Peters, Cole; Rabkin, Samuel D
Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be “armed” with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity. PMID:26462293
Campadelli-Fiume, Gabriella; Petrovic, Biljana; Leoni, Valerio; Gianni, Tatiana; Avitabile, Elisa; Casiraghi, Costanza; Gatta, Valentina
Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. To overcome the attenuation limits, a strategy is to render the virus highly cancer-specific, e.g., by retargeting their tropism to cancer-specific receptors, and detargeting from natural receptors. The target we selected is HER-2, overexpressed in breast, ovarian and other cancers. Entry of wt-HSV requires the essential glycoproteins gD, gH/gL and gB. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors’ binding sites. Recently, we showed that also gH/gL can be a retargeting tool. The insertion of an scFv to HER-2 at the gH N-terminus, coupled with deletions in gD, led to a recombinant capable to use HER-2 as the sole receptor. The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. They might be further modified to express immunomodulatory molecules. PMID:26927159
Campadelli-Fiume, Gabriella; Petrovic, Biljana; Leoni, Valerio; Gianni, Tatiana; Avitabile, Elisa; Casiraghi, Costanza; Gatta, Valentina
Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. To overcome the attenuation limits, a strategy is to render the virus highly cancer-specific, e.g., by retargeting their tropism to cancer-specific receptors, and detargeting from natural receptors. The target we selected is HER-2, overexpressed in breast, ovarian and other cancers. Entry of wt-HSV requires the essential glycoproteins gD, gH/gL and gB. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors' binding sites. Recently, we showed that also gH/gL can be a retargeting tool. The insertion of an scFv to HER-2 at the gH N-terminus, coupled with deletions in gD, led to a recombinant capable to use HER-2 as the sole receptor. The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. They might be further modified to express immunomodulatory molecules.
Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for brain tumors and other solid cancers. They can replicate in situ, spread and exhibit oncolytic activity via a direct cytocidal effect. One of the advantages of HSV-1 is the capacity to incorporate large and/or multiple transgenes within the viral genome. Oncolytic HSV-1 can therefore be "armed" to add certain functions. Recently, the field of armed oncolytic HSV-1 has drastically advanced, due to development of recombinant HSV-1 generation systems that utilize bacterial artificial chromosome and multiple DNA recombinases. Because antitumor immunity is induced in the course of oncolytic activities of HSV-1, transgenes encoding immunomodulatory molecules have been most frequently used for arming. Other armed oncolytic HSV-1 include those that express antiangiogenic factors, fusogenic membrane glycoproteins, suicide gene products, and proapoptotic proteins. Provided that the transgene product does not interfere with viral replication, such arming of oncolytic HSV-1 results in augmentation of antitumor efficacy. Immediate-early viral promoters are often used to control the arming transgenes, but strict-late viral promoters have been shown useful to restrict the expression in the late stage of viral replication when desirable. Some armed oncolytic HSV-1 have been created for the purpose of noninvasive in vivo imaging of viral infection and replication. Development of a wide variety of armed oncolytic HSV-1 will lead to an establishment of a new genre of therapy for brain tumors as well as other cancers.
AD_________________ Award Number: DAMD17-03-1-0434 TITLE: A Fusogenic Oncolytic Herpes Simplex ...TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Fusogenic Oncolytic Herpes Simplex Virus for Therapy of Advanced Ovarian Cancer 5b. GRANT NUMBER...oncolytic herpes simplex virus (HSV) can significantly enhance the anti-tumor effect of the virus. Three specific aims have been proposed and they are: 1
Friedman, Gregory K; Pressey, Joseph G; Reddy, Alyssa T; Markert, James M; Gillespie, G Yancey
Despite improving survival rates for children with cancer, a subset of patients exist with disease resistant to traditional therapies such as surgery, chemotherapy, and radiation. These patients require newer, targeted treatments used alone or in combination with more traditional approaches. Oncolytic herpes simplex virus (HSV) is one of these newer therapies that offer promise for several difficult to treat pediatric malignancies. The potential benefit of HSV therapy in pediatric solid tumors including brain tumors, neuroblastomas, and sarcomas is reviewed along with the many challenges that need to be addressed prior to moving oncolytic HSV therapy from the laboratory to the beside in the pediatric population. PMID:19367259
Friedman, Gregory K; Pressey, Joseph G; Reddy, Alyssa T; Markert, James M; Gillespie, G Yancey
Despite improving survival rates for children with cancer, a subset of patients exist with disease resistant to traditional therapies such as surgery, chemotherapy, and radiation. These patients require newer, targeted treatments used alone or in combination with more traditional approaches. Oncolytic herpes simplex virus (HSV) is one of these newer therapies that offer promise for several difficult to treat pediatric malignancies. The potential benefit of HSV therapy in pediatric solid tumors including brain tumors, neuroblastomas, and sarcomas is reviewed along with the many challenges that need to be addressed prior to moving oncolytic HSV therapy from the laboratory to the beside in the pediatric population.
Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for cancer. They can replicate in situ, spread, and exhibit oncolytic activity via a direct cytocidal effect. In addition, oncolytic HSV-1 can transfer and express foreign genes in host cells. The phase I clinical study with G207, a double-mutated HSV-1, in recurrent malignant glioma patients has shown that oncolytic HSV-1 can be safely administered into human brains. The therapeutic benefits of oncolytic HSV-1 depend on the extent of both intratumoral viral replication and induction of host antitumor immune responses. We develop new-generation oncolytic HSV-1 by enhancing these properties while retaining the safety features. G47delta was created from G207 by introducing another genetic mutation. Compared with G207, G47delta showed 1) better stimulation of human antitumor immune cells, 2) better growth properties leading to higher virus yields and increased cytopathic effect in vitro, 3) better antitumor efficacy in both immuno-competent and -incompetent animals, and 4) preserved safety in the brain of HSV-1-sensitive mice. Preparation is under way for a clinical trial using G47delta in progressive glioblastoma patients. G47delta is also suited as a backbone vector for expressing foreign molecules. Using bacterial artificial chromosome and two DNA recombinases, we have created an "armed" oncolytic HSV-1 generation system that allows insertion of transgene(s) into the genome of G47delta in a rapid and accurate manner. We found that expression of immunostimulatory molecules can significantly enhance the antitumor efficacy of G47delta. Based on these advances, we anticipate that oncolytic virus therapy using oncolytic HSV-1 will soon be established as an important modality of cancer treatment.
Uchida, Hiroaki; Hamada, Hirofumi; Nakano, Kenji; Kwon, Heechung; Tahara, Hideaki; Cohen, Justus B; Glorioso, Joseph C
Oncolytic virotherapy is a novel therapeutic modality for malignant diseases that exploits selective viral replication in cancer cells. Herpes simplex virus (HSV) is a promising agent for oncolytic virotherapy due to its broad cell tropism and the identification of mutations that favor its replication in tumor over normal cells. However, these attenuating mutations also tend to limit the potency of current oncolytic HSV vectors that have entered clinical studies. As an alternative, vector retargeting to novel entry receptors has the potential to achieve tumor specificity at the stage of virus entry, eliminating the need for replication-attenuating mutations. Here we summarize the molecular mechanism of HSV entry and recent advances in the development of fully retargeted HSV vectors for oncolytic virotherapy. Retargeted HSV vectors offer an attractive platform for the creation of a new generation of oncolytic HSV with improved efficacy and specificity.
Sokolowski, Nicolas As; Rizos, Helen; Diefenbach, Russell J
Oncolytic virotherapy exploits the properties of human viruses to naturally cytolysis of cancer cells. The human pathogen herpes simplex virus (HSV) has proven particularly amenable for use in oncolytic virotherapy. The relative safety of HSV coupled with extensive knowledge on how HSV interacts with the host has provided a platform for manipulating HSV to enhance the targeting and killing of human cancer cells. This has culminated in the approval of talimogene laherparepvec for the treatment of melanoma. This review focuses on the development of HSV as an oncolytic virus and where the field is likely to head in the future.
Sokolowski, Nicolas AS; Rizos, Helen; Diefenbach, Russell J
Oncolytic virotherapy exploits the properties of human viruses to naturally cytolysis of cancer cells. The human pathogen herpes simplex virus (HSV) has proven particularly amenable for use in oncolytic virotherapy. The relative safety of HSV coupled with extensive knowledge on how HSV interacts with the host has provided a platform for manipulating HSV to enhance the targeting and killing of human cancer cells. This has culminated in the approval of talimogene laherparepvec for the treatment of melanoma. This review focuses on the development of HSV as an oncolytic virus and where the field is likely to head in the future. PMID:27512683
Li, Qi-Xiang; Liu, Guohong; Zhang, Xiaoliu
The recent FDA approval of Sipuleucel-T for the treatment of prostate cancer represents an important milestone of cancer immunotherapy, which, for the first time, validates the concept of bringing true clinical benefit to cancer patients by stimulating patients' own anti-tumor immunity. Among the different experimental cancer immunotherapies, oncolytic virotherapy may represent a low-cost yet potent and personalized cancer vaccine for the treatment of solid tumors. This review describes the constructions of several human herpes simplex virus (HSV)-derived oncolytic viruses as candidate cancer vaccines, which induce specific and potent anti-tumor immunity in pre-clinical models, and thus resulting in stronger overall anti-tumor efficacy as compared to oncolytic effect alone. This article also describes the approaches to enhance the antitumor immunity of oncolytic HSVs, and in particular, the key role played by integrating membrane-fusion activity into these viruses. Additionally, this article reviews the potential effect of certain chemotherapeutic agents (e.g. cyclophosphamide) in boosting antitumor immunity induced by oncolytic HSV, and the mechanisms behind it. In summary, all the preclinical and clinical data have suggested that HSV-based oncolytic virotherapies could likely be developed as a new generation of cancer vaccines for the treatment of solid tumors.
AWARD NUMBER: W81XWH-15-1-0108 TITLE: Intraventricular Delivery of Engineered Oncolytic Herpes Simplex Virotherapy to Treat Localized and...children with brain tumors. Introduced mutations in the engineered virus prevent a productive infection in normal cells in the brain while...HSV-1 on day 2 indicating the engineered virus was able to enter the ependymal cells. By day 3, there was more diffuse disruption of the ependymal
Cripe, Timothy P; Chen, Chun-Yu; Denton, Nicholas L; Haworth, Kellie B; Hutzen, Brian; Leddon, Jennifer L; Streby, Keri A; Wang, Pin-Yi; Markert, James M; Waters, Alicia M; Gillespie, George Yancey; Beierle, Elizabeth A; Friedman, Gregory K
Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors.
Waters, Alicia M; Stafman, Laura L; Garner, Evan F; Mruthyunjayappa, Smitha; Stewart, Jerry E; Friedman, Gregory K; Coleman, Jennifer M; Markert, James M; Gillespie, G Yancey; Beierle, Elizabeth A
Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV), are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS) cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.
Passer, B J; Wu, C-l; Wu, S; Rabkin, S D; Martuza, R L
Oncolytic herpes simplex viruses type 1 (oHSVs) such as G47Delta and G207 are genetically engineered for selective replication competence in cancer cells. Several factors can influence the overall effectiveness of oHSV tropism, including HSV-1 receptor expression, extracellular matrix milieu and cellular permissiveness. We have taken advantage of human prostate organ cultures derived from radical prostatectomies to investigate oHSV tropism. In this study, we show that both G47Delta and G207 specifically replicate in epithelial cells of the prostatic glands but not in the surrounding stroma. In contrast, both the epithelial and stromal cell compartments were readily infected by wild-type HSV-1. Analysis of oHSV replication in prostate surgical specimens 3 days post infection showed that G47Delta generated approximately 30-fold more viral progeny than did G207. This correlated with the enhanced expression of G47Delta-derived glycoprotein gB protein levels as compared with G207. In benign prostate tissues, G207 and G47Delta titers were notably reduced, whereas strain F titers were maintained at similar levels compared with prostate cancer specimens. Overall, our results show that these oncolytic herpes vectors show both target specificity and replication competence in human prostate cancer specimens and point to the utility of using human prostate organ cultures in assessing oHSV tropism and cellular specificity.
Varghese, Susan; Rabkin, Samuel D; Nielsen, G Petur; MacGarvey, Usha; Liu, Renbin; Martuza, Robert L
Oncolytic viruses are an innovative therapeutic strategy for cancer, wherein viral replication and cytotoxicity are selective for tumor cells. Here we show the efficacy of systemically administered oncolytic viruses for the treatment of spontaneously arising tumors, specifically the use of oncolytic herpes simplex viruses (HSV) administered i.v. to treat spontaneously developing primary and metastatic prostate cancer in the transgenic TRAMP mouse, which recapitulates human prostate cancer progression. Four administrations of systemically delivered NV1023 virus, an HSV-1/HSV-2 oncolytic recombinant, to TRAMP mice at 12 or 18 weeks of age (presence of prostate adenocarcinoma or metastatic disease, respectively) inhibited primary tumor growth and metastases to lymph nodes. Expression of interleukin 12 (IL-12) from NV1042 virus, a derivative of NV1023, was additionally effective, significantly reducing the frequency of development of prostate cancer and lung metastases, even when the mice were treated after the onset of metastasis at 18 weeks of age. NV1042-infected cells, as detected by 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining for Lac Z expressed by the virus, were present in prostate tumors 1 week after the final virus injection and viral DNA was detected at 2 weeks after final virus injection by real-time PCR in primary and metastatic tumors but not in liver or blood. No toxicity was observed in any of the treated mice. The efficacy of the IL-12-expressing NV1042 virus in this aggressive prostate cancer model using a clinically relevant treatment paradigm merits its consideration for clinical studies.
Future cancer therapies will be molecular cures. They will correct, block or destroy cancer cells by targeting molecular changes that lead to carcinogenesis. Destroying cancer cells can be done using oncolytic viruses. By blocking antibody mediated neutralization of oncolytic viruses, Herpes simplex virus type 1 glycoproteins E and I could be used in the adjuvant treatment of cancer for improving the chances of oncolytic viruses to kill cancer cells in vivo.
Longo, Sharon L.; Griffith, Christopher; Glass, Aaron; Shillitoe, Edward J.; Post, Dawn E.
