; Dold, Neil M; Jewell, Christopher M

    2016-03-29

    Immunotherapies for cancer have progressed enormously over the past few decades, and hold great promise for the future. The successes of these therapies, with some patients showing durable and complete remission, demonstrate the power of harnessing the immune system to eradicate tumors. However, the effectiveness of current immunotherapies is limited by hurdles ranging from immunosuppressive strategies employed by tumors, to inadequate specificity of existing therapies, to heterogeneity of disease. Further, the vast majority of approved immunotherapies employ systemic delivery of immunomodulators or cells that make addressing some of these challenges more difficult. Natural and synthetic biomaterials - such as biocompatible polymers, self-assembled lipid particles, and implantable biodegradable devices - offer unique potential to address these hurdles by harnessing the benefits of therapeutic targeting, tissue engineering, co-delivery, controlled release, and sensing. However, despite the enormous investment in new materials and nanotechnology, translation of these ideas to the clinic is still an uncommon outcome. Here we review the major challenges facing immunotherapies and discuss how the newest biomaterials and nanotechnologies could help overcome these challenges to create new clinical options for patients.

  10. Improving the clinical impact of biomaterials in cancer immunotherapy

    PubMed Central

    Gammon, Joshua M.; Dold, Neil M.; Jewell, Christopher M.

    2016-01-01

    Immunotherapies for cancer have progressed enormously over the past few decades, and hold great promise for the future. The successes of these therapies, with some patients showing durable and complete remission, demonstrate the power of harnessing the immune system to eradicate tumors. However, the effectiveness of current immunotherapies is limited by hurdles ranging from immunosuppressive strategies employed by tumors, to inadequate specificity of existing therapies, to heterogeneity of disease. Further, the vast majority of approved immunotherapies employ systemic delivery of immunomodulators or cells that make addressing some of these challenges more difficult. Natural and synthetic biomaterials–such as biocompatible polymers, self-assembled lipid particles, and implantable biodegradable devices–offer unique potential to address these hurdles by harnessing the benefits of therapeutic targeting, tissue engineering, co-delivery, controlled release, and sensing. However, despite the enormous investment in new materials and nanotechnology, translation of these ideas to the clinic is still an uncommon outcome. Here we review the major challenges facing immunotherapies and discuss how the newest biomaterials and nanotechnologies could help overcome these challenges to create new clinical options for patients. PMID:26871948

  11. [Cutaneous ulcerating nodules after many years of immunotherapy].

    PubMed

    Bouten, Hanneke; Nijsten, Tamar E C; Noordhoek Hegt, Vincent

    2016-01-01

    A 40-year-old female patient was referred to the department of Dermatology with subcutaneous nodules and ulcers years after starting with immunotherapy injections (Purethal) for hay fever. The skin reaction appeared to be due to aluminium hydroxide, which is used as an adjuvant to many injections and vaccins. Aluminium hydroxide can cause delayed granulomatous contact dermatitis or foreign body reactions.

  12. Dendritic-tumor fusion cells in cancer immunotherapy.

    PubMed

    Takakura, Kazuki; Kajihara, Mikio; Ito, Zensho; Ohkusa, Toshifumi; Gong, Jianlin; Koido, Shigeo

    2015-03-01

    A promising area of clinical investigation is the use of cancer immunotherapy to treat cancer patients. Dendritic cells (DCs) operate as professional antigen-presenting cells (APCs) and play a critical role in the induction of antitumor immune responses. Thus, DC-based cancer immunotherapy represents a powerful strategy. One DC-based cancer immunotherapy strategy that has been investigated is the administration of fusion cells generated with DCs and whole tumor cells (DC-tumor fusion cells). The DC-tumor fusion cells can process a broad array of tumor-associated antigens (TAAs), including unidentified molecules, and present them through major histocompatibility complex (MHC) class I and II pathways in the context of co-stimulatory signals. Improving the therapeutic efficacy of DC-tumor fusion cell-based cancer immunotherapy requires increased immunogenicity of DCs and whole tumor cells. We discuss the potential ability of DC-tumor fusion cells to activate antigen-specific T cells and strategies to improve the immunogenicity of DC-tumor fusion cells as anticancer vaccines. PMID:25828520

  13. Systemic and local reactions of bee venom immunotherapy in Iran.

    PubMed

    Bemanian, Mohammad Hassan; Farhoudi, Abolhassan; Pourpak, Zahra; Gharagozlou, Mohammad; Movahedi, Masoud; Nabavi, Mohammad; Mozafari, Habibeh; Mohammadzadeh, Iraj; Chavoshzadeh, Zahra; Shirkhoda, Zahra

    2007-12-01

    Severe allergic reactions during specific immunotherapy may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during specific immunotherapy in patients with allergy towards hymenoptera venom in the Iranian population. A prospective study was performed using the clinical reports of 27 patients with anaphylaxis to bee venom (Apis melifera, Geupes vespula and Geupes Polites). Ten patients treated with Cluster protocol during 2002 and 2006 After diagnosis of hymenoptera sting allergy according to history and intradermal tests, the patient were treated with Cluster protocol immunotherapy. The protocol lasted 6 weeks with an increase in the concentration of venom from 0.01 microg/ml to 100 microg/ml. None of the patient received premedication. All patients with hymenoptera venom allergy received 120 injections. Anaphylactic reactions were classified according to the Mueller-classification. The frequencies of systemic reactions during Cluster protocol were 8.33% and 5% for yellow jacket and honey bee venom respectively. No patient experienced severe systemic reaction. Cluster protocol for hymenoptera immunotherapy is a reliable method for the treatment of anaphylactic reactions to bee venom. It is safe with low cost and do not need hospitalization.

  14. Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy

    PubMed Central

    De Souza Rebouças, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, María Luisa; Irache, Juan Manuel; Gamazo, Carlos

    2012-01-01

    In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines. PMID:22496608

  15. Nanoparticulate adjuvants and delivery systems for allergen immunotherapy.

    PubMed

    De Souza Rebouças, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, María Luisa; Irache, Juan Manuel; Gamazo, Carlos

    2012-01-01

    In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines.

  16. NK Cell-based Immunotherapies in Pediatric Oncology

    PubMed Central

    McDowell, Kimberly A.; Hank, Jacquelyn A.; DeSantes, Kenneth B.; Capitini, Christian M.; Otto, Mario; Sondel, Paul M.

    2015-01-01

    The past decade has seen several anti-cancer immunotherapeutic strategies transition from “promising preclinical models” to treatments with proven clinical activity or benefit. In 2013, the journal Science selected the field of Cancer Immunotherapy as the overall number-1 breakthrough for the year in all of scientific research. In the setting of cancer immunotherapy for adult malignancies, many of these immunotherapy strategies have relied on the cancer patient’s endogenous anti-tumor T cell response. While much promising research in pediatric oncology is similarly focused on T cell reactivity, several pediatric malignancies themselves, or the chemo-radiotherapy used to achieve initial responses, can be associated with profound immune suppression, particularly of the T cell system. A separate component of the immune system, also able to mediate anti-tumor effects and less suppressed by conventional cancer treatment, is the NK cell system. In recent years, several distinct immunotherapeutic approaches that rely on the activity of NK cells have moved from preclinical development into clinical testing, and some have shown clear antitumor benefit. This review provides an overview of NK cell-based immunotherapy efforts that are directed towards childhood malignancies, with an emphasis on protocols that are already in clinical testing. PMID:25590232

  17. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy.

    PubMed

    Swift, Stephanie L; Stojdl, David F

    2016-02-05

    Large-scale assays, such as microarrays, next-generation sequencing and various "omics" technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy-from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse-has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system.

  18. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    PubMed

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy. PMID:26469159

  19. Cancer immunotherapy: the beginning of the end of cancer?

    PubMed

    Farkona, Sofia; Diamandis, Eleftherios P; Blasutig, Ivan M

    2016-01-01

    These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies. PMID:27151159

  20. Seasonal versus perennial immunotherapy: evaluation after three years of treatment.

    PubMed

    Muñoz Lejarazu, D; Bernaola, G; Fernández, E; Audícana, M; Ventas, P; Martín, S; Fernández de Corres, L

    1993-01-01

    We have performed a comparative study to evaluate seasonal and perennial schedules after 3 years of immunotherapy. Sixty patients suffering from rhinitis and/or asthma due to grass pollen sensitization were randomly allocated to receive a semi-depot extract of Phleum pratense according to a perennial or seasonal schedule. The last year of the study, 14 patients were recruited as a control group without immunotherapy. The cumulative dose was 602 BU in the perennial group and 372 BU in the seasonal group. The frequency and severity of side-effects were similar and very low in both treated groups. The IgE level was significantly lower after perennial immunotherapy at the end of the first 2 years. A seasonal decrease in specific IgG levels was observed in patients who interrupted immunotherapy, while this was not observed in patients under the perennial schedule. Symptoms and medication scores did not show differences between groups. Nevertheless, we found a significant difference between treated patients and the control group. PMID:8281355

  1. Oral Immunotherapy for Treatment of Egg Allergy in Children

    PubMed Central

    Burks, A. Wesley; Jones, Stacie M.; Wood, Robert A.; Fleischer, David M.; Sicherer, Scott H.; Lindblad, Robert W.; Stablein, Donald; Henning, Alice K.; Vickery, Brian P.; Liu, Andrew H.; Scurlock, Amy M.; Shreffler, Wayne G.; Plaut, Marshall; Sampson, Hugh A.

    2012-01-01

    BACKGROUND For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy. METHODS In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months. RESULTS After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months. CONCLUSIONS These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; Clinical

  2. Systems biology applied to vaccine and immunotherapy development

    PubMed Central

    2011-01-01

    Immunotherapies, including vaccines, represent a potent tool to prevent or contain disease with high morbidity or mortality such as infections and cancer. However, despite their widespread use, we still have a limited understanding of the mechanisms underlying the induction of protective immune responses. Immunity is made of a multifaceted set of integrated responses involving a dynamic interaction of thousands of molecules; among those is a growing appreciation for the role the innate immunity (i.e. pathogen recognition receptors - PRRs) plays in determining the nature and duration (immune memory) of adaptive T and B cell immunity. The complex network of interactions between immune manipulation of the host (immunotherapy) on one side and innate and adaptive responses on the other might be fully understood only employing the global level of investigation provided by systems biology. In this framework, the advancement of high-throughput technologies, together with the extensive identification of new genes, proteins and other biomolecules in the "omics" era, facilitate large-scale biological measurements. Moreover, recent development of new computational tools enables the comprehensive and quantitative analysis of the interactions between all of the components of immunity over time. Here, we review recent progress in using systems biology to study and evaluate immunotherapy and vaccine strategies for infectious and neoplastic diseases. Multi-parametric data provide novel and often unsuspected mechanistic insights while enabling the identification of common immune signatures relevant to human investigation such as the prediction of immune responsiveness that could lead to the improvement of the design of future immunotherapy trials. Thus, the paradigm switch from "empirical" to "knowledge-based" conduct of medicine and immunotherapy in particular, leading to patient-tailored treatment. PMID:21933421

  3. Preliminary buprenorphine sublingual tablet pharmacokinetic data in plasma, oral fluid and sweat during treatment of opioid-dependent pregnant women

    PubMed Central

    Concheiro, Marta; Jones, Hendreé E.; Johnson, Rolley E.; Choo, Robin; Huestis, Marilyn A.