We exploited the differential activation of hypoxia-inducible factor (HIF)-dependent gene expression in tumors versus normal tissue for the design of a targeted oncolytic Herpes simplex virus type-1 (HSV-1). A gene that is essential for viral replication, ICP4, was placed under the regulation of a HIF-responsive promoter and then introduced into the thymidine kinase locus (UL23) of HSV d120 which contains partial deletions in the two endogenous ICP4 genes. Recombinant HIF-HSV were isolated and their derivation from d120 was verified by expression of a truncated, nonfunctional form of ICP4 protein. Disruption of the UL23 locus was confirmed by loss of thymidine kinase expression and resistance to acyclovir. Unexpectedly, HIF-HSV expressed ICP4 and induced tumor cell lysis at similar levels under normoxia and hypoxia. The lack of HIF-dependent ICP4 transgene expression by HIF-HSV was due to two factors that have not previously been reported- reversion of the ICP4 gene region to its wild-type configuration and increased HIF-transcriptional activity under normoxia when cells were infected with any strain of HSV-1. The findings that an oncolytic HSV-1 is genetically unstable and can activate a tumor-related promoter in a non-specific manner have important implications for any proposed use of this virus in cancer therapy. PMID:20930860
Zhang, Shaun Xiaoliu
Viruses have the intrinsic capability to kill host cells. Even when the initial infection consists of only a few viruses, they can reproduce themselves in large quantities within a short time and quickly spread to nearby cells, causing substantial tissue damage. These same infectious properties become desirable if they can be converted into killer agents with specificity for malignant cells. Cancer virotherapy is doing exactly that by modifying viruses in ways that allow them to replicate in malignant cells but not in normal cells. Although relatively young, the field has seen significant progress in recent years. For example, the most recent phase III trial data on a herpes simplex virus (HSV)-based oncolytic virus (T-VEC) show substantial improvement in objective and durable responses over the control arm in melanoma patients, prompting speculation that a virotherapy may receive FDA approval for clinical use in the very near future. This review focuses on HSV-based oncolytic viruses, from their early history to their most recent development, with discussion of promising directions for further improvement.
Megison, Michael L; Gillory, Lauren A; Stewart, Jerry E; Nabers, Hugh C; Mroczek-Musulman, Elizabeth; Waters, Alicia M; Coleman, Jennifer M; Kelly, Virginia; Markert, James M; Gillespie, G Yancey; Friedman, Gregory K; Beierle, Elizabeth A
Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.
Yamada, S; Kuroda, T; Fuchs, B C; He, X; Supko, J G; Schmitt, A; McGinn, C M; Lanuti, M; Tanabe, K K
Yeast cytosine deaminase (yCD) is a well-characterized prodrug/enzyme system that converts 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), and has been combined with oncolytic viruses. However, in vivo studies of the interactions between 5-FC bioactivation and viral replication have not been previously reported, nor have the kinetics of transgene expression and the pharmacokinetics of 5-FC and 5-FU. We constructed a replication-conditional Herpes simplex virus 1 (HSV-1) expressing yCD and examined cytotoxicity when 5-FC was initiated at different times after viral infection, and observed that earlier 5-FC administration led to greater cytotoxicity than later 5-FC administration in vitro and in vivo. In animal models, 12 days of 5-FC administration was superior to 6 days, but dosing beyond 12 days did not further enhance efficacy. Consistent with the dosing-schedule results, both viral genomic DNA copy number and viral titers were observed to peak on Day 3 after viral injection and gradually decrease thereafter. The virus is replication-conditional and was detected in tumors for as long as 2 weeks after viral injection. The maximum relative extent of yCD conversion of 5-FC to 5-FU in tumors was observed on Day 6 after viral injection and it decreased progressively thereafter. The observation that 5-FU generation within tumors did not lead to appreciable levels of systemic 5-FU (<10 ng ml⁻¹) is important and has not been previously reported. The approaches used in these studies of the relationship between the viral replication kinetics, transgene expression, prodrug administration and anti-tumor efficacy are useful in the design of clinical trials of armed, oncolytic viruses.
Friedman, Gregory K; Beierle, Elizabeth A; Gillespie, George Yancey; Markert, James M; Waters, Alicia M; Chen, Chun-Yu; Denton, Nicholas L; Haworth, Kellie B; Hutzen, Brian; Leddon, Jennifer L; Streby, Keri A; Wang, Pin-Yi; Cripe, Timothy P
Oncolytic engineered herpes simplex viruses (HSVs) possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy.
Yin, Lei; Zhao, Chunhong; Han, Jixia; Li, Zengjun; Zhen, Yanan; Xiao, Ruixue; Xu, Zhongfa; Sun, Yanlai
Background The incidence of colorectal cancer (CRC) is on the rise. Furthermore, late-stage diagnoses and limited efficacious treatment options make CRC a complex clinical challenge. Therefore, a new therapeutic regimen with a completely novel therapeutic mechanism is necessary for CRC. In the present study, the therapeutic efficacy of oncolytic herpes simplex virus type 2 (oHSV2) in CRC was assessed in vitro and in vivo. oHSV2 is an oncolytic agent derived from herpes simplex virus type 2 that encodes granulocyte-macrophage colony-stimulating factor. Materials and methods We investigated the cytopathic effects of oHSV2 in CRC cell lines using the MTT assay. Then, cell cycle progression and apoptosis of oHSV2 were examined by flow cytometry. We generated a model of CRC with mouse CRC cell CT26 in BALB/c mice. The antitumor effects and adaptive immune response of oHSV2 were assessed in tumor-bearing mice. The therapeutic efficacy of oHSV2 was compared with the traditional chemotherapeutic agent, 5-fluorouracil. Results The in vitro data showed that oHSV2 infected the CRC cell lines successfully and that the tumor cells formed a significant number of syncytiae postinfection. The oHSV2 killed cancer cells independent of the cell cycle and mainly caused tumor cells necrosis. The in vivo results showed that oHSV2 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice without weight loss. With virus replication, oHSV2 not only resulted in a reduction of myeloid-derived suppressor cells and regulatory T cells in the spleen, but also increased the number of mature dendritic cells in tumor-draining lymph nodes and the effective CD4+T and CD8+T-cells in the tumor microenvironment. Conclusion Our study provides the first evidence that oHSV2 induces cell death in CRC in vitro and in vivo. These findings indicate that oHSV2 is an effective therapeutic cancer candidate that causes an oncolytic effect and recruits adaptive immune responses for an
therapy of solid tumors such as ovarian cancer, two obstacles need to be overcome before the therapeutic potential of virotherapy could be fully... virotherapy could be fully materialized. Firstly, the potency of oncolytic HSVs needs to be improved. During the first two years of this funded
Benencia, Fabian; Courrèges, Maria C; Fraser, Nigel W; Coukos, George
We have previously shown that intratumor administration of HSV-1716 (an ICP34.5 null mutant) resulted in significant reduction of tumor growth and a significant survival advantage in a murine model of ovarian cancer. Herewith we report that oncolytic HSV-1716 generates vaccination effects in the same model. Upon HSV-1716 infection, mouse ovarian tumor cells showed high levels of expression viral glycoproteins B and D and were highly phagocyted by dendritic cells (DCs). Interestingly, increased phagocytosis of tumor-infected cells by DCs was impaired by heparin, and anti-HSV glycoproteins B and D, indicating that viral infection enhances adhesive interactions between DCs and tumor apoptotic bodies. Moreover, HSV-1716 infected cells expressed high levels of heat shock proteins 70 and GRP94, molecules that have been reported to induce maturation of DCs, increase cross-presentation of antigens and promote antitumor immune response. After phagocytosis of tumor-infected cells, DCs acquired a mature status in vitro and in vivo, upregulated the expression of costimulatory molecule and increased migration towards MIP-3beta. Furthermore, HSV-1716 oncolytic treatment markedly reduced vascular endothelial growth factor (VEGF) levels in tumor-bearing animals thus abrogating tumor immunosuppressive milieu. These mechanisms may account for the highly enhanced antitumoral immune responses observed in HSV-1716 treated animals. Oncolytic treatment induced a significantly higher frequency of tumor-reactive IFNgamma producing cells, and induced a robust tumor infiltration by T cells. These results indicate that oncolytic therapy with HSV-1716 facilitates antitumor immune responses.
Russell, Stephen J; Peng, Kah-Whye; Bell, John C
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.
Zager, J. S.; Delman, K. A.; Malhotra, S.; Ebright, M. I.; Bennett, J. J.; Kates, T.; Halterman, M.; Federoff, H.; Fong, Y.
BACKGROUND: Herpes simplex type I (HSV)-based vectors have been used experimentally for suicide gene therapy, immunomodulatory gene delivery, and direct oncolytic therapy. The current study utilizes the novel concept of regional delivery of an oncolytic virus in combination with or serving as the helper virus for packaging herpes-based amplicon vectors carrying a cytokine transgene, with the goal of identifying if this combination is more efficacious than either modality alone. MATERIALS AND METHODS: A replication competent oncolytic HSV (G207) and a replication incompetent HSV amplicon carrying the gene for the immunomodulatory cytokine IL-2 (HSV-IL2) were tested in murine syngeneic colorectal carcinoma and in rat hepatocellular carcinoma models. Liver tumors were treated with vascular delivery of (1) phosphate-buffered saline (PBS), (2) G207, (3) HSV-IL2, (4) G207 and HSV-IL2 mixed in combination (mG207/HSV- IL2), and (5) G207 as the helper virus for packaging the construct HSV-IL2 (pG207/HSV-IL2). RESULTS: Tumor burden was significantly reduced in all treatment groups in both rats and mice treated with high-dose G207, HSV-IL2, or both (p < 0.02). When a low dose of virus was used in mice, anti-tumor efficacy was improved by use of G207 and HSV-IL2 in combination or with HSV-IL2 packaged by G207 (p < 0.001). This improvement was abolished when CD4(+) and CD8(+) lymphocytes were depleted, implying that the enhanced anti-tumor response to low-dose combined therapy is immune mediated. CONCLUSIONS: Vascular regional delivery of oncolytic and amplicon HSV vectors can be used to induce improved anti-tumor efficacy by combining oncolytic and immunostimulatory strategies. PMID:11591892
Sze, Daniel Y; Iagaru, Andrei H; Gambhir, Sanjiv S; De Haan, Hans A; Reid, Tony R
Oncolytic virotherapy poses unique challenges to the evaluation of tumor response. We hypothesized that the addition of [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to standard computed tomography (CT) evaluation would improve diagnostic and prognostic power of the measurement of tumor response to oncolytic virotherapy. A phase I/II trial was conducted to investigate treatment of hepatic metastases from colorectal carcinoma using intra-arterial administration of the oncolytic herpes virus NV1020. Both contrast-enhanced CT and FDG PET were obtained on each patient at each time point. Quantitative FDG PET and CT responses were correlated with each other and with clinical outcome metrics. A majority of patients showed initial post-viral infusion increases in tumor size (69%) or in standardized uptake value (SUV) (80%) large enough to qualify as progressive disease. Most showed subsequent decreases in tumor size (64%) or SUV (83%) enough to be reclassified as partial response or stable disease. Late PET and CT imaging results correlated well with each other and with clinical outcomes, but results from early in the treatment scheme did not correlate with each other, with later results, or with clinical outcomes. The addition of FDG PET to the evaluation of tumor response to the oncolytic virus NV1020 did not provide useful diagnostic or prognostic data. More sophisticated molecular imaging will need to be developed to monitor the effects of this novel class of antineoplastic agents.
Fong, Yuman; Kim, Teresa; Bhargava, Amit; Schwartz, Larry; Brown, Karen; Brody, Lynn; Covey, Anne; Karrasch, Matthias; Getrajdman, George; Mescheder, Axel; Jarnagin, William; Kemeny, Nancy
Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and are candidates for use as oncolytic therapy. This long-term report of a phase I trial examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal cancer within the liver failing first-line chemotherapy were treated in four cohorts with a single dose (3 × 106 to 1 × 108 particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterial administration, subjects were observed for 4 weeks before starting intra-arterial chemotherapy. All patients exhibited progression of disease before HSV injection. During observation, levels of the tumor marker carcinoembryonic antigen (CEA) decreased (median % drop = 24%; range 13–74%; P < 0.02). One of three individuals at the 108 level showed a 39% radiologic decrease in tumor size by cross-section and 75% by volume. HSV infection was documented from liver tumor biopsies. After beginning regional chemotherapy, all patients demonstrated a further decrease in CEA (median 96%; range 50–98%; P < 0.008) and a radiologic partial response. Median survival for this group was 25 months. During follow-up, no signs of virus reactivation were found. Multimutated HSV can be delivered safely into the human bloodstream to produce selective infection of tumor tissues and biologic effects. PMID:19018254
Braidwood, Lynne; Learmonth, Kirsty; Graham, Alex; Conner, Joe
Oncolytic herpes simplex virus (HSV1716), lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies of glioma, melanoma, head and neck squamous cell carcinoma, pediatric non-central nervous system solid tumors, and malignant pleural mesothelioma. To date, 88 patients have received HSV1716 and the virus is well tolerated, with selective replication in tumor cells and no spread to surrounding normal tissue. We assessed the potential value of HSV1716 in preclinical studies with two human hepatocellular carcinoma cell lines, HuH7 and HepG2-luc. HSV1716 displayed excellent replication kinetics in vitro in HepG2-luc cells, a cell line engineered to express luciferase, and virus-mediated cell killing correlated with loss of light emissions from the cells. In vivo, the HepG2-luc cells readily formed light-emitting xenografts that were easily visualized by an in vivo imaging system and efficiently eliminated by HSV1716 oncolysis after intratumoral injection. HSV1716 also demonstrated strong efficacy signals in subcutaneous HuH7 xenografts in nude mice after intravenous administration of virus. In the HuH7 model, the intravenously injected virus replicated prolifically immediately after efficient tumor localization, resulting in highly significant reductions in tumor growth and enhanced survival. Our preclinical results demonstrate excellent tumor uptake of HSV1716, with prolific replication and potent oncolysis. These observations warrant a clinical study of HSV1716 in hepatocellular carcinoma.
Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O’Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman
Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556
Chen, Xilin; Han, Jianfeng; Chu, Jianhong; Zhang, Lingling; Zhang, Jianying; Chen, Charlie; Chen, Luxi; Wang, Youwei; Wang, Hongwei; Yi, Long; Elder, J Bradley; Wang, Qi-En; He, Xiaoming; Kaur, Balveen; Chiocca, E Antonio; Yu, Jianhua
Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs.