    2011-01-01

    Background Buprenorphine is currently under investigation as a pharmacotherapy to treat pregnant women for opioid dependence. This research evaluates buprenorphine (BUP), norbuprenophine (NBUP), buprenorphine-glucuronide (BUP-Gluc) and norbuprenorphine-glucuronide (NBUP-Gluc) pharmacokinetics after high dose (14–20 mg) BUP sublingual tablet administration in three opioid-dependent pregnant women. Methods Oral fluid and sweat specimens were collected in addition to plasma specimens for 24 h during gestation weeks 28 or 29 and 34, and 2 months after delivery. Tmax was not affected by pregnancy; however, BUP and NBUP Cmax and AUC0–24h tended to be lower during pregnancy compared to postpartum levels. Results Statistically significant but weak positive correlations were found for BUP plasma and OF concentrations, and BUP/NBUP ratios in plasma and OF. Conclusion Statistically significant negative correlations were observed for times of specimen collection and BUP and NBUP OF/plasma ratios. BUP-Gluc and NBUP-Gluc were detected in only 5% of OF specimens. In sweat, BUP and NBUP were detected in only 4 of 25 (12 or 24 h) specimens in low concentrations (<2.4 ng/patch). These preliminary data describe BUP and metabolite pharmacokinetics in pregnant women and suggest that, like methadone, upward dose adjustments may be needed with advancing gestation. PMID:21860340

  4. Safety of allergen immunotherapy: a review of premedication and dose adjustment.

    PubMed

    Morris, A Erika; Marshall, Gailen D

    2012-03-01

    From the first allergen immunotherapy proposed in the early 1900s to the present day, numerous studies have proven the efficacy of allergen immunotherapy for the treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma and stinging insect hypersensitivity. The major risk, however small, with allergen immunotherapy is anaphylaxis. There has been considerable interest and debate regarding risk factors for immunotherapy reactions (local and systemic) and interventions to reduce the occurrence of these reactions. One of these interventions that is especially debated regards dose adjustment for various reasons, but in particular for local reactions. In this review, we discuss the safety of immunotherapy and provide a comprehensive review of the literature regarding immunotherapy schedules and doses.

  5. Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges.

    PubMed

    Cynis, Holger; Frost, Jeffrey L; Crehan, Helen; Lemere, Cynthia A

    2016-01-01

    Immunization against amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) has shown considerable therapeutic effect in animal models however, the translation into human Alzheimer's patients is challenging. In recent years, a number of promising Aβ immunotherapy trials failed to reach primary study endpoints. Aside from uncertainties in the selection of patients and the start and duration of treatment, these results also suggest that the mechanisms underlying AD are still not fully understood. Thorough characterizations of protein aggregates in AD brain have revealed a conspicuous heterogeneity of Aβ peptides enabling the study of the toxic potential of each of the major forms. One such form, amino-terminally truncated and modified pyroglutamate (pGlu)-3 Aβ peptide appears to play a seminal role for disease initiation, qualifying it as novel target for immunotherapy approaches. PMID:27363697

  6. Current clinical trials testing the combination of immunotherapy with radiotherapy.

    PubMed

    Kang, Josephine; Demaria, Sandra; Formenti, Silvia

    2016-01-01

    Increasing evidence demonstrates that radiation acts as an immune stimulus, recruiting immune mediators that enable anti-tumor responses within and outside the radiation field. There has been a rapid expansion in the number of clinical trials harnessing radiation to enhance antitumor immunity. If positive, results of these trials will lead to a paradigm shift in the use of radiotherapy. In this review, we discuss the rationale for trials combining radiation with various immunotherapies, provide an update of recent clinical trial results and highlight trials currently in progress. We also address issues pertaining to the optimal incorporation of immunotherapy with radiation, including sequencing of treatment, radiation dosing and evaluation of clinical trial endpoints. PMID:27660705

  7. DNA-inorganic hybrid nanovaccine for cancer immunotherapy

    NASA Astrophysics Data System (ADS)

    Zhu, Guizhi; Liu, Yijing; Yang, Xiangyu; Kim, Young-Hwa; Zhang, Huimin; Jia, Rui; Liao, Hsien-Shun; Jin, Albert; Lin, Jing; Aronova, Maria; Leapman, Richard; Nie, Zhihong; Niu, Gang; Chen, Xiaoyuan

    2016-03-01

    Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit

  8. Nanotechnology to augment immunotherapy for the treatment of glioblastoma multiforme.

    PubMed

    Ung, Nolan; Yang, Isaac

    2015-07-01

    Glioblastoma multiforme (GBM) is characterized as one of the most common and most deadly malignant primary brain tumors. Current treatment modalities include the use of surgical resection and adjuvant chemotherapy and radiation therapy, though survival is still limited. Because of this, new treatment strategies are needed to improve overall survival. Immunotherapy has emerged as a potential treatment, but still possesses certain limitations to have a substantial clinical effect. In addition, nanotechnology has emerged as potent treatment effectors that have been shown to augment the effects of therapies including chemotherapy, gene therapy, and more. Nanoparticles possess a novel approach due to the myriad of functional groups that can create targeted treatments, though further optimization is still required. In this review, the authors will present the current uses and abilities of nanotechnology and its implication for use with immunotherapy in the treatment of GBM.

  9. CD40 ligand immunotherapy in cancer: an efficient approach.

    PubMed

    Kuwashima, N; Kageyama, S; Eto, Y; Urashima, M

    2001-01-01

    Cancer cells do not elicit a clinically sufficient anti-tumor immune response that results in tumor rejection. Recently, many investigators have been trying to enhance anti-tumor immunity and encouraging results have been reported. This review will discuss current anti-cancer immunotherapy; interleukin-2 therapy, tumor vaccine secreting Granulocyte macrophage-colony stimulating factor, dendritic cells fused with tumor cells, and CD40 ligand immunotherapy. Moreover, we introduce our two kinds of CD40 ligand immuno-genetherapy; (1) oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium (published in BLOOD 2000), (2) cancer vaccine transfected with CD40 ligand ex vivo for neuroblastoma (unpublished). Both approaches resulted in a high degree of protection against the tumor progression and they are simple and safe in the murine system.