Fan, Jingjing; Jiang, Hua; Cheng, Lin; Liu, Renbin
The aim of the present study was to establish a tamoxifen-resistant cell line (MCF-7/TAM-R) and to investigate the therapeutic effect of G47Δ on this cell line both in vitro and in vivo. In the present study, the MCF-7/TAM-R monoclonal subline was established after exposing MCF-7 cells to tamoxifen for 21 days. Then, it was compared with a wild-type MCF-7 subline (MCF-7W), which was not treated with tamoxifen. Cell proliferation, viability, cell cycle and apoptosis analyses were carried out to examine the characteristics of the MCF-7/TAM-R cells. Both in vitro and in vivo toxicity studies were conducted to investigate the therapeutic effect of G47Δ on the MCF-7/TAM-R cells. Compared to the MCF-7W cells, we found that the MCF-7/TAM-R cells exhibited a higher proliferation ability (P<0.05) and a stronger resistance to the cytotoxic effects induced by 4-hydroxytamoxifen (4-OHT) (P<0.05). G47Δ demonstrated a high cytotoxic effect on both the MCF-7/TAM-R and MCF-7W cell lines. After being infected with G47Δ at an MOI of 0.01, >90% of the MCF-7/TAM-R and MCF-7W cells died on day 5. G47Δ induced cell cycle arrest in the G2/M phase. Furthermore, G47Δ inhibited tumor growth in subcutaneous tumor models of both MCF-7/TAM-R and MCF-7W. Thus, we conclude that G47Δ, a third generation oncolytic herpes simplex virus, is highly sensitive and safe in targeting tamoxifen-resistant breast cancer cells both in vitro and in vivo.
Gayral, Marion; Lulka, Hubert; Hanoun, Naima; Biollay, Coline; Sèlves, Janick; Vignolle-Vidoni, Alix; Berthommé, Hervé; Trempat, Pascal; Epstein, Alberto L; Buscail, Louis; Béjot, Jean-Luc; Cordelier, Pierre
As many other cancers, pancreatic ductal adenocarcinoma (PDAC) progression is associated with a series of hallmark changes for cancer cells to secure their own growth success. Yet, these very changes render cancer cells highly sensitive to viral infection. A promising strategy may rely on and exploit viral replication for tumor destruction, whereby infection of tumor cells by a replication-conditional virus may lead to cell destruction and simultaneous release of progeny particles that can spread and infect adjacent tumor cells, while sparing healthy tissues. In the present study, we used Myb34.5, a second-generation replication-conditional herpes simplex virus type 1 (HSV-1) mutant in which ICP6 gene expression is defective and expression of the HSV-1 γ134.5 gene is regulated by the cellular B-myb promoter. We found that B-myb is present in experimental PDAC and tumors, and is overexpressed in patients' tumors, as compared with normal adjacent pancreas. Myb34.5 replicates to high level in human PDAC cell lines and is associated with cell death by apoptosis. In experimental models of PDAC, mice receiving intratumoral Myb34.5 injections appeared healthy and tumor progression was inhibited, with evidence of tumor necrosis, hemorrhage, viral replication, and cancer cell death by apoptosis. Combining standard-of-care chemotherapy with Myb34.5 successfully led to a very impressive antitumoral effect that is rarely achieved in this experimental model, and resulted in a greater reduction in tumor growth than chemotherapy alone. These promising results warrant further evaluation in early phase clinical trial for patients diagnosed with PDAC for whom no effective treatment is available.
... Was this page helpful? Also known as: Herpes Culture; Herpes Simplex Viral Culture; HSV DNA; HSV by PCR; HSV-1 or ... of testing for the virus are the herpes culture and HSV DNA testing (PCR). PCR testing is ...
Nakamori, Mikihito; Yamaue, Hiroki
Oncolytic virotherapy is an emerging treatment strategy that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, and strategies to maximize the immunotherapeutic action of oncolytic viruses. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using OncoVEX for metastatic melanoma. In Japan, clinical treatments such as oncolytic adenoviruses(OBP-301)for esophageal cancer and oncolytic herpes simplex viruses(G47b)for brain cancer have accelerated considerably. We hope that a steady stream of new oncolytic viruses will enter the clinical arena in our country.
Friedman, Gregory K.; Moore, Blake P.; Nan, Li; Kelly, Virginia M.; Etminan, Tina; Langford, Catherine P.; Xu, Hui; Han, Xiaosi; Markert, James M.; Beierle, Elizabeth A.; Gillespie, G. Yancey
Background Childhood medulloblastoma is associated with significant morbidity and mortality that is compounded by neurotoxicity for the developing brain caused by current therapies, including surgery, craniospinal radiation, and chemotherapy. Innate therapeutic resistance of some aggressive pediatric medulloblastoma has been attributed to a subpopulation of cells, termed cancer-initiating cells or cancer stemlike cells (CSCs), marked by the surface protein CD133 or CD15. Brain tumors characteristically contain areas of pathophysiologic hypoxia, which has been shown to drive the CSC phenotype leading to heightened invasiveness, angiogenesis, and metastasis. Novel therapies that target medulloblastoma CSCs are needed to improve outcomes and decrease toxicity. We hypothesized that oncolytic engineered herpes simplex virus (oHSV) therapy could effectively infect and kill pediatric medulloblastoma cells, including CSCs marked by CD133 or CD15. Methods Using 4 human pediatric medulloblastoma xenografts, including 3 molecular subgroup 3 tumors, which portend worse patient outcomes, we determined the expression of CD133, CD15, and the primary HSV-1 entry molecule nectin-1 (CD111) by fluorescence activated cell sorting (FACS) analysis. Infectability and cytotoxicity of clinically relevant oHSVs (G207 and M002) were determined in vitro and in vivo by FACS, immunofluorescent staining, cytotoxicity assays, and murine survival studies. Results We demonstrate that hypoxia increased the CD133+ cell fraction, while having the opposite effect on CD15 expression. We established that all 4 xenografts, including the CSCs, expressed CD111 and were highly sensitive to killing by G207 or M002. Conclusions Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted. PMID:26188016
Thorne, Amy Haseley; Meisen, Walter H; Russell, Luke; Yoo, Ji Young; Bolyard, Chelsea M; Lathia, Justin D; Rich, Jeremy; Puduvalli, Vinay K; Mao, Hsiaoyin; Yu, Jianhua; Caligiuri, Michael A; Tridandapani, Susheela; Kaur, Balveen
Glioblastoma is a devastating disease, and there is an urgent need to develop novel therapies, such as oncolytic HSV1 (OV) to effectively target tumor cells. OV therapy depends on tumor-specific replication leading to destruction of neoplastic tissues. Host responses that curtail virus replication limit its efficacy in vivo. We have previously shown that cysteine-rich 61 protein (CCN1) activates a type 1 IFN antiviral defense response in glioblastoma cells. Incorporating TCGA data, we found CCN1 expression to be a negative prognostic factor for glioblastoma patients. Based on this, we used neutralizing antibodies against CCN1 to investigate its effect on OV therapy. Use of an anti-CCN1 antibody in mice bearing glioblastomas treated with OV led to enhanced virus expression along with reduced immune cell infiltration. OV-induced CCN1 increases macrophage migration toward infected glioblastoma cells by directly binding macrophages and also by enhancing the proinflammatory activation of macrophages inducing MCP-1 expression in glioblastoma cells. Activation of macrophages by CCN1 also increases viral clearance. Neutralization of integrin αMβ2 reversed CCN1-induced macrophage activation and migration, and reduced MCP-1 expression by glioblastoma cells. Our findings reveal that CCN1 plays a novel role in pathogen clearance; increasing macrophage infiltration and activation resulting in increased virus clearance in tumors.
Geevarghese, Sunil K; Geller, David A; de Haan, Hans A; Hörer, Markus; Knoll, Anette E; Mescheder, Axel; Nemunaitis, John; Reid, Tony R; Sze, Daniel Y; Tanabe, Kenneth K; Tawfik, Hoda
This multicenter phase I/II study evaluated the safety, pharmacokinetics, and antitumor effects of repeated doses of NV1020, a genetically engineered oncolytic herpes simplex virus, in patients with advanced metastatic colorectal cancer (mCRC). Patients with liver-dominant mCRC received four fixed NV1020 doses via weekly hepatic artery infusion, followed by two or more cycles of conventional chemotherapy. Phase I included cohorts receiving 3 × 10(6), 1 × 10(7), 3 × 10(7), and 1 × 10(8) plaque-forming units (PFU)/dose to determine the optimal biological dose (OBD) for phase II. Blind independent computed tomography scan review was based on RECIST (response evaluation criteria in solid tumors) to assess hepatic tumor response. Phase I and II enrolled 13 and 19 patients, respectively. Patients experienced transient mild-moderate febrile reactions after each NV1020 infusion. Grade 3/4 virus-related toxicity was limited to transient lymphopenia in two patients. NV1020 shedding was not detected. Simultaneous cytokine and grade 1 coagulation perturbations were dose-limiting at 1 × 10(8) PFU/dose, considered the OBD. All 22 OBD patients had previously received 5-fluorouracil; most had received oxaliplatin or irinotecan (50% had both), many with at least one targeted agent. After NV1020 administration, 50% showed stable disease. The best overall tumor control rate after chemotherapy was 68% (1 partial response, 14 stable disease); this did not correlate with baseline variables or chemotherapy. Median time to progression was 6.4 months (95% confidence interval: 2, 8.9); median overall survival was 11.8 months (95% confidence interval: 8.3, 20.7). One-year survival was 47.2%. We conclude that NV1020 stabilizes liver metastases with minimal toxicity in mCRC. It may resensitize metastases to salvage chemotherapy and extend overall survival. A randomized phase II/III trial now appears justified.
Chan, Winnie M.; McFadden, Grant
Current standard treatments of cancer can prolong survival of many cancer patients but usually do not effectively cure the disease. Oncolytic virotherapy is an emerging therapeutic for the treatment of cancer that exploits replication-competent viruses to selectively infect and destroy cancerous cells while sparing normal cells and tissues. Clinical and/or preclinical studies on oncolytic viruses have revealed that the candidate viruses being tested in trials are remarkably safe and offer potential for treating many classes of currently incurable cancers. Among these candidates are vaccinia and myxoma viruses, which belong to the family Poxviridae and possess promising oncolytic features. This article describes poxviruses that are being developed for oncolytic virotherapy and summarizes the outcomes of both clinical and preclinical studies. Additionally, studies demonstrating superior efficacy when poxvirus oncolytic virotherapy is combined with conventional therapies are described. PMID:25839047
Cervantes-García, Daniel; Ortiz-López, Rocío; Mayek-Pérez, Netzahualcoyotl; Rojas-Martínez, Augusto
Current oncolytic virotherapy strategies are based in the accumulated understanding of the common molecular mechanisms displayed during cell transformation and viral infection, like cell cycle and apoptosis deregulations. Oncolytic virotherapy aims to achieve a strong cytolytic effect, highly restricted to transformed cells. Here, we describe the oncolytic virotherapy defined as the use of viruses like antitumor agents (wild and gene-modified oncolytic viruses) and the developed strategies to increase antitumor efficacy and safety. In addition, we discuss the advances and challenges concerning the use virotherapy in animal models and clinical trials. Some clinical trials of virotherapy have demonstrated promising results, particularly when combined with standard antineoplastic therapies. These preliminary accomplishments are opening the field for more research in several aspects, like vector modifications, pharmacodynamics, biosafety, new clinical applications, etc.
Sze, Daniel Y; Reid, Tony R; Rose, Steven C
Oncolytic virotherapy is an emerging technology that uses engineered viruses to treat malignancies. Viruses can be designed with biological specificity to infect cancerous cells preferentially, and to replicate in these cells exclusively. Malignant cells may be killed directly by overwhelming viral infection and lysis, which releases additional viral particles to infect neighboring cells and distant metastases. Viral infections may also activate the immune system, unmask stealthy tumor antigens, and aid the immune system to recognize and attack neoplasms. Delivery of live virus particles is potentially complex, and may require the expertise of the interventional community.
Taguchi, Satoru; Fukuhara, Hiroshi; Homma, Yukio; Todo, Tomoki
Oncolytic virus therapy has recently been recognized as a promising new option for cancer treatment. Oncolytic viruses replicate selectively in cancer cells, thus killing them without harming normal cells. Notably, T-VEC (talimogene laherparepvec, formerly called OncoVEX(GM)(-)(CSF) ), an oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in October 2015, and was subsequently approved in Europe and Australia in 2016. The efficacies of many types of oncolytic viruses against urological cancers have been investigated in preclinical studies during the past decade, and some have already been tested in clinical trials. For example, a phase I trial of the third-generation oncolytic Herpes simplex virus type 1, G47Δ, in patients with prostate cancer was completed in 2016. We summarize the current status of clinical trials of oncolytic virus therapy in patients with the three major urological cancers: prostate, bladder and renal cell cancers. In addition to Herpes simplex virus type 1, adenoviruses, reoviruses, vaccinia virus, Sendai virus and Newcastle disease virus have also been used as parental viruses in these trials. We believe that oncolytic virus therapy is likely to become an important and major treatment option for urological cancers in the near future.
Friedman, Gregory K; Cassady, Kevin A; Beierle, Elizabeth A; Markert, James M; Gillespie, G Yancey
Cancer stem cells (CSCs), also termed "cancer-initiating cells" or "cancer progenitor cells," which have the ability to self-renew, proliferate, and maintain the neoplastic clone, have recently been discovered in a wide variety of pediatric tumors. These CSCs are thought to be responsible for tumorigenesis and tumor maintenance, aggressiveness, and recurrence due to inherent resistance to current treatment modalities such as chemotherapy and radiation. Oncolytic virotherapy offers a novel, targeted approach for eradicating pediatric CSCs using mechanisms of cell killing that differ from conventional therapies. Moreover, oncolytic viruses have the ability to target specific features of CSCs such as cell-surface proteins, transcription factors, and the CSC microenvironment. Through genetic engineering, a wide variety of foreign genes may be expressed by oncolytic viruses to augment the oncolytic effect. We review the current data regarding the ability of several types of oncolytic viruses (herpes simplex virus-1, adenovirus, reovirus, Seneca Valley virus, vaccinia virus, Newcastle disease virus, myxoma virus, vesicular stomatitis virus) to target and kill both CSCs and tumor cells in pediatric tumors. We highlight advantages and limitations of each virus and potential ways in which next-generation engineered viruses may target resilient CSCs.