  10. Novel targets for natural killer/T-cell lymphoma immunotherapy.

    PubMed

    Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

    2016-01-01

    Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL. PMID:26642249

  11. Molecular imaging of cell-based cancer immunotherapy

    PubMed Central

    Liu, Gang; Swierczewska, Magdalena; Zhang, Xiaoming

    2011-01-01

    Cell-based cancer immunotherapy represents a new and powerful weapon in the arsenal of anticancer treatments. Non-invasive monitoring of the disposition, migration and destination of therapeutic cells will facilitate the development of cell based therapy. The therapeutic cells can be modified intrinsically by a reporter gene or labeled extrinsically by introducing imaging probes into the cells or on the cell surface before transplant. Various advanced non-invasive molecular imaging techniques are playing important roles in optimizing cellular therapy by tracking cells and monitoring the therapeutic effects of transplanted cells in vivo. This review will summarize the application of multiple molecular imaging modalities in cell-based cancer immunotherapy. PMID:21308113

  12. Rationale for anti-CD137 cancer immunotherapy.

    PubMed

    Makkouk, Amani; Chester, Cariad; Kohrt, Holbrook E

    2016-02-01

    The consideration of the complex interplay between the tumour microenvironment (TME) and the immune response is the key for designing effective immunotherapies. Therapeutic strategies that harness co-stimulatory receptors have recently gained momentum in the clinic. One such strategy with promising clinical applications is the targeting of CD137, a member of the tumour necrosis factor receptor superfamily. Its expression on both innate and adaptive immune cells, coupled with its unique ability to potentiate antitumour responses through modulating the TME and to ameliorate autoimmune responses, has established it as an appealing target. In this review, we will discuss the various CD137-targeted immunotherapeutics that have reached clinical development, with a focus on recent advances and novel modalities such as CD137 chimeric antigen receptors and CD137 bispecific antibodies. We will also highlight the effect of CD137 targeting on the TME and discuss the importance of probing TME changes for predicting and testing the efficacy of CD137-mediated immunotherapy.

  13. Combinations of Immunotherapy and Radiation in Cancer Therapy

    PubMed Central

    Vatner, Ralph E.; Cooper, Benjamin T.; Vanpouille-Box, Claire; Demaria, Sandra; Formenti, Silvia C.

    2014-01-01

    The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer. PMID:25506582

  14. Modulation of immune responses by immunotherapy in allergic diseases.

    PubMed

    Cavkaytar, Ozlem; Akdis, Cezmi A; Akdis, Mübeccel

    2014-08-01

    Allergen immunotherapy (AIT) has been used for 100 years and until now different immunoregulatory pathways have been shown to take place in its mechanisms of action. It is characterized by administration of the causative allergen and is shown to be clinically efficient even after discontinuation of therapy particularly in allergic respiratory diseases, bee venom allergy, and food allergy. Generation of antigen/allergen-specific peripheral tolerance is the key mechanism during immunotherapy. It is mediated by development of T and B regulatory cells, IgG4 isotype allergen-specific antibodies and the involvement of multiple suppressor factors, which lead to decreased tissue inflammation, early and late phase responses. Describing novel regulatory mechanisms in the process of immune tolerance induction will help to identify treatment modalities not only for allergic disorders, but also for autoimmune diseases, organ transplantation, chronic infections, and cancer.

  15. Management of polysensitized patient: from molecular diagnostics to biomolecular immunotherapy.

    PubMed

    Ciprandi, Giorgio; Incorvaia, Cristoforo; Frati, Franco

    2015-01-01

    A panel of Italian allergists gathered to discuss the issue concerning the management of polysensitized patients. The main conclusions were as follows: polysensitization is a relevant clinical characteristic as it affects about 70-80% of the global allergic population; the diagnostic pathway needs the use of an adequate and thorough methodology, based on the demonstration of consistency between history and documented sensitization; polysensitization and polyallergy are not synonymous: true allergy should always be demonstrated; polysensitization does not constitute a limitation to allergen immunotherapy prescription, as 1-2 allergen extracts could be effective in polysensitized patients; the allergen immunotherapy product characteristics should include the following: high efficacy and optimal safety profile, standardized production, and documented presence and titration of the major allergen. PMID:26144241

  16. The Interplay of Immunotherapy and Chemotherapy: Harnessing Potential Synergies

    PubMed Central

    Emens, Leisha A.; Middleton, Gary

    2016-01-01

    Although cancer chemotherapy has historically been considered immune suppressive, it is now accepted that certain chemotherapies can augment tumor immunity. The recent success of immune checkpoint inhibitors has renewed interest in immunotherapies, and in combining them with chemotherapy to achieve additive or synergistic clinical activity. Two major ways that chemotherapy promotes tumor immunity are by inducing immunogenic cell death as part of its intended therapeutic effect, and by disrupting strategies that tumors use to evade immune recognition. This second strategy in particular is dependent on the drug, its dose, and the schedule of chemotherapy administration in relation to antigen exposure or release. In this Cancer Immunology at the Crossroads article we focus on cancer vaccines and immune checkpoint blockade as a forum for reviewing preclinical and clinical data demonstrating the interplay between immunotherapy and chemotherapy. PMID:25941355

  17. CD40 ligand immunotherapy in cancer: an efficient approach.

    PubMed

    Kuwashima, N; Kageyama, S; Eto, Y; Urashima, M

    2001-01-01

    Cancer cells do not elicit a clinically sufficient anti-tumor immune response that results in tumor rejection. Recently, many investigators have been trying to enhance anti-tumor immunity and encouraging results have been reported. This review will discuss current anti-cancer immunotherapy; interleukin-2 therapy, tumor vaccine secreting Granulocyte macrophage-colony stimulating factor, dendritic cells fused with tumor cells, and CD40 ligand immunotherapy. Moreover, we introduce our two kinds of CD40 ligand immuno-genetherapy; (1) oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium (published in BLOOD 2000), (2) cancer vaccine transfected with CD40 ligand ex vivo for neuroblastoma (unpublished). Both approaches resulted in a high degree of protection against the tumor progression and they are simple and safe in the murine system. PMID:11911421

  18. Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases.