Conditionally replicating herpes simplex viruses Type 1 (HSV-1) are promising therapeutic agents for glioma. They can replicate in situ, spread and exhibit oncolytic activity via a direct cytocidal effect. In addition, specific antitumor immunity is effectively induced in the course of oncolytic activities. G47Δ is a genetically engineered HSV-1 with triple mutations that realized augmented viral replication in tumor cells, strong induction of antitumor immunity and enhanced safety in normal tissues. A clinical trial of G47Δ in patients with recurrent glioblastoma has started in 2009. One of the advantages of HSV-1 is its capacity to incorporate large and/or multiple transgenes within the viral genome. In preclinical studies, "arming" of an oncolytic HSV-1 with transgenes encoding immunomodulatory molecules, such as interleukin 12, has been shown to greatly augment the efficacy of oncolytic HSV-1 therapy. Oncolytic virus therapy using HSV-1 may be a useful treatment for glioma that can also function as an efficient in situ tumor vaccination.
Genital herpes - resources; Resources - genital herpes ... The following organizations are good resources for information on genital herpes : March of Dimes -- www.marchofdimes.com/pregnancy/complications-herpes The American College of Obstetricians and Gynecologists -- ...
Waters, Alicia M; Friedman, Gregory K; Ring, Eric K; Beierle, Elizabeth A
Pediatric solid tumors remain a major health concern, with nearly 16,000 children diagnosed each year. Of those, ~2,000 succumb to their disease, and survivors often suffer from lifelong disability secondary to toxic effects of current treatments. Countless multimodality treatment regimens are being explored to make advances against this deadly disease. One targeted treatment approach is oncolytic virotherapy. Conditionally replicating viruses can infect tumor cells while leaving normal cells unharmed. Four viruses have been advanced to pediatric clinical trials, including herpes simplex virus-1, Seneca Valley virus, reovirus, and vaccinia virus. In this review, we discuss the mechanism of action of each virus, pediatric preclinical studies conducted to date, past and ongoing pediatric clinical trials, and potential future direction for these novel viral therapeutics.
Waters, Alicia M; Friedman, Gregory K; Ring, Eric K; Beierle, Elizabeth A
Pediatric solid tumors remain a major health concern, with nearly 16,000 children diagnosed each year. Of those, ~2,000 succumb to their disease, and survivors often suffer from lifelong disability secondary to toxic effects of current treatments. Countless multimodality treatment regimens are being explored to make advances against this deadly disease. One targeted treatment approach is oncolytic virotherapy. Conditionally replicating viruses can infect tumor cells while leaving normal cells unharmed. Four viruses have been advanced to pediatric clinical trials, including herpes simplex virus-1, Seneca Valley virus, reovirus, and vaccinia virus. In this review, we discuss the mechanism of action of each virus, pediatric preclinical studies conducted to date, past and ongoing pediatric clinical trials, and potential future direction for these novel viral therapeutics. PMID:27579298
Hammill, Adrienne M; Conner, Joseph; Cripe, Timothy P
Lytic viruses kill cells as a consequence of their normal replication life cycle. The idea of harnessing viruses to kill cancer cells arose over a century ago, before viruses were even discovered, from medical case reports of infections associated with cancer remissions. Since then, there has been no shortage of hype, hope, or fear regarding the prospect of oncolytic virotherapy for cancer. Early developments in the field included encouraging antitumor efficacy both in animal studies in the 1920s-1940s and in human clinical trials in the 1950s-1970s. Despite its long-standing history, oncolytic virotherapy was an idea ahead of its time. Without needed advances in molecular biology, virology, immunology, and clinical research ethics, early clinical trials resulted in infectious complications and were fraught with controversial research conduct, so that enthusiasm in the medical community waned. Oncolytic virotherapy is now experiencing a major growth spurt, having sustained numerous laboratory advances and undergone multiple encouraging adult clinical trials, and is now witnessing the emergence of pediatric trials. Here we review the history and salient biology of the field, including preclinical and clinical data, with a special emphasis on those agents now being tested in pediatric cancer patients.
... is caused by a herpes simplex virus (HSV). Oral herpes causes cold sores around the mouth or face. Genital herpes affects the genitals, buttocks ... type 2 is the usual cause of genital herpes, but it also can infect the mouth. HSV spreads through direct contact. Some people have ...
Fukuhara, Hiroshi; Ino, Yasushi; Todo, Tomoki
Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T-Vec (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1 (HSV-1) armed with GM-CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T-Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX-594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM-CSF-expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild-type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47∆, a third-generation oncolytic HSV-1, is ongoing in glioblastoma patients. G47∆ was recently designated as a "Sakigake" breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47∆ with priority reviews and a fast-track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor-specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients.
Babiker, Hani M; Riaz, Irbaz Bin; Husnain, Muhammad; Borad, Mitesh J
The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients. This is certainly a burgeoning time in immunotherapy drug development, and the aforementioned efforts along with the recent US Food and Drug Administration approval of talimogene laherparepvec (T-VEC), a recombinant oncolytic herpes virus, have paved the way to exploring the role of additional oncolytic viruses, such as the echovirus Rigvir, as new and innovative treatment modalities in patients with melanoma. Herein, we discuss the current standard of care treatment in melanoma with an emphasis on immunotherapy and oncolytic viruses in development.
Babiker, Hani M; Riaz, Irbaz Bin; Husnain, Muhammad; Borad, Mitesh J
The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients. This is certainly a burgeoning time in immunotherapy drug development, and the aforementioned efforts along with the recent US Food and Drug Administration approval of talimogene laherparepvec (T-VEC), a recombinant oncolytic herpes virus, have paved the way to exploring the role of additional oncolytic viruses, such as the echovirus Rigvir, as new and innovative treatment modalities in patients with melanoma. Herein, we discuss the current standard of care treatment in melanoma with an emphasis on immunotherapy and oncolytic viruses in development. PMID:28224120
... the lips, mouth, or gums due to the herpes simplex virus. It causes small, painful blisters commonly called cold ... the mouth area. It is caused by the herpes simplex virus type 1 (HSV-1). Most people in the ...
... 5 Some persons who contract genital herpes have concerns about how it will impact their overall health, ... a patientâs relationships. 10 Clinicians can address these concerns by encouraging patients to recognize that while herpes ...
... who have sex with women get genital herpes? Yes. It is possible to get genital herpes, or any other STI, if you are a woman who ... sex and avoid sexual activity during an outbreak. Yes. It is possible to get genital herpes, or any other STI, if you are a woman who ...
Brown, Michael C; Dobrikova, Elena Y; Dobrikov, Mikhail I; Walton, Ross W; Gemberling, Sarah L; Nair, Smita K; Desjardins, Annick; Sampson, John H; Friedman, Henry S; Friedman, Allan H; Tyler, Douglas S; Bigner, Darell D; Gromeier, Matthias
Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.
Breitbach, Caroline J; Lichty, Brian D; Bell, John C
Oncolytic viruses (OV) are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a "one-size fits all" approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms.
these tumors. We have been working with genetically engineered human herpes simplex virus (HSV) as a means of treating nervous system tumors. We have... genetically modified these viruses to make them safe and unable to grow in normal cells, but that can grow in tumor cells causing them to die, a...the sporadic susceptibility or resistance to infection of MPNST cells to genetically engineered, oncolytic herpes simplex viruses (oHSVs) in our
Hartkopf, Andreas D; Fehm, Tanja; Wallwiener, Diethelm; Lauer, Ulrich M
The use of replication competent viruses that selectively target and destroy cancer cells has rapidly evolved over the past decade and numerous innovative oncolytic viruses have been created. Many of these promising anti-cancer agents have recently entered into clinical trials (including those on breast cancer) and demonstrated encouraging safety and efficacy. Virotherapeutic strategies are thus of considerable interest to combat breast cancer in both (i) the primary disease situation in which relapse should be avoided as good as possible and (ii) in the metastatic situation which remains incurable to date. Here, we summarize data from preclinical and clinical trials using oncolytic virotherapy to treat breast cancer. This includes strategies to specifically target breast cancer cells, to arm oncolytic viruses with additional therapeutic transgenes and an outlining of future challenges when translating these promising therapeutics "from bench to bedside".
... a sexually transmitted disease (STD) caused by a herpes simplex virus (HSV). It can cause sores on your genital or rectal area, buttocks, and thighs. You can get it from having vaginal, anal, or ... of herpes are called outbreaks. You usually get sores near ...
Delwar, Zahid; Zhang, Kaixin; Rennie, Paul S; Jia, William
Oncolytic virotherapy is a cancer treatment in which replication-competent viruses are used that specifically infect, replicate in and lyse malignant tumour cells, while minimizing harm to normal cells. Anecdotal evidence of the effectiveness of this strategy has existed since the late nineteenth century, but advances and innovations in biotechnological methods in the 1980s and 1990s led to a renewed interest in this type of therapy. Multiple clinical trials investigating the use of agents constructed from a wide range of viruses have since been performed, and several of these enrolled patients with urological malignancies. Data from these clinical trials and from preclinical studies revealed a number of challenges to the effectiveness of oncolytic virotherapy that have prompted the development of further sophisticated strategies. Urological cancers have a range of distinctive features, such as specific genetic mutations and cell surface markers, which enable improving both effectiveness and safety of oncolytic virus treatments. The strategies employed in creating advanced oncolytic agents include alteration of the virus tropism, regulating transcription and translation of viral genes, combination with chemotherapy, radiotherapy or gene therapy, arming viruses with factors that stimulate the immune response against tumour cells and delivery technologies to ensure that the viral agent reaches its target tissue.
Moehler, Markus; Goepfert, Katrin; Heinrich, Bernd; Breitbach, Caroline J.; Delic, Maike; Galle, Peter Robert; Rommelaere, Jean
Human tumors develop multiple strategies to evade recognition and efficient suppression by the immune system. Therefore, a variety of immunotherapeutic strategies have been developed to reactivate and reorganize the human immune system. The recent development of new antibodies against immune check points may help to overcome the immune silencing induced by human tumors. Some of these antibodies have already been approved for treatment of various solid tumor entities. Interestingly, targeting antibodies may be combined with standard chemotherapy or radiation protocols. Furthermore, recent evidence indicates that intratumoral or intravenous injections of replicative oncolytic viruses such as herpes simplex-, pox-, parvo-, or adenoviruses may also reactivate the human immune system. By generating tumor cell lysates in situ, oncolytic viruses overcome cellular tumor resistance mechanisms and induce immunogenic tumor cell death resulting in the recognition of newly released tumor antigens. This is in particular the case of the oncolytic parvovirus H-1 (H-1PV), which is able to kill human tumor cells and stimulate an anti-tumor immune response through increased presentation of tumor-associated antigens, maturation of dendritic cells, and release of pro-inflammatory cytokines. Current research and clinical studies aim to assess the potential of oncolytic virotherapy and its combination with immunotherapeutic agents or conventional treatments to further induce effective antitumoral immune responses. PMID:24822170
Moehler, Markus; Goepfert, Katrin; Heinrich, Bernd; Breitbach, Caroline J; Delic, Maike; Galle, Peter Robert; Rommelaere, Jean
Human tumors develop multiple strategies to evade recognition and efficient suppression by the immune system. Therefore, a variety of immunotherapeutic strategies have been developed to reactivate and reorganize the human immune system. The recent development of new antibodies against immune check points may help to overcome the immune silencing induced by human tumors. Some of these antibodies have already been approved for treatment of various solid tumor entities. Interestingly, targeting antibodies may be combined with standard chemotherapy or radiation protocols. Furthermore, recent evidence indicates that intratumoral or intravenous injections of replicative oncolytic viruses such as herpes simplex-, pox-, parvo-, or adenoviruses may also reactivate the human immune system. By generating tumor cell lysates in situ, oncolytic viruses overcome cellular tumor resistance mechanisms and induce immunogenic tumor cell death resulting in the recognition of newly released tumor antigens. This is in particular the case of the oncolytic parvovirus H-1 (H-1PV), which is able to kill human tumor cells and stimulate an anti-tumor immune response through increased presentation of tumor-associated antigens, maturation of dendritic cells, and release of pro-inflammatory cytokines. Current research and clinical studies aim to assess the potential of oncolytic virotherapy and its combination with immunotherapeutic agents or conventional treatments to further induce effective antitumoral immune responses.
Workenhe, Samuel T; Pol, Jonathan G; Lichty, Brian D; Cummings, Derek T; Mossman, Karen L
Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death-inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 μmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8(+) T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death-inducing chemotherapeutics enhance the immunogenicity of the tumor-associated antigens, breaking immunologic tolerance established toward these antigens.
Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells which are shown to be relatively resistant to conventional anticancer therapies and have been correlated to disease recurrence. Oncolytic viruses utilize methods of cell killing that differ from traditional therapies and thus are able to elude the typical mechanisms that CSCs use to resist current chemotherapies and radiotherapies. Moreover, genetically engineered oncolytic viruses may further augment the oncolytic effects. Here we review the recent data regarding the ability of several oncolytic viruses to eradicate CSCs. PMID:27358866
... to another person's genitals. Genital herpes is a sexually transmitted disease (STD) . It can cause sores in the genital ... TOPIC Talking to Your Partner About Condoms About Sexually Transmitted Diseases (STDs) Talking to Your Partner About STDs 5 ...
... fetal scalp electrode (tiny wire used to check fetal heart rate). Cesarean birth may be recommended if you have an active herpes sore or prodromal symptoms such as pain or burning when you go into labor. After ...
Targeting of an Oncolytic HSV - 1 Amplicon/Helper Virus for Prostate Cancer Treatment PRINCIPAL INVESTIGATOR: Cleo Lee CONTRACTING...5a. CONTRACT NUMBER Prostate-Specific and Tumor-Specific Targeting of an Oncolytic HSV - 1 Amplicon/Helper Virus for Prostate Cancer Treatment...untranslated region (3’UTR) of a herpes simplex virus- 1 ( HSV - 1 ) essential viral gene, ICP4, to create CMV-ICP4-143T and CMV-ICP4-145T amplicon viruses. Our
Li, Shoudong; Tong, Jessica; Rahman, Masmudur M; Shepherd, Trevor G; McFadden, Grant
In the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (OVs) for treatments of a variety of malignancies. Of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. So far, nine phase I or II clinical trials have been conducted or initiated using four different types of OVs in patients with recurrent ovarian cancers. In this article, we summarize the different OVs that are being assessed as therapeutics for ovarian cancer. We also present an overview of recent advances in identification of key genetic or immune-response pathways involved in tumorigenesis of ovarian cancer, which provides a better understanding of the tumor specificities and oncolytic properties of OVs. In addition, we discuss how next-generation OVs could be genetically modified or integrated into multimodality regimens to improve clinical outcomes based on recent advances in ovarian cancer biology.