    PubMed

    Tran, Thanh-Huyen; Mattheolabakis, George; Aldawsari, Hibah; Amiji, Mansoor

    2015-09-01

    Cell secreted exosomes (30-100nm vesicles) play a major role in intercellular communication due to their ability to transfer proteins and nucleic acids from one cell to another. Depending on the originating cell type and the cargo, exosomes can have immunosuppressive or immunostimulatory effects, which have potential application as immunotherapies for cancer and autoimmune diseases. Cellular components shed from tumor cells or antigen presenting cells (APCs), such as dendritic cells, macrophages and B cells, have been shown to be efficiently packaged in exosomes. In this review, we focus on the application of exosomes as nanocarriers and immunological agents for cancer and autoimmune immunotherapy. APC-derived exosomes demonstrate effective therapeutic efficacy for the treatment of cancer and experimental autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In addition to their intrinsic immunomodulating activity, exosomes have many advantages over conventional nanocarriers for drug and gene delivery.

  19. Management of polysensitized patient: from molecular diagnostics to biomolecular immunotherapy.

    PubMed

    Ciprandi, Giorgio; Incorvaia, Cristoforo; Frati, Franco

    2015-01-01

    A panel of Italian allergists gathered to discuss the issue concerning the management of polysensitized patients. The main conclusions were as follows: polysensitization is a relevant clinical characteristic as it affects about 70-80% of the global allergic population; the diagnostic pathway needs the use of an adequate and thorough methodology, based on the demonstration of consistency between history and documented sensitization; polysensitization and polyallergy are not synonymous: true allergy should always be demonstrated; polysensitization does not constitute a limitation to allergen immunotherapy prescription, as 1-2 allergen extracts could be effective in polysensitized patients; the allergen immunotherapy product characteristics should include the following: high efficacy and optimal safety profile, standardized production, and documented presence and titration of the major allergen.

  20. Targeting CD8+ T-cell tolerance for cancer immunotherapy.

    PubMed

    Jackson, Stephanie R; Yuan, Jinyun; Teague, Ryan M

    2014-01-01

    In the final issue of Science in 2013, the American Association of Science recognized progress in the field of cancer immunotherapy as the 'Breakthrough of the Year.' The achievements were actually twofold, owing to the early success of genetically engineered chimeric antigen receptors (CAR) and to the mounting clinical triumphs achieved with checkpoint blockade antibodies. While fundamentally very different, the common thread of these independent strategies is the ability to prevent or overcome mechanisms of CD8(+) T-cell tolerance for improved tumor immunity. Here we discuss how circumventing T-cell tolerance has provided experimental insights that have guided the field of clinical cancer immunotherapy to a place where real breakthroughs can finally be claimed.

  1. Cancer-associated fibroblasts as targets for immunotherapy.

    PubMed

    Kakarla, Sunitha; Song, Xiao-Tong; Gottschalk, Stephen

    2012-11-01

    Immunotherapy for solid tumors has shown promise in preclinical as well as early clinical studies. However, its efficacy remains limited. The hindrance to achieving objective, long-lasting therapeutic responses in solid tumors is, in part, mediated by the dynamic nature of the tumor and its complex microenvironment. Tumor-directed therapies fail to eliminate components of the microenvironment, which can reinstate a tumorigenic milieu and contribute to recurrence. Cancer-associated fibroblasts (CAFs) form the most preponderant cell type in the solid tumor microenvironment. Given their pervasive role in facilitating tumor growth and metastatic dissemination, CAFs have emerged as attractive therapeutic targets in the tumor microenvironment. In this article, we highlight the cross-talk between CAFs and cancer cells, and discuss how targeting CAFs has the potential to improve current immunotherapy approaches for cancer.

  2. Novel targets for natural killer/T-cell lymphoma immunotherapy.

    PubMed

    Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

    2016-01-01

    Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL.

  3. Preamble to the 2015 SITC immunotherapy biomarkers taskforce.

    PubMed

    Butterfield, Lisa H; Disis, Mary L; Fox, Bernard A; Khleif, Samir N; Marincola, Francesco M

    2015-01-01

    The Society for Immunotherapy of Cancer (SITC) has regularly hosted workshops and working groups focused on immunologic monitoring and immune biomarkers. Due to advances in cancer immunotherapy, including positive results from clinical trials testing new agents and combinations, emerging new technologies for measuring aspects of immunity, and novel candidate biomarkers from early phase trials, the SITC Immune Biomarkers Taskforce has reconvened to review the state of the art, identify current hurdles to further success and to make recommendations to the field. Topics being addressed by individual working groups include: (1) validation of candidate biomarkers, (2) identification of the most promising technologies, (3) testing of high throughput immune signatures and (4) investigation of the pre-treatment tumor microenvironment. Resultant recommendations will be published in JITC.