Li, Shoudong; Tong, Jessica; Rahman, Masmudur M; Shepherd, Trevor G; McFadden, Grant
In the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (OVs) for treatments of a variety of malignancies. Of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. So far, nine phase I or II clinical trials have been conducted or initiated using four different types of OVs in patients with recurrent ovarian cancers. In this article, we summarize the different OVs that are being assessed as therapeutics for ovarian cancer. We also present an overview of recent advances in identification of key genetic or immune-response pathways involved in tumorigenesis of ovarian cancer, which provides a better understanding of the tumor specificities and oncolytic properties of OVs. In addition, we discuss how next-generation OVs could be genetically modified or integrated into multimodality regimens to improve clinical outcomes based on recent advances in ovarian cancer biology. PMID:25977900
Harrington, Kevin J
Oncolytic virotherapy is a novel treatment for cancer that exerts direct lytic and indirect immune-mediated antitumor effects. A Finnish research team has reported on an advanced therapy access program for oncolytic adenovirus. The strengths and weaknesses of this approach are highlighted with a view to informing future study conduct.
Mairos, João S; Veca, Concetta P; Ribeiro, Rui
Herpes Gestationis is a serious dermatological disease, albeit rare, associated to pregnancy or to the trophoblast diseases. Contrary to what the name suggests, it is not a viral disease but an auto-immune disease. We present the clinical case of a 38 year-old woman to whom a case of Herpes Gestationis was diagnosed when she was 15 weeks pregnant and whom has been treated with corticosteroids and antihistamine's showing positive results and without major complications for the mother or the embryo. The authors are undertaking a review of the existing literature, based on this clinic case.
The purposes of this paper are to discuss the US Department of Energy's (DOE's) experience with dual regulation under the Resource Conservation and Recovery Act (RCRA), as amended, and the Atomic Energy Act (AEA), as amended, of mixed waste and to describe one mechanism for the resolution of inconsistencies that may arise. To date, the department has not identified any unresolvable inconsistency between the AEA and RCRA, although technical differences are being discussed among DOE, EPA, and state regulators at several locations. As long as the flexibilities of RCRA are explored with careful consideration of the radiological hazard of each mixed-waste stream, the potential for inconsistencies between AEA and RCRA that DOE must resolve is expected to remain small.
Gentschev, Ivaylo; Patil, Sandeep S; Petrov, Ivan; Cappello, Joseph; Adelfinger, Marion; Szalay, Aladar A
Cancer is the leading cause of disease-related death in companion animals such as dogs and cats. Despite recent progress in the diagnosis and treatment of advanced canine and feline cancer, overall patient treatment outcome has not been substantially improved. Virotherapy using oncolytic viruses is one promising new strategy for cancer therapy. Oncolytic viruses (OVs) preferentially infect and lyse cancer cells, without causing excessive damage to surrounding healthy tissue, and initiate tumor-specific immunity. The current review describes the use of different oncolytic viruses for cancer therapy and their application to canine and feline cancer.
Gentschev, Ivaylo; Patil, Sandeep S.; Petrov, Ivan; Cappello, Joseph; Adelfinger, Marion; Szalay, Aladar A.
Cancer is the leading cause of disease-related death in companion animals such as dogs and cats. Despite recent progress in the diagnosis and treatment of advanced canine and feline cancer, overall patient treatment outcome has not been substantially improved. Virotherapy using oncolytic viruses is one promising new strategy for cancer therapy. Oncolytic viruses (OVs) preferentially infect and lyse cancer cells, without causing excessive damage to surrounding healthy tissue, and initiate tumor-specific immunity. The current review describes the use of different oncolytic viruses for cancer therapy and their application to canine and feline cancer. PMID:24841386
Scappatura, F. Philip
The author reviews the prevalence of genital herpes, outlines the typical clinical courses of the disease in its primary and recurrent forms. He discusses the physical, psychological and social effects of this sexually transmitted disease and provides three protocols for the use of oral acyclovir in its treatment. PMID:21263803
... best way to prevent genital herpes is abstinence. Teens who do have sex must properly use a latex condom every time ... Date reviewed: February 2016 previous 1 • ... Boyfriend Has an STD Before We Have Sex? Telling Your Partner You Have an STD Contact ...
Currier, Mark A; Eshun, Francis K; Sholl, Allyson; Chernoguz, Artur; Crawford, Kelly; Divanovic, Senad; Boon, Louis; Goins, William F; Frischer, Jason S; Collins, Margaret H; Leddon, Jennifer L; Baird, William H; Haseley, Amy; Streby, Keri A; Wang, Pin-Yi; Hendrickson, Brett W; Brekken, Rolf A; Kaur, Balveen; Hildeman, David; Cripe, Timothy P
Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b(+) cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.
Sobol, Paul T; Boudreau, Jeanette E; Stephenson, Kyle; Wan, Yonghong; Lichty, Brian D; Mossman, Karen L
Oncolytic virotherapy, the selective killing of tumor cells by oncolytic viruses (OVs), has emerged as a promising avenue of anticancer research. We have previously shown that KM100, a Herpes simplex virus type-1 (HSV) deficient for infected cell protein 0 (ICP0), possesses substantial oncolytic properties in vitro and has antitumor efficacy in vivo, in part by inducing antitumor immunity. Here, we illustrate through T-cell immunodepletion studies in nontolerized tumor-associated antigen models of breast cancer that KM100 treatment promotes antiviral and antitumor CD8(+) cytotoxic T-cell responses necessary for complete tumor regression. In tolerized tumor-associated antigen models of breast cancer, antiviral CD8(+) cytotoxic T-cell responses against infected tumor cells correlated with the induction of significant tumoristasis in the absence of tumor-associated antigen-specific CD8(+) cytotoxic T-cells. To enhance oncolysis, we tested a more cytopathic ICP0-null HSV and a vesicular stomatitis virus M protein mutant and found that despite improved in vitro replication, oncolysis in vivo did not improve. These studies illustrate that the in vitro cytolytic properties of OVs are poor prognostic indicators of in vivo antitumor activity, and underscore the importance of adaptive antiviral CD8(+) cytotoxic T-cells in effective cancer virotherapy.
Tsang, Jovian J; Atkins, Harold L
Hematological malignancies are treated with intensive high-dose chemotherapy, with or without radiation. This is followed by hematopoietic stem cell (HSC) transplantation (HSCT) to rescue or reconstitute hematopoiesis damaged by the anticancer therapy. Autologous HSC grafts may contain cancer cells and purging could further improve treatment outcomes. Similarly, allogeneic HSCT may be improved by selectively purging alloreactive effector cells from the graft rather than wholesale immune cell depletion. Viral agents that selectively replicate in specific cell populations are being studied in experimental models of cancer and immunological diseases and have potential applications in the context of HSC graft engineering. This review describes preclinical studies involving oncolytic virus strains of adenovirus, herpes simplex virus type 1, myxoma virus, and reovirus as ex vivo purging agents for HSC grafts, as well as in vitro and in vivo experimental studies using oncolytic coxsackievirus, measles virus, parvovirus, vaccinia virus, and vesicular stomatitis virus to eradicate hematopoietic malignancies. Alternative ex vivo oncolytic virus strategies are also outlined that aim to reduce the risk of relapse following autologous HSCT and mitigate morbidity and mortality due to graft-versus-host disease in allogeneic HSCT. PMID:27512666
Tsang, Jovian J; Atkins, Harold L
Hematological malignancies are treated with intensive high-dose chemotherapy, with or without radiation. This is followed by hematopoietic stem cell (HSC) transplantation (HSCT) to rescue or reconstitute hematopoiesis damaged by the anticancer therapy. Autologous HSC grafts may contain cancer cells and purging could further improve treatment outcomes. Similarly, allogeneic HSCT may be improved by selectively purging alloreactive effector cells from the graft rather than wholesale immune cell depletion. Viral agents that selectively replicate in specific cell populations are being studied in experimental models of cancer and immunological diseases and have potential applications in the context of HSC graft engineering. This review describes preclinical studies involving oncolytic virus strains of adenovirus, herpes simplex virus type 1, myxoma virus, and reovirus as ex vivo purging agents for HSC grafts, as well as in vitro and in vivo experimental studies using oncolytic coxsackievirus, measles virus, parvovirus, vaccinia virus, and vesicular stomatitis virus to eradicate hematopoietic malignancies. Alternative ex vivo oncolytic virus strategies are also outlined that aim to reduce the risk of relapse following autologous HSCT and mitigate morbidity and mortality due to graft-versus-host disease in allogeneic HSCT.
Garland, Suzanne M; Steben, Marc
Genital herpes is a relatively common infection caused by herpes simplex virus (HSV) type one or two (HSV-1, HSV-2) respectively. It is acquired most commonly via sexual activity. More recently there has been an increase in infections due to HSV-1. Most new cases of genital HSV are not diagnosed due to HSV infections having short-lived signs and symptoms, or in many instances are asymptomatic. Hence many people infected with HSV are unaware that they have it. The risk of transmission to a partner is highest during outbreak periods, when there are visible lesions, although genital HSV can also be transmitted during asymptomatic periods. Use of condoms and antiviral medications assist in preventing transmission. Antiviral agents are effective in controlling clinical episodes, but do not eradicate infection, which remains latent for the life of a patient. Despite the surge in vaccine research, there is unfortunately no readily available preventative or therapeutic vaccine for HSV to date.
Legoff, Jérôme; Aymard, Michèle; Braig, Suzanne; Ramel, Françoise; Dreno, Brigitte; Bélec, Laurent; Malkin, Jean-Elie
The epidemiology of genital herpes is changing. The seroprevalence of HSV-2 infections is increasing, while HSV-1 is an increasingly common cause of herpetic ulcerations. The reference examination provides direct diagnosis after viral isolation in a cell culture or genome amplification. Herpes serology is indicated principally if direct examination is negative and in the absence of lesions. Non-type-specific serology detects antibodies common to HSV-1 and HSV-2. Its specificity and sensitivity are excellent, and it is approved as a reimbursable laboratory procedure. It cannot specify the viral type involved. Type-specific serology can distinguish between anti-HSV-1 and anti-HSV-2 antibodies. Currently available kits have a sensitivity and specificity, depending on the population studied, of 90 to 100%. It is not approved as a reimbursable laboratory procedure. HSV-1-specific serology cannot diagnose old HSV-1 genital infections, but seropositivity for HSV-2 generally suffices to diagnose HSV-2 genital herpes. The indication for type-specific serology must be discussed according to clinical context. The value of non-type-specific serology is limited.
Describes some of the characteristics of "herps" (amphibians and reptiles). Contains teaching activities dealing with ancient herps, learning stations that encourage sensory experiences with herps, and games, puzzles, and a dramatic play about herps. Includes reproducible handouts designed to be used with the activities, as well as a quiz. (TW)
Kalra, Sanjay; Chawla, Aastha
This review is a succinct description of the relationship between herpes zoster and diabetes. It makes a strong case for screening for diabetes in all patients of herpes zoster, and for using insulin to achieve optimal glycaemic control in persons with concomitant diabetes and herpes zoster. It highlights potential impact of dipeptidyl peptidase 4 inhibitor therapy and statin usage on herpes zoster incidence.
Chan, Winnie M; Rahman, Masmudur M; McFadden, Grant
Many common neoplasms are still noncurative with current standards of cancer therapy. More therapeutic modalities need to be developed to significantly prolong the lives of patients and eventually cure a wider spectrum of cancers. Oncolytic virotherapy is one of the promising new additions to clinical cancer therapeutics. Successful oncolytic virotherapy in the clinic will be those strategies that best combine tumor cell oncolysis with enhanced immune responses against tumor antigens. The current candidate oncolytic viruses all share the common property that they are relatively nonpathogenic to humans, yet they have the ability to replicate selectively in human cancer cells and induce cancer regression by direct oncolysis and/or induction of improved anti-tumor immune responses. Many candidate oncolytic viruses are in various stages of clinical and preclinical development. One such preclinical candidate is myxoma virus (MYXV), a member of the Poxviridae family that, in its natural setting, exhibits a very restricted host range and is only pathogenic to European rabbits. Despite its narrow host range in nature, MYXV has been shown to productively infect various classes of human cancer cells. Several preclinical in vivo modeling studies have demonstrated that MYXV is an attractive and safe candidate oncolytic virus, and hence, MYXV is currently being developed as a potential therapeutic for several cancers, such as pancreatic cancer, glioblastoma, ovarian cancer, melanoma, and hematologic malignancies. This review highlights the preclinical cancer models that have shown the most promise for translation of MYXV into human clinical trials.
Chan, Winnie M.; Rahman, Masmudur M.; McFadden, Grant
Many common neoplasms are still noncurative with current standards of cancer therapy. More therapeutic modalities need to be developed to significantly prolong the lives of patients and eventually cure a wider spectrum of cancers. Oncolytic virotherapy is one of the promising new additions to clinical cancer therapeutics. Successful oncolytic virotherapy in the clinic will be those strategies that best combine tumor cell oncolysis with enhanced immune responses against tumor antigens. The current candidate oncolytic viruses all share the common property that they are relatively nonpathogenic to humans, yet they have the ability to replicate selectively in human cancer cells and induce cancer regression by direct oncolysis and/or induction of improved anti-tumor immune responses. Many candidate oncolytic viruses are in various stages of clinical and preclinical development. One such preclinical candidate is myxoma virus (MYXV), a member of the Poxviridae family that, in its natural setting, exhibits a very restricted host range and is only pathogenic to European rabbits. Despite its narrow host range in nature, MYXV has been shown to productively infect various classes of human cancer cells. Several preclinical in vivo modeling studies have demonstrated that MYXV is an attractive and safe candidate oncolytic virus, and hence, MYXV is currently being developed as a potential therapeutic for several cancers, such as pancreatic cancer, glioblastoma, ovarian cancer, melanoma, and hematologic malignancies. This review highlights the preclinical cancer models that have shown the most promise for translation of MYXV into human clinical trials. PMID:23726825
Allan, KJ; Stojdl, David F; Swift, SL
High-throughput screens can rapidly scan and capture large amounts of information across multiple biological parameters. Although many screens have been designed to uncover potential new therapeutic targets capable of crippling viruses that cause disease, there have been relatively few directed at improving the efficacy of viruses that are used to treat disease. Oncolytic viruses (OVs) are biotherapeutic agents with an inherent specificity for treating malignant disease. Certain OV platforms – including those based on herpes simplex virus, reovirus, and vaccinia virus – have shown success against solid tumors in advanced clinical trials. Yet, many of these OVs have only undergone minimal engineering to solidify tumor specificity, with few extra modifications to manipulate additional factors. Several aspects of the interaction between an OV and a tumor-bearing host have clear value as targets to improve therapeutic outcomes. At the virus level, these include delivery to the tumor, infectivity, productivity, oncolysis, bystander killing, spread, and persistence. At the host level, these include engaging the immune system and manipulating the tumor microenvironment. Here, we review the chemical- and genome-based high-throughput screens that have been performed to manipulate such parameters during OV infection and analyze their impact on therapeutic efficacy. We further explore emerging themes that represent key areas of focus for future research. PMID:27579293
Liu, Guang Bin; Zhao, Liang; Zhang, Lifang; Zhao, Kong-Nan
Prostate cancer (PCa), a disease, is characterized by abnormal cell growth in the prostate - a gland in the male reproductive system. PCa is one of the leading causes of cancer death among men of all races. Although older age and a family history of the disease have been recognized as the risk factors of PCa, the cause of this cancer remains unclear. Mounting evidence suggests that infections with various viruses are causally linked to PCa pathogenesis. Published studies have provided strong evidence that at least two viruses (RXMV and HPV) contribute to prostate tumourigenicity and impact on the survival of patients with malignant PCa. Traditional therapies including chemotherapy and radiotherapy are unable to distinguish cancer cells from normal cells, which are a significant drawback and leads to toxicities for PCa patients undergoing treatment. So far, few other options are available for treating patients with advanced PCa. Virotherapy is being developed to be a novel therapy for cancers, which uses oncotropic and oncolytic viruses with their abilities to find and destroy malignant cells in the body. For PCa treatment, oncolytic virotherapy appears to be much more attractive, which uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cancer cell lysis through virus replication and expression of cytotoxic proteins. As oncolytic viruses are a relatively new class of anti-cancer immunotherapy agents, several important barriers still exist on the road to the use of oncolytic viruses for PCa therapy. In this review, we first discuss the controversy of the contribution of virus infection to PCa, and subsequently summarize the development of oncolytic virotherapy for PCa in the past several years.
Bais, Swarna; Bartee, Eric; Rahman, Masmudur M.; McFadden, Grant; Cogle, Christopher R.
Hematological malignancies such as leukemias, lymphomas, multiple myeloma (MM), and the myelodysplastic syndromes (MDSs) primarily affect adults and are difficult to treat. For high-risk disease, hematopoietic stem cell transplant (HCT) can be used. However, in the setting of autologous HCT, relapse due to contamination of the autograft with cancer cells remains a major challenge. Ex vivo manipulations of the autograft to purge cancer cells using chemotherapies and toxins have been attempted. Because these past strategies lack specificity for malignant cells and often impair the normal hematopoietic stem and progenitor cells, prior efforts to ex vivo purge autografts have resulted in prolonged cytopenias and graft failure. The ideal ex vivo purging agent would selectively target the contaminating cancer cells while spare normal stem and progenitor cells and would be applied quickly without toxicities to the recipient. One agent which meets these criteria is oncolytic viruses. This paper details experimental progress with reovirus, myxoma virus, measles virus, vesicular stomatitis virus, coxsackievirus, and vaccinia virus as well as requirements for translation of these results to the clinic. PMID:22312362
... transmitted disease (STD) that's usually caused by the herpes simplex virus type 2 (HSV2), although it also can be caused by herpes simplex virus type 1 (HSV1), which normally causes cold sores ...
Muñoz-Álvarez, Kim A; Altomonte, Jennifer; Laitinen, Iina; Ziegler, Sibylle; Steiger, Katja; Esposito, Irene; Schmid, Roland M; Ebert, Oliver
Hepatocellular carcinoma (HCC) is the most predominant form of liver cancer and the third leading cause of cancer-related death worldwide. Due to the relative ineffectiveness of conventional HCC therapies, oncolytic viruses have emerged as novel alternative treatment agents. Our previous studies have demonstrated significant prolongation of survival in advanced HCC in rats after oncolytic vesicular stomatitis virus (VSV) treatment. In this study, we aimed to establish a reporter system to reliably and sensitively image VSV in a clinically relevant model of HCC for clinical translation. To this end, an orthotopic, unifocal HCC model in immune-competent Buffalo rats was employed to test a recombinant VSV vector encoding for an enhanced version of the herpes simplex virus 1 (HSV-1) thymidine kinase (sr39tk) reporter, which would allow the indirect detection of VSV via positron emission tomography (PET). The resulting data revealed specific tracer uptake in VSV-HSV1-sr39tk-treated tumors. Further characterization of the VSV-HSV1-sr39tk vector demonstrated its optimal detection time-point after application and its detection limit via PET. In conclusion, oncolytic VSV expressing the HSV1-sr39tk reporter gene allows for highly sensitive in vivo imaging via PET. Therefore, this imaging system may be directly translatable and beneficial in further clinical applications.
Palladini, Arianna; Nicoletti, Giordano; Ranieri, Dario; Dall'Ora, Massimiliano; Grosso, Valentina; Rossi, Martina; Alviano, Francesco; Bonsi, Laura; Nanni, Patrizia; Lollini, Pier-Luigi; Campadelli-Fiume, Gabriella
Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain. PMID:26430966
Zhang, K-X; Matsui, Y; Lee, C; Osamu, O; Skinner, L; Wang, J; So, A; Rennie, P S; Jia, W W
Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, local administration of oncolytic Herpes Simplex virus (oHSV-1) can provide a promising new therapy for this disease. However, its inherent neurotoxicity has been a perceived limitation for such application. In this study, we present a novel microRNA-regulatory approach to reduce HSV-1-induced neurotoxicity by suppressing viral replication in neurons while maintaining oncolytic selectivity toward urothelial tumors. Specifically, we designed a recombinant virus that utilizes differentially expressed endogenous microR143 (non-cancerous, ubiquitous) and microR124 (neural-specific) to regulate expression of ICP-4, a gene essential for HSV-1 replication. We found that expression of ICP-4 must be controlled by a combination of both miR143 and miR124 to achieve the most effective attenuation in HSV-1-induced toxicity while retaining maximal oncolytic capacity. These results suggest that interaction between miR143 and miR124 may be required to successfully regulate HSV-1 replication. Our resent study is the first proof-in-principle that miRNA combination can be exploited to fine-tune the replication of HSV-1 to treat human cancers.
Tsun, A; Miao, X N; Wang, C M; Yu, D C
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.
Haddad, Dana; Fong, Yuman
Oncolytic viruses have made their mark on the cancer world as a potential therapeutic option, with the possible advantages of reduced side effects and strengthened treatment efficacy due to higher tumor selectivity. Results have been so promising, that oncolytic viral treatments have now been approved for clinical trials in several countries. However, clinical studies may benefit from the ability to noninvasively and serially identify sites of viral targeting via molecular imaging in order to provide safety, efficacy, and toxicity information. Furthermore, molecular imaging of oncolytic viral therapy may provide a more sensitive and specific diagnostic technique to detect tumor origin and, more importantly, presence of metastases. Several strategies have been investigated for molecular imaging of viral replication broadly categorized into optical and deep tissue imaging, utilizing several reporter genes encoding for fluorescence proteins, conditional enzymes, and membrane protein and transporters. Various imaging methods facilitate molecular imaging, including computer tomography, magnetic resonance imaging, positron emission tomography, single photon emission CT, gamma-scintigraphy, and photoacoustic imaging. In addition, several molecular probes are used for medical imaging, which act as targeting moieties or signaling agents. This review will explore the preclinical and clinical use of in vivo molecular imaging of replication-competent oncolytic viral therapy. PMID:27119098
Oncol. 2005 May 20;23(15):3605-13. 2. Nakamura H, Kasuya H, Mullen JT, et al. Regulation of Herpes simplex virus g134.5 expression and oncolysis of...diffuse liver metastases by Myb34.5. J Clin Invest 2002;109:871–82. 3. Kuruppu D, Tanabe KK. Viral oncolysis by herpes simplex virus and other viruses...emission tomography of herpes simplex virus 1 oncolysis. Cancer Research. 2007; 67(7): 3295.
Kohlhapp, Frederick J; Kaufman, Howard L
Oncolytic viruses are native or engineered viruses that preferentially replicate in and lyse cancer cells. Selective tumor cell replication is thought to depend on infection of neoplastic cells, which harbor low levels of protein kinase R (PKR) and dysfunctional type I IFN signaling elements. These changes allow more efficient viral replication, and with selected deletion of specific viral genes, replication in normal cells with activated PKR may not be possible. Direct tumor cell lysis, release of soluble tumor antigens, and danger-associated molecular factors are all thought to help prime and promote tumor-specific immunity. Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus, type I and is the first oncolytic virus to demonstrate a clinical benefit in patients with melanoma. T-VEC has also been evaluated for the treatment of head and neck cancer, pancreatic cancer, and likely other types of cancer will be targeted in the near future. T-VEC has been modified for improved safety, tumor-selective replication, and induction of host immunity by deletion of several viral genes and expression of human granulocyte-macrophage colony stimulating factor. Although the mechanism of action for T-VEC is incompletely understood, the safety profile of T-VEC and ability to promote immune responses suggest future combination studies with other immunotherapy approaches including checkpoint blockade through PD-1, PD-L1, and CTLA-4 to be a high priority for clinical development. Oncolytic viruses also represent unique regulatory and biosafety challenges but offer a potential new class of agents for the treatment of cancer.
Adusumilli, Prasad S.; Stiles, Brendon M.; Chan, Mei-Ki; Mullerad, Michael; Eisenberg, David P.; Ben-Porat, Leah; Huq, Rumana; Rusch, Valerie W.; Fong, Yuman
Background Malignant pleural mesothelioma (MPM) is an aggressive cancer that is refractory to current treatment modalities. Oncolytic herpes simplex viruses (HSV) used for gene therapy are genetically engineered, replication-competent viruses that selectively target tumor cells while sparing normal host tissue. The localized nature, the potential accessibility and the relative lack of distant metastasis, make MPM a particularly suitable disease for oncolytic viral therapy. Methods The infectivity, selective replication, vector spread and cytotoxic ability of three oncolytic HSV: G207, NV1020 and NV1066 were tested against eleven pathological types of MPM cell lines including those that are resistant to radiation therapy, gemcitabine or cisplatin. The therapeutic efficacy and the effect on survival of NV1066 were confirmed in a murine MPM model. Results All three oncolytic HSV were highly effective against all the MPM cell lines tested. Even at very low concentrations of MOI 0.01 (MOI: multiplicity of viral infection, ratio of viral particles per cancer cell), HSV were highly effective against MPM cells that are resistant to radiation, gemcitabine and cisplatin. NV1066, an oncolytic HSV that expresses green fluorescent protein (GFP) was able to delineate the extent of the disease in a murine model of MPM due to selective infection and expression of GFP in tumor cells. Furthermore, NV1066 was able to reduce the tumor burden and prolong survival even when treated at an advanced stage of the disease. Conclusion These findings support the continued investigation of oncolytic HSV as potential therapy for patients with therapy resistant malignant pleural mesothelioma. PMID:16475242
Beier, R; Hermiston, T; Mumberg, D
Newcastle disease virus (NDV) is an oncolytic paramyxovirus with a nonsegmented single-stranded RNA genome. In this report, a recombinant oncolytic NDV was passaged in human tumor xenografts and reisolated and characterized after two rounds of bioselection. Several isolates could be recovered that differed from the parental virus with respect to virus spread in tumor cells and the ability to form syncytia in human tumor cells. Three isolates were identified that demonstrated superior oncolytic potency compared with the parental virus as measured by increased oncolytic potency in confluent tumor cell monolayers, in tumor cell spheroids and in a mouse xenograft tumor model. The surface proteins F and HN were sequence analyzed and characterized for fusogenicity. The present study demonstrates that in vivo NDV bioselection can enable the isolation of novel, oncolytic NDV and thus represents a powerful methodology for the development of highly potent oncolytic viruses.
Yamaguchi, Teruhide; Uchida, Eriko
Oncolytic viruses, which include both naturally occurring wild-type viruses/attenuated viruses and genetically modified viruses, have recently been developed for use in innovative cancer therapies. Genetically modified oncolytic viruses possess the unique ability to replicate conditionally as a unique gene therapy product. Since oncolytic viruses exhibit prolonged persistence in patients, viral shedding and transmission to third parties should be major concerns for clinical trials, along with the clinical safety and efficacy. Accordingly, studies are now underway to establish the safety and efficacy of oncolytic viruses.
Pol, Jonathan; Buqué, Aitziber; Aranda, Fernando; Bloy, Norma; Cremer, Isabelle; Eggermont, Alexander; Erbs, Philippe; Fucikova, Jitka; Galon, Jérôme; Limacher, Jean-Marc; Preville, Xavier; Sautès-Fridman, Catherine; Spisek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo
Oncolytic virotherapy relies on the administration of non-pathogenic viral strains that selectively infect and kill malignant cells while favoring the elicitation of a therapeutically relevant tumor-targeting immune response. During the past few years, great efforts have been dedicated to the development of oncolytic viruses with improved specificity and potency. Such an intense wave of investigation has culminated this year in the regulatory approval by the US Food and Drug Administration (FDA) of a genetically engineered oncolytic viral strain for use in melanoma patients. Here, we summarize recent preclinical and clinical advances in oncolytic virotherapy.
Lopez, M. Verónica; Viale, Diego L.; Cafferata, Eduardo G. A.; Bravo, Alicia I.; Carbone, Cecilia; Gould, David; Chernajovsky, Yuti; Podhajcer, Osvaldo L.