  4. Is immunotherapy an opportunity for effective treatment of drug addiction?

    PubMed

    Zalewska-Kaszubska, Jadwiga

    2015-11-27

    Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy. PMID:26432911

  5. Advances in chimeric antigen receptor immunotherapy for neuroblastoma.

    PubMed

    Heczey, Andras; Louis, Chrystal U

    2013-12-01

    Neuroblastoma (NBL) is the most common extracranial pediatric solid tumor and has heterogeneous biology and behavior. Patients with high-risk disease have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. Immunotherapy is a novel therapeutic approach that harnesses the inherent activity of the immune system to control and eliminate malignant cells. One form of immunotherapy uses chimeric antigen receptors (CAR) to target tumor-associated antigens. CARs are derived from the antigen-binding domain of a monoclonal antibody (MAb) coupled with the intracellular signaling portion of the T cell receptor. CARs can combine the specificity and effectiveness of MAbs with the active bio-distribution, direct cytotoxicity, and long-term persistence of T cells. NBL provides an attractive target for CAR immunotherapy as many of its tumor-associated antigens are not expressed at significant levels on normal tissues, thus decreasing potential treatment related toxicity. Two previous clinical trials utilizing L1-cell adhesion molecule (L1-CAM) and disialoganglioside (GD2) specific CARs (GD2-CAR) have demonstrated safety and anti-tumor efficacy in heavily pretreated relapsed/refractory neuroblastoma patients. Based on these promising results and on improved techniques that can further potentiate CAR therapies, two clinical trials are currently investigating the use of GD2-CARs in children with NBL. Several approaches may further enhance anti-tumor activity and persistence of CAR modified cells, and if these can be safely translated into the clinic, CAR-based immunotherapy could become a viable adjunct or potential alternative to conventional treatment options for patients with NBL.

  6. Immunotherapy in prostate cancer: review of the current evidence.

    PubMed

    Fernández-García, E M; Vera-Badillo, F E; Perez-Valderrama, B; Matos-Pita, A S; Duran, I

    2015-05-01

    Prostate cancer is the most common male malignancy in the Western world. Once it metastasizes, it is incurable. The current gold standard for metastatic disease is the combined docetaxel/prednisone regimen. Prostate cancer shows several characteristics that make it a suitable candidate for immunotherapy, as recently exemplified by the approval of sipuleucel-T, the first vaccine to treat any malignancy. Here, we review different tumor-associated antigen immunotherapy strategies currently being investigated, from a humanized radiolabeled monoclonal antibody (J-591) that targets radiation into tumor cells, moving on to vaccines and through to immunomodulator agents such as anti-CPLA-4 and anti-PD-1 monoclonal antibodies that activate T-cell responses via immune checkpoint inhibition. We explore different opinions on the best approach to integrate immunotherapy into existing standard therapies, such as androgen-deprivation therapy, radiotherapy or chemotherapy, and review different combination sequences, patient types and time points during the course of the disease to achieve a lasting immune response. We present data from recent phase III clinical trials that call for a change in trial endpoint design with immunotherapy agents, from the traditional tumor progression to overall survival and how such trials should include immune response measurements as secondary or intermediate endpoints to help identify patient clinical benefit in the earlier phases of treatment. Finally, we join in the recent questioning on the validity of RECIST criteria to measure response to immunotherapeutic agents, as initial increases in the size of tumors/lymph nodes, which are part of a normal immune response, could be categorized as disease progression under RECIST.

  7. DNA-inorganic hybrid nanovaccine for cancer immunotherapy.

    PubMed

    Zhu, Guizhi; Liu, Yijing; Yang, Xiangyu; Kim, Young-Hwa; Zhang, Huimin; Jia, Rui; Liao, Hsien-Shun; Jin, Albert; Lin, Jing; Aronova, Maria; Leapman, Richard; Nie, Zhihong; Niu, Gang; Chen, Xiaoyuan

    2016-03-28

    Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.

  8. Advances in Chimeric Antigen Receptor Immunotherapy for Neuroblastoma

    PubMed Central

    Heczey, Andras; Louis, Chrystal U.

    2014-01-01

    Neuroblastoma (NBL) is the most common extracranial pediatric solid tumor and has heterogeneous biology and behavior. Patients with high-risk disease have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. Immunotherapy is a novel therapeutic approach that harnesses the inherent activity of the immune system to control and eliminate malignant cells. One form of immunotherapy uses chimeric antigen receptors (CAR) to target tumor-associated antigens. CARs are derived from the antigen-binding domain of a monoclonal antibody (MAb) coupled with the intracellular signaling portion of the T cell receptor. CARs can combine the specificity and effectiveness of MAbs with the active bio-distribution, direct cytotoxicity, and long-term persistence of T cells. NBL provides an attractive target for CAR immunotherapy as many of its tumor-associated antigens are not expressed at significant levels on normal tissues, thus decreasing potential treatment related toxicity. Two previous clinical trials utilizing L1-cell adhesion molecule (L1-CAM) and disialoganglioside (GD2) specific CARs (GD2-CAR) have demonstrated safety and anti-tumor efficacy in heavily pretreated relapsed/refractory neuroblastoma patients. Based on these promising results and on improved techniques that can further potentiate CAR therapies, two clinical trials are currently investigating the use of GD2-CARs in children with NBL. Several approaches may further enhance anti-tumor activity and persistence of CAR modified cells, and if these can be safely translated into the clinic, CAR-based immunotherapy could become a viable adjunct or potential alternative to conventional treatment options for patients with NBL. PMID:24333408