The clinical efficacy of conditionally replicative oncolytic adenoviruses (CRAd) is still limited by the inefficient infection of the tumor mass. Since tumor growth is essentially the result of a continuous cross-talk between malignant and tumor-associated stromal cells, targeting both cell compartments may profoundly influence viral efficacy. Therefore, we developed SPARC promoter-based CRAds since the SPARC gene is expressed both in malignant cells and in tumor-associated stromal cells. These CRAds, expressing or not the Herpes Simplex thymidine kinase gene (Ad-F512 and Ad(I)-F512-TK, respectively) exerted a lytic effect on a panel of human melanoma cells expressing SPARC; but they were completely attenuated in normal cells of different origins, including fresh melanocytes, regardless of whether cells expressed or not SPARC. Interestingly, both CRAds displayed cytotoxic activity on SPARC positive-transformed human microendothelial HMEC-1 cells and WI-38 fetal fibroblasts. Both CRAds were therapeutically effective on SPARC positive-human melanoma tumors growing in nude mice but exhibited restricted efficacy in the presence of co-administered HMEC-1 or WI-38 cells. Conversely, co-administration of HMEC-1 cells enhanced the oncolytic efficacy of Ad(I)-F512-TK on SPARC-negative MIA PaCa-2 pancreatic cancer cells in vivo. Moreover, conditioned media produced by stromal cells pre-infected with the CRAds enhanced the in vitro viral oncolytic activity on pancreatic cancer cells, but not on melanoma cells. The whole data indicate that stromal cells might play an important role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses. PMID:19337591
vesicular stomatitis virus (VSV) can exert a dual antitumor effect by triggering direct tumor lysis and eliciting tumor specific immunity. VSV can also...tumors, and the levels of infiltrating leukocytes were similar across the VSV-treated tumors. Altogether the data indicate that VSV-based therapy is...effective against a cisplatin-resistant lung tumor model. 15. SUBJECT TERMS Drug resistance, oncolytic virotherapy, vesicular stomatitis virus, lung
Oncolytic virotherapy is a new strategy to reduce tumor burden through selective virus replication in rapidly proliferating cells. Oncolytic viruses are members of at least ten virus families, each with its advantages and disadvantages. Here, I briefly review the recent advances and key challenges, as exemplified by the best-studied platforms. Recent advances include preclinical proof of feasibility, clinical evidence of tolerability and effectiveness, and the development of new strategies to improve efficacy. These include engineered tumor selectivity and expression of antitumorigenic genes that could function independently of virus replication, identification of combinatorial therapies that accelerate intratumoral virus propagation, and modification of immune responses and vascular delivery for treatment of metastatic disease. Key challenges are to select "winners" from the distinct oncolytic platforms that can stimulate anti-cancer immunity without affecting virus replication and can lyse cancer stem cells, which are most likely responsible for tumor maintenance, aggressiveness, and recurrence. Preventing the emergence of resistant tumor cells during virotherapy through the activation of multiple death pathways, the development of a better understanding of the mechanisms of cancer stem-cell lysis, and the development of more meaningful preclinical animal models are additional challenges for the next-generation of engineered viruses.
Haseley, Amy; Alvarez-Breckenridge, Christopher; Chaudhury, Abhik Ray; Kaur, Balveen
The World Health Organization grossly classifies the various types of astrocytomas using a grade system with grade IV gliomas having the worst prognosis. Oncolytic virus therapy is a novel treatment option for GBM patients. Several patents describe various oncolytic viruses used in preclinical and clinical trials to evaluate safety and efficacy. These viruses are natural or genetically engineered from different viruses such as HSV-1, Adenovirus, Reovirus, and New Castle Disease Virus. While several anecdotal studies have indicated therapeutic advantage, recent clinical trials have revealed the safety of their usage, but demonstration of significant efficacy remains to be established. Oncolytic viruses are being redesigned with an interest in combating the tumor microenvironment in addition to defeating the cancerous cells. Several patents describe the inclusion of tumor microenvironment modulating genes within the viral backbone and in particular those which attack the tumor angiotome. The very innovative approaches being used to improve therapeutic efficacy include: design of viruses which can express cytokines to activate a systemic antitumor immune response, inclusion of angiostatic genes to combat tumor vasculature, and also enzymes capable of digesting tumor extra cellular matrix (ECM) to enhance viral spread through solid tumors. As increasingly more novel viruses are being tested and patented, the future battle against glioma looks promising. PMID:19149710
Herpes simplex virus g134.5 expression and oncolysis of diffuse liver metastases by Myb34.5. J Clin...Invest 2002;109:871–82. Kuruppu D, Tanabe KK. Viral oncolysis by herpes simplex virus and other viruses. Cancer Biology & Therapy. 2005; 4(5...524-31 Kuruppu D, Brownell A, Zhu A, Yu M, Wang X, Kulu Y, Fuchs B, Kawasaki H, Tanabe KK. Positron emission tomography of herpes simplex virus 1 oncolysis. Cancer Research. 2007; 67(7): 3295.
Woolery, William Alan
Varicella zoster virus (VZV) is the etiologic agent of varicella and herpes zoster (HZ) in humans. Herpes zoster is the result of reactivation of VZV within certain sensory ganglia. The burden of illness from HZ and post-herpetic neuralgia (PHN) is high. Herpes-zoster vaccine contains live attenuated varicella-zoster virus in an amount approximately 14 times greater than that found in the varicella virus vaccine. Herpes zoster vaccine is approved for the prevention of shingles in appropriate persons aged 60 and older. The vaccine is administered in a single subcutaneous dose. Reported side effects are mild and generally limited to localized injection site findings. Herpes-zoster vaccine reportedly decreases the occurrence of herpes zoster by approximately 50 percent and prevents the development of PHN by two thirds. The vaccine appears to be minimally effective in those individuals over the age of 80 and is not recommended in this age group.
Kelly, Kaitlyn J; Wong, Joyce; Fong, Yuman
Background Patients with hepatic malignancy have a dismal prognosis with standard therapies. NV1020 is an oncolytic herpes simplex virus that has potential to be a safe and effective therapeutic agent for this disease. Objective We set out to discuss the development of NV1020 as an oncolytic agent and explore the potential role of this particular virus in the setting of human hepatic cancer. Methods The scope of this review includes an overview of preclinical experience with NV1020, as well as an examination of current standard and developing therapies for liver cancer. The primary focus, however, is on the safety and potential clinical efficacy of NV1020 against hepatic malignancy. Results/conclusion We have found that NV1020 is a safe, novel therapeutic agent for treatment of refractory hepatic malignancy. PMID:18549346
Bloom, David C.; Feller, Joyce; McAnany, Peterjon; Vilaboa, Nuria
ABSTRACT We present the development and characterization of a replication-competent controlled herpes simplex virus 1 (HSV-1). Replication-essential ICP4 and ICP8 genes of HSV-1 wild-type strain 17syn+ were brought under the control of a dually responsive gene switch. The gene switch comprises (i) a transactivator that is activated by a narrow class of antiprogestins, including mifepristone and ulipristal, and whose expression is mediated by a promoter cassette that comprises an HSP70B promoter and a transactivator-responsive promoter and (ii) transactivator-responsive promoters that drive the ICP4 and ICP8 genes. Single-step growth experiments in different cell lines demonstrated that replication of the recombinant virus, HSV-GS3, is strictly dependent on an activating treatment consisting of administration of a supraphysiological heat dose in the presence of an antiprogestin. The replication-competent controlled virus replicates with an efficiency approaching that of the wild-type virus from which it was derived. Essentially no replication occurs in the absence of activating treatment or if HSV-GS3-infected cells are exposed only to heat or antiprogestin. These findings were corroborated by measurements of amounts of viral DNA and transcripts of the regulated ICP4 gene and the glycoprotein C (gC) late gene, which was not regulated. Similar findings were made in experiments with a mouse footpad infection model. IMPORTANCE The alphaherpesviruses have long been considered vectors for recombinant vaccines and oncolytic therapies. The traditional approach uses vector backbones containing attenuating mutations that restrict replication to ensure safety. The shortcoming of this approach is that the attenuating mutations tend to limit both the immune presentation and oncolytic properties of these vectors. HSV-GS3 represents a novel type of vector that, when activated, replicates with the efficiency of a nonattenuated virus and whose safety is derived from deliberate
Lee, Michael R; Ryman, William
A 56-year-old man developed reactivation of herpes zoster infection on his right forehead after treatment of several solar keratoses with cryosurgery. The rash was blistering and painful. Treatment with oral aciclovir was instituted and the lesions healed within 2 weeks. Known risk factors for reactivation include age and decreased immunity. Previous case reports have indicated trauma may be a risk factor in herpes zoster. We report a case of herpes zoster as a complication of cryosurgery.
... if a person has been infected with the herpes simplex virus (I or II). This test does not detect the virus itself. If antibodies to the virus are present, the person has been infected with herpes simplex at some point in his or her life. ...
Tummon, I. S.; Dudley, D. K.; Walters, J. H.
Genital herpes is a sexually transmitted disease caused by the herpes simplex virus. Following the initial infection the virus becomes latent in the sacral ganglia. Approximately 80% of patients are then subject to milder but unpredictable recurrences and may shed the virus even when they are asymptomatic. The disorder causes concern because genital herpes in the mother can result in rare but catastrophic neonatal infection and because of a possible association between genital herpes and cancer of the cervix. No effective treatment is as yet available. Weekly monitoring for virus by cervical culture from 32 weeks' gestation is recommended for women with a history of genital herpes and for those whose sexual partner has such a history. Images FIG. 1 FIG. 4 FIG. 5 PMID:7020907
Tayeb, Shay; Zakay-Rones, Zichria; Panet, Amos
Newcastle disease virus (NDV) features a natural preference for replication in many tumor cells compared with normal cells. The observed antitumor effect of NDV appears to be a result of both selective killing of tumor cells and induction of immune responses. Genetic manipulations to change viral tropism and arming the virus with genes encoding for cytokines improved the oncolytic capacity of NDV. Several intracellular proteins in tumor cells, including antiapoptotic proteins (Livin) and oncogenic proteins (H-Ras), are relevant for the oncolytic activity of NDV. Defects in the interferon system, found in some tumor cells, also contribute to the oncolytic selectivity of NDV. Notwithstanding, NDV displays effective oncolytic activity in many tumor types, despite having intact interferon signaling. Taken together, several cellular systems appear to dictate the selective oncolytic activity of NDV. Some barriers, such as neutralizing antibodies elicited during NDV treatment and the extracellular matrix in tumor tissue appear to interfere with spread of NDV and reduce oncolysis. To further understand the oncolytic activity of NDV, we compared two NDV strains, ie, an attenuated virus (NDV-HUJ) and a pathogenic virus (NDV-MTH-68/H). Significant differences in amino acid sequence were noted in several viral proteins, including the fusion precursor (F0) glycoprotein, an important determinant of replication and pathogenicity. However, no difference in the oncolytic activity of the two strains was noted using human tumor tissues maintained as organ cultures or in mouse tumor models. To optimize virotherapy in clinical trials, we describe here a unique organ culture methodology, using a biopsy taken from a patient’s tumor before treatment for ex vivo infection with NDV to determine the oncolytic potential on an individual basis. In conclusion, oncolytic NDV is an excellent candidate for cancer therapy, but more knowledge is needed to ensure success in clinical trials. PMID
Ady, Justin; Thayanithy, Venugopal; Mojica, Kelly; Wong, Phillip; Carson, Joshua; Rao, Prassanna; Fong, Yuman; Lou, Emil
Tunneling nanotubes (TNTs) are ultrafine, filamentous actin-based cytoplasmic extensions which form spontaneously to connect cells at short and long-range distances. We have previously described long-range intercellular communication via TNTs connecting mesothelioma cells in vitro and demonstrated TNTs in intact tumors from patients with mesothelioma. Here, we investigate the ability of TNTs to mediate a viral thymidine kinase based bystander effect after oncolytic viral infection and administration of the nucleoside analog ganciclovir. Using confocal microscopy we assessed the ability of TNTs to propagate enhanced green fluorescent protein (eGFP), which is encoded by the herpes simplex virus NV1066, from infected to uninfected recipient cells. Using time-lapse imaging, we observed eGFP expressed in infected cells being transferred via TNTs to noninfected cells; additionally, increasing fluorescent activity in recipient cells indicated cell-to-cell transmission of the eGFP-expressing NV1066 virus had also occurred. TNTs mediated cell death as a form of direct cell-to-cell transfer following viral thymidine kinase mediated activation of ganciclovir, inducing a unique long-range form of the bystander effect through transmission of activated ganciclovir to nonvirus-infected cells. Thus, we provide proof-of-principle demonstration of a previously unknown and alternative mechanism for inducing apoptosis in noninfected recipient cells. The conceptual advance of this work is that TNTs can be harnessed for delivery of oncolytic viruses and of viral thymidine kinase activated drugs to amplify the bystander effect between cancer cells over long distances in stroma-rich tumor microenvironments. PMID:27933314
Fatahzadeh, M; Schwartz, R A
Humans are the natural host for eight of more than 80 known herpes viruses. Infections with herpes simplex virus type 1 (HSV-1) are ubiquitous worldwide and highly transmissible. Herpes simplex labialis (HSL) is the best-recognized recrudescent infection of the lips and perioral tissues caused by HSV-1. Facial lesions of HSL may be unsightly, frequent outbreaks unpleasant, and the infection itself more severe locally and systemically in immunocompromised people. This article highlights the pathogenesis, clinical presentation, diagnostic features and management issues for HSL.
Johnson, Julie L; Amzat, Rianot; Martin, Nicolle
Herpes zoster is a commonly encountered disorder. It is estimated that there are approximately 1 million new cases of herpes zoster in the United States annually, with an incidence of 3.2 per 1000 person-years. Patients with HIV have the greatest risk of developing herpes zoster ophthalmicus compared with the general population. Other risk factors include advancing age, use of immunosuppressive medications, and primary infection in infancy or in utero. Vaccination against the virus is a primary prevention modality. Primary treatments include antivirals, analgesics, and anticonvulsants. Management may require surgical intervention and comanagement with pain specialists, psychiatrists, and infectious disease specialists.
Ebrahimi, Safieh; Ghorbani, Elnaz; Khazaei, Majid; Avan, Amir; Ryzhikov, Mikhail; Azadmanesh, Keyhan; Hassanian, Seyed Mahdi
Interferons (INFs) elicit antiviral responses in tumor cells upon binding to cell surface receptors. Oncolytic virotherapy (OV) is an effective antitumor therapeutic approach which in combination with standard radiotherapy or chemotherapy regimens potentiates treatment responses in cancer patients. However, oncolytic viruses are susceptible to the IFN-induced antiviral state in the tumor microenvironment. A number of studies have therefore investigated the effects of combined therapy of IFN signaling pharmacological inhibitors with oncolytic viruses, which result in improved virus replication and oncolysis. This review summarizes the current knowledge of the mechanisms of interferon-mediated tumor resistance to oncolytic virotherapy and provides new insights regarding the effectiveness of combinatorial treatment strategies to attenuate INF-induced OV resistance for greater clinical significance in the treatment of cancer patients. This article is protected by copyright. All rights reserved.
Boisgerault, Nicolas; Achard, Carole; Delaunay, Tiphaine; Cellerin, Laurent; Tangy, Frédéric; Grégoire, Marc; Fonteneau, Jean-François
Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM.
Boisgerault, Nicolas; Achard, Carole; Delaunay, Tiphaine; Cellerin, Laurent; Tangy, Frédéric; Grégoire, Marc; Fonteneau, Jean-François
Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM. PMID:27512676
Msaouel, P.; Iankov, I.D.; Dispenzieri, A.; Galanis, E.
Attenuated measles virus vaccine strains have emerged as a promising oncolytic vector platform, having shown significant anti-tumor activity against a broad range of malignant neoplasms. Measles virus strains derived from the attenuated Edmonston-B (MV-Edm) vaccine lineage have been shown to selectively infect, replicate in and lyse cancer cells while causing minimal cytopathic effect on normal tissues. This review summarizes the preclinical data that led to the rapid clinical translation of oncolytic measles vaccine strains and provides an overview of early clinical data using this oncolytic platform. Furthermore, novel approaches currently under development to further enhance the oncolytic efficacy of MV-Edm strains, including strategies to circumvent immunity or modulate immune system responses, combinatorial approaches with standard treatment modalities, virus retargeting as well as strategies for in vivo monitoring of viral replication are discussed. PMID:21740361
Covington, Matthew F; Curiel, Clara N; Lattimore, Lois; Avery, Ryan J; Kuo, Phillip H
61-year-old woman with stage IIIa (T3a N1a M0) left lower leg melanoma with lesions suggestive of in-transit metastases 8 months following wide local excision and femoral nodal dissection. FDG-PET/CT demonstrated 5 FDG-avid in-transit nodal metastases in the distal left leg, confirmed on biopsy. Talimogene laherparepvec (T-VEC) oncolytic immunotherapy consisting of intralesional injections of modified herpes simplex virus-expressing granulocyte-macrophage colony-stimulating factor was completed over 6 months. Subsequent FDG-PET/CT demonstrated reduced or resolved FDG activity in the treated in-transit metastases and a new FDG-avid left thigh in-transit metastasis. FDG-PET/CT can monitor response to T-VEC and potentially other novel viral immunotherapies.
SUPPLEMENTARY NOTES 14. ABSTRACT Abstract follows. 15. SUBJECT TERMS Oncolytic HSV, angiogenesis, MPNST , mouse model 16. SECURITY CLASSIFICATION OF: 17...reliable tumor models for malignant peripheral nerve sheath tumors ( MPNST ). Several existing and novel oncolytic HSV vectors will then be tested on these...from G47A increases cytotoxicity in vitro to human endothelial cells and murine Nfl" MPNST cell lines. Inhibition of MPNST M2 tumor growth in vivo was
Bitzer, M; Lauer, U M
Gastroenterological oncology requires new strategies with new mechanisms of action and without cross-resistance to currently available treatment regimes. Virotherapy which is based on the employment of replication-competent viral vectors exhibiting strong oncolytic properties is such an approach currently under preclinical/clinical investigation. Techniques of molecular virology are required for further improvement of current vectors, particularly with respect to oncolytic activity, tumour selectivity, tumour spread capacity, and safety.
Uusi-Kerttula, Hanni; Hulin-Curtis, Sarah; Davies, James; Parker, Alan L.
Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies. PMID:26610547
Zhang, L; Hedjran, F; Larson, C; Perez, G L; Reid, T
Oncolytic adenoviruses are under investigation as a promising novel strategy for cancer immunotherapeutics. Unfortunately, there is no immunocompetent mouse cancer model to test oncolytic adenovirus because murine cancer cells are generally unable to produce infectious viral progeny from human adenoviruses. We find that the murine K-ras-induced lung adenocarcinoma cell line ADS-12 supports adenoviral infection and generates infectious viral progeny. ADS-12 cells express the coxsackie and adenovirus receptor and infected ADS-12 cells express the viral protein E1A. We find that our previously described oncolytic virus, adenovirus TAV-255 (AdTAV-255), kills ADS-12 cells in a dose- and time-dependent manner. We investigated ADS-12 cells as an in-vivo model system for replicating oncolytic adenoviruses. Subcutaneous injection of ADS-12 cells into immunocompetent 129 mice led to tumor formation in all injected mice. Intratumoral injection of AdTAV-255 in established tumors causes a significant reduction in tumor growth. This model system represents the first fully immunocompetent mouse model for cancer treatment with replicating oncolytic adenoviruses, and therefore will be useful to study the therapeutic effect of oncolytic adenoviruses in general and particularly immunostimulatory viruses designed to evoke an antitumor immune response. PMID:25525035
Dayan, A. D.; Ogul, E.; Graveson, G. S.
Widespread neurological disorders following herpes zoster are exceptional. They include encephalitis and myelitis, and a type of polyneuropathy. The latter is particularly rare as only 16 cases have been described since the first account by Wohlwill in 1924. We present two clinical cases of polyneuropathy following herpes zoster with neuropathological studies on one of them, and discuss its possible aetiology and pathogenesis in the light of previous reports and recent experimental studies. Images PMID:5037030
Herpes zoster (shingles) normally occurs in a limited area that follows a dermatome (see the "dermatome" picture). In individuals with damaged immune systems, herpes zoster may be widespread (disseminated), causing serious illness. ...
Patil, Sandeep S; Gentschev, Ivaylo; Nolte, Ingo; Ogilvie, Gregory; Szalay, Aladar A
Oncolytic viruses refer to those that are able to eliminate malignancies by direct targeting and lysis of cancer cells, leaving non-cancerous tissues unharmed. Several oncolytic viruses including adenovirus strains, canine distemper virus and vaccinia virus strains have been used for canine cancer therapy in preclinical studies. However, in contrast to human studies, clinical trials with oncolytic viruses for canine cancer patients have not been reported. An 'ideal' virus has yet to be identified. This review is focused on the prospective use of oncolytic viruses in the treatment of canine tumors - a knowledge that will undoubtedly contribute to the development of oncolytic viral agents for canine cancer therapy in the future.
Foreman, Paul M; Friedman, Gregory K; Cassady, Kevin A; Markert, James M
Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of just over 14 months. Given the poor outcomes with standard-of-care treatments, novel treatment strategies are needed. The concept of virotherapy for the treatment of malignant tumors dates back more than a century and can be divided into replication-competent oncolytic viruses and replication-deficient viral vectors. Oncolytic viruses are designed to selectively target, infect, and replicate in tumor cells, while sparing surrounding normal brain. A host of oncolytic viruses has been evaluated in early phase human trials with promising safety results, but none has progressed to phase III trials. Despite the 25 years that has passed since the initial publication of genetically engineered oncolytic viruses for the treatment of glioma, much remains to be learned about the use of this therapy, including its mechanism of action, optimal treatment paradigm, appropriate targets, and integration with adjuvant agents. Oncolytic viral therapy for glioma remains promising and will undoubtedly impact the future of patient care.
Wang, P-Y; Currier, M A; Hansford, L; Kaplan, D; Chiocca, E A; Uchida, H; Goins, W F; Cohen, J B; Glorioso, J C; van Kuppevelt, T H; Mo, X; Cripe, T P
Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. As PKR is a major cellular defense against Herpes simplex virus (HSV), and oncolytic HSV-1 (oHSV) mutants have shown promising antitumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was the most susceptible, NB122R was intermediate and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas downregulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a NB cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases, due to low virus receptor expression but also due to intact antiviral PKR signaling.
Wang, Pin-Yi; Currier, Mark A; Hansford, Loen; Kaplan, David; Chiocca, E. Antonio; Uchida, Hiroaki; Goins, William F.; Cohen, Justus B.; Glorioso, Joseph C.; van Kuppevelt, Toin H.; Mo, Xiaokui; Cripe, Timothy P
Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. Because PKR is a major cellular defense against Herpes simplex virus, and oncolytic HSV-1 (oHSV) mutants have shown promising anti-tumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was most susceptible, NB122R was intermediate, and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas down-regulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a neuroblastoma cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases due to low virus receptor expression but also due to intact anti-viral PKR signaling. PMID:23254370
Koks, Carolien A E; De Vleeschouwer, Steven; Graf, Norbert; Van Gool, Stefaan W
Oncolytic viruses have been seriously considered for glioma therapy over the last 20 years. The oncolytic activity of several oncolytic strains has been demonstrated against human glioma cell lines and in in vivo xenotransplant models. So far, four of these stains have additionally completed the first phase I/II trials in relapsed glioma patients. Though safety and feasibility have been demonstrated, therapeutic efficacy in these initial trials, when described, was only minor. The role of the immune system in oncolytic virotherapy for glioma remained much less studied until recent years. When investigated, the immune system, adept at controlling viral infections, is often hypothesized to be a strong hurdle to successful oncolytic virotherapy. Several preclinical studies have therefore aimed to improve oncolytic virotherapy efficacy by combining it with immune suppression or evasion strategies. More recently however, a new paradigm has developed in the oncolytic virotherapy field stating that oncolytic virus-mediated tumor cell death can be accompanied by elicitation of potent activation of innate and adaptive anti-tumor immunity that greatly improves the efficacy of certain oncolytic strains. Therefore, it seems the three-way interaction between oncolytic virus, tumor and immune system is critical to the outcome of antitumor therapy. In this review we discuss the studies which have investigated how the immune system and oncolytic viruses interact in models of glioma. The novel insights generated here hold important implications for future research and should be incorporated into the design of novel clinical trials.
Nakashima, Hiroshi; Nguyen, Tran; Chiocca, Ennio Antonio
Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi.
A live attenuated varicella-zoster vaccine (Zostavax--Merck) has been approved by the FDA for prevention of herpes zoster (HZ; zoster; shingles) in persons > or = 60 years old. Each dose of Zostavax contains about 14 times as much varicella-zoster virus (VZV) as Varivax, which has been used in the US since 1995 to vaccinate against varicella (chicken pox).
The herpes zoster vaccine is made using high doses of live attenuated varicella/zoster virus. The vaccine is well tolerated and has few adverse effects: the most common one is pain at the injection site. Complications can occur mainly in persons who had prior zoster keratitis or uveitis. The vaccine can prevent this disease with low mortality but high morbidity.
Science Activities, 1987
Presents a hands-on activity to help primary, intermediate, and advanced students learn about and compare the general characteristics of reptiles and amphibians. Suggests "herp stations" to provide experiences. Details materials, background and procedures necessary for using this activity. (CW)
Groves, Mary Jo
Genital herpes is a common sexually transmitted disease, affecting more than 400 million persons worldwide. It is caused by herpes simplex virus (HSV) and characterized by lifelong infection and periodic reactivation. A visible outbreak consists of single or clustered vesicles on the genitalia, perineum, buttocks, upper thighs, or perianal areas that ulcerate before resolving. Symptoms of primary infection may include malaise, fever, or localized adenopathy. Subsequent outbreaks, caused by reactivation of latent virus, are usually milder. Asymptomatic shedding of transmissible virus is common. Although HSV-1 and HSV-2 are indistinguishable visually, they exhibit differences in behavior that may affect management. Patients with HSV-2 have a higher risk of acquiring human immunodeficiency virus (HIV) infection. Polymerase chain reaction assay is the preferred method of confirming HSV infection in patients with active lesions. Treatment of primary and subsequent outbreaks with nucleoside analogues is well tolerated and reduces duration, severity, and frequency of recurrences. In patients with HSV who are HIV-negative, treatment reduces transmission of HSV to uninfected partners. During pregnancy, antiviral prophylaxis with acyclovir is recommended from 36 weeks of gestation until delivery in women with a history of genital herpes. Elective cesarean delivery should be performed in laboring patients with active lesions to reduce the risk of neonatal herpes.
Binz, Eike; Lauer, Ulrich M
Oncolytic virotherapy has made significant progress in recent years, however, widespread approval of virotherapeutics is still limited. Primarily, this is due to the fact that currently available virotherapeutics are mostly tested in monotherapeutic clinical trials exclusively (ie, not in combination with other therapies) and so far have achieved only small and often clinically insignificant responses. Given that the predominantly immunotherapeutic mechanism of virotherapeutics is somewhat time-dependent and rapidly growing tumors therefore exhibit only minor chances of being captured in time, scenarios with combination partners are postulated to be more effective. Combinatory settings would help to achieve a rapid stabilization or even reduction of onset tumor masses while providing enough time (numerous months) for achieving immuno(viro)therapeutic success. For this reason, combination strategies of virotherapy with highly genotoxic regimens, such as chemotherapy, are of major interest. A number of clinical trials bringing the concepts of chemotherapy and virotherapy together have previously been undertaken, but optimal scheduling of chemovirotherapy (maximizing the anti-tumor effect while minimizing the risk of overlapping toxicity) still constitutes a major challenge. Therefore, an overview of published as well as ongoing Phase I-III trials should improve our understanding of current challenges and future developments in this field.
Mahoney, D J; Stojdl, D F
Functional genomic screening has emerged as a powerful approach for understanding complex biological phenomena. Of the available tools, genome-wide RNA interference (RNAi) technology is unquestionably the most incisive, as it directly probes gene function. Recent applications of RNAi screening have been impressive. Notable amongst these are its use in elucidated mechanism(s) for signal transduction, various aspects of cell biology, tumourigenesis and metastasis, resistance to cancer therapeutics, and the host's response to a pathogen. Herein we discuss how recent RNAi screening efforts have helped turn our attention to the targetability of non-oncogene support pathways for cancer treatment, with a particular focus on a recent study that identified a non-oncogene addiction to the ER stress response as a synergist target for oncolytic virus therapy (OVT). Moreover, we give our thoughts on the future of RNAi screening as a tool to enhance OVT and describe recent technical improvements that are poised to make genome-scale RNAi experiments more sensitive, less noisy