  9. Determination of the optimal therapeutic protocols in cancer immunotherapy.

    PubMed

    Cappuccio, Antonio; Castiglione, Filippo; Piccoli, Benedetto

    2007-09-01

    Cancer immunotherapy aims at eliciting an immune system response against the tumor. However, it is often characterized by toxic side-effects. Limiting the tumor growth and, concurrently, avoiding the toxicity of a drug, is the problem of protocol design. We formulate this question as an optimization problem and derive an algorithm for its solution. Unlike the standard optimal control approach, the algorithm simulates impulse-like drug administrations. It relies on an exact computation of the gradient of the cost function with respect to any protocol by means of the variational equations, that can be solved in parallel with the system. In comparison with previous versions of this method [F. Castiglione, B. Piccoli, Optimal control in a model of dendritic cell transfection cancer immunotherapy, Bull. Math. Biol. 68 (2006) 255-274; B. Piccoli, F. Castiglione, Optimal vaccine scheduling in cancer immunotherapy, Physica A. 370 (2) (2007) 672-680], we optimize both the timing and the dosage of each administration and introduce a penalty term to avoid clustering of subsequent injections, a requirement consistent with the clinical practice. In addition, we implement the optimization scheme to simulate the case of multi-therapies. The procedure works for any ODE system describing the pharmacokinetics and pharmacodynamics of an arbitrary number of therapeutic agents. In this work, it was tested for a well known model of the tumor-immune system interaction [D. Kirschner, J.C. Panetta, Modeling immunotherapy of tumor-immune interaction, J. Math. Biol. 37 (1998) 235-252]. Exploring three immunotherapeutic scenarios (CTL therapy, IL-2 therapy and combined therapy), we display the stability and efficacy of the optimization method, obtaining protocols that are successful compromises between various clinical requirements.

  10. Mechanistic Basis of Immunotherapies for Type 1 Diabetes Mellitus

    PubMed Central

    CHEN, WENHAO; XIE, AINI; CHAN, LAWRENCE

    2013-01-01

    Type 1 diabetes (T1D) is an autoimmune disease for which there is no cure. The pancreatic beta cells are the source of insulin that keeps blood glucose normal. When susceptible individuals develop T1D, their beta cells are destroyed by autoimmune T lymphocytes and no longer produce insulin. T1D patients therefore depend on daily insulin injections for survival. Gene therapy in T1D aims at the induction of new islets to replace those that have been destroyed by autoimmunity. A major goal of T1D research is to restore functional beta cell mass while eliminating diabetogenic T cells in the hope of achieving insulin independence. Multiple therapeutic strategies for the generation of new beta cells have been under intense investigations. However, newly formed beta cells would be immediately destroyed by diabetogenic T cells. Therefore, successful islet induction therapy must be supported by potent immunotherapy that will protect the newly formed beta cells. Herein, we will summarize the current information on immunotherapies that aim at modifying T cell response to beta cells. We will first outline the immune mechanisms that underlie T1D development and progression and review the scientific background and rationale for specific modes of immunotherapy. Numerous clinical trials using antigen-specific strategies and immune-modifying drugs have been published, though most have proved too toxic or have failed to provide long-term beta cell protection. In order to develop an effective immunotherapy, there must be a continued effort on defining the molecular basis that underlies T cell response to pancreatic islet antigens in T1D. PMID:23348026

  11. [Cellular immunotherapy: complexity of immune system and industrial development].

    PubMed

    Abastado, J-P

    2003-01-01

    Cell immunotherapy aims at treating patients by stimulating their own immune system using appropriate cells. This approach is one of the most promising therapeutic strategy against cancer. The use of cells, the mobilization of a system, the targeting of interactions between the immune system and the tumor constitute the hallmarks of complexity, an area of intense academic and industrial research during the past twenty years. The present article reviews some unique characteristics of the industrial development of these cell drugs.

  12. Mechanistic basis of immunotherapies for type 1 diabetes mellitus.

    PubMed

    Chen, Wenhao; Xie, Aini; Chan, Lawrence

    2013-04-01

    Type 1 diabetes (T1D) is an autoimmune disease for which there is no cure. The pancreatic beta cells are the source of insulin that keeps blood glucose normal. When susceptible individuals develop T1D, their beta cells are destroyed by autoimmune T lymphocytes and no longer produce insulin. T1D patients therefore depend on daily insulin injections for survival. Gene therapy in T1D aims at the induction of new islets to replace those that have been destroyed by autoimmunity. A major goal of T1D research is to restore functional beta cell mass while eliminating diabetogenic T cells in the hope of achieving insulin independence. Multiple therapeutic strategies for the generation of new beta cells have been under intense investigations. However, newly formed beta cells would be immediately destroyed by diabetogenic T cells. Therefore, successful islet induction therapy must be supported by potent immunotherapy that will protect the newly formed beta cells. Herein, we will summarize the current information on immunotherapies that aim at modifying T cell response to beta cells. We will first outline the immune mechanisms that underlie T1D development and progression and review the scientific background and rationale for specific modes of immunotherapy. Numerous clinical trials using antigen-specific strategies and immune-modifying drugs have been published, though most have proved too toxic or have failed to provide long-term beta cell protection. To develop an effective immunotherapy, there must be a continued effort on defining the molecular basis that underlies T cell response to pancreatic islet antigens in T1D.

  13. Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy.

    PubMed

    Pilon-Thomas, Shari; Kodumudi, Krithika N; El-Kenawi, Asmaa E; Russell, Shonagh; Weber, Amy M; Luddy, Kimberly; Damaghi, Mehdi; Wojtkowiak, Jonathan W; Mulé, James J; Ibrahim-Hashim, Arig; Gillies, Robert J

    2016-03-15

    Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation. PMID:26719539

  14. Oncogenic cancer/testis antigens: prime candidates for immunotherapy.

    PubMed

    Gjerstorff, Morten F; Andersen, Mads H; Ditzel, Henrik J

    2015-06-30

    Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.

  15. Targeting NK Cells for Anticancer Immunotherapy: Clinical and Preclinical Approaches

    PubMed Central

    Carotta, Sebastian

    2016-01-01

    The recent success of checkpoint blockade has highlighted the potential of immunotherapy approaches for cancer treatment. Although the majority of approved immunotherapy drugs target T cell subsets, it is appreciated that other components of the immune system have important roles in tumor immune surveillance as well and thus represent promising additional targets for immunotherapy. Natural killer (NK) cells are the body’s first line of defense against infected or transformed cells, as they kill target cells in an antigen-independent manner. Although several studies have clearly demonstrated the active role of NK cells in cancer immune surveillance, only few clinically approved therapies currently exist that harness their potential. Our increased understanding of NK cell biology over the past few years has renewed the interest in NK cell-based anticancer therapies, which has lead to a steady increase of NK cell-based clinical and preclinical trials. Here, the role of NK cells in cancer immune surveillance is summarized, and several novel approaches to enhance NK cell cytotoxicity against cancer are discussed. PMID:27148271

  16. Bubble-Assisted Ultrasound: Application in Immunotherapy and Vaccination.

    PubMed

    Escoffre, Jean-Michel; Deckers, Roel; Bos, Clemens; Moonen, Chrit

    2016-01-01

    Bubble-assisted ultrasound is a versatile technology with great potential in immunotherapy and vaccination. This technology involves the exposure of immune cells (i.e., dendritic cells, lymphocytes) in-vitro or diseased tissues (i.e., brain, tumor) in-vivo to ultrasound treatment with gas bubbles. Bubble destruction leads to physical forces that induce the direct delivery of weakly permeant immuno-stimulatory molecules either into the cytoplasm of immune cells, or through the endothelial barrier of diseased tissues. Hence, therapeutic antibodies (i.e., antibody-based immunotherapy) and cytokine-encoding nucleic acids (i.e., cytokine gene therapy) can be successfully delivered into diseased tissues, thus improving immune responses. In addition, protein antigens, as well as antigen-encoding nucleic acids (pDNA, mRNA), can be delivered into dendritic cells (i.e., dendritic cell-based vaccines), thus leading to a long-lasting prophylactic or therapeutic immunization. This chapter focuses on the state-of-the-art of bubble-assisted ultrasound in the field of immunotherapy and vaccination.

  17. Recent advances in immunotherapy and vaccine development for peanut allergy

    PubMed Central

    2015-01-01

    Peanut allergy is a common problem and can be the cause of severe, life-threatening allergic reactions. It rarely resolves, with the majority of patients carrying the disease onto adulthood. Peanut allergy poses a significant burden on the quality of life of sufferers and their families, which results mainly from the fear of accidental peanut ingestion, but is also due to dietary and social restrictions. Current standard management involves avoidance, patient education and provision of emergency medication, for use in allergic reactions, when they occur. Efforts have been made to develop a vaccine for peanut allergy. Recent developments have also highlighted the use of immunotherapy, which has shown promise as an active form of treatment and may present a disease-modifying therapy for peanut allergy. So far, results, especially from oral immunotherapy studies, have shown good efficacy in achieving desensitization to peanut with a good safety profile. However, the capacity to induce long-term tolerance has not been demonstrated conclusively yet and larger, phase III studies are required to further investigate safety and efficacy of this intervention. Peanut immunotherapy is not currently recommended for routine clinical use or outside specialist allergy units. PMID:26288733

  18. Therapeutic cancer vaccines and combination immunotherapies involving vaccination

    PubMed Central

    Nguyen, Trang; Urban, Julie; Kalinski, Pawel

    2014-01-01

    Recent US Food and Drug Administration approvals of Provenge® (sipuleucel-T) as the first cell-based cancer therapeutic factor and ipilimumab (Yervoy®/anticytotoxic T-lymphocyte antigen-4) as the first “checkpoint blocker” highlight recent advances in cancer immunotherapy. Positive results of the clinical trials evaluating additional checkpoint blocking agents (blockade of programmed death [PD]-1, and its ligands, PD-1 ligand 1 and 2) and of several types of cancer vaccines suggest that cancer immunotherapy may soon enter the center stage of comprehensive cancer care, supplementing surgery, radiation, and chemotherapy. This review discusses the current status of the clinical evaluation of different classes of therapeutic cancer vaccines and possible avenues for future development, focusing on enhancing the magnitude and quality of cancer-specific immunity by either the functional reprogramming of patients’ endogenous dendritic cells or the use of ex vivo-manipulated dendritic cells as autologous cellular transplants. This review further discusses the available strategies aimed at promoting the entry of vaccination-induced T-cells into tumor tissues and prolonging their local antitumor activity. Finally, the recent improvements to the above three modalities for cancer immunotherapy (inducing tumor-specific T-cells, prolonging their persistence and functionality, and enhancing tumor homing of effector T-cells) and rationale for their combined application in order to achieve clinically effective anticancer responses are addressed. PMID:27471705

  19. Tumour immunogenicity, antigen presentation and immunological barriers in cancer immunotherapy.

    PubMed

    Escors, David

    2014-01-01

    Since the beginning of the 20(th) century, scientists have tried to stimulate the anti-tumour activities of the immune system to fight against cancer. However, the scientific effort devoted on the development of cancer immunotherapy has not been translated into the expected clinical success. On the contrary, classical anti-neoplastic treatments such as surgery, radiotherapy and chemotherapy are the first line of treatment. Nevertheless, there is compelling evidence on the immunogenicity of cancer cells, and the capacity of the immune system to expand cancer-specific effector cytotoxic T cells. However, the effective activation of anti-cancer T cell responses strongly depends on efficient tumour antigen presentation from professional antigen presenting cells such as dendritic cells (DCs). Several strategies have been used to boost DC antigen presenting functions, but at the end cancer immunotherapy is not as effective as would be expected according to preclinical models. In this review we comment on these discrepancies, focusing our attention on the contribution of regulatory T cells and myeloid-derived suppressor cells to the lack of therapeutic success of DC-based cancer immunotherapy. PMID:24634791

  20. Can Alzheimer disease be prevented by amyloid-β immunotherapy?

    PubMed Central

    Lemere, Cynthia A.; Masliah, Eliezer

    2010-01-01

    Alzheimer disease (AD) is the most common form of dementia. The amyloid-β (Aβ) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive Aβ immunotherapies have been shown to lower cerebral Aβ levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 Aβ vaccine was stopped when ~6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive Aβ immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active Aβ vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, Aβ immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Aβ immunization. PMID:20140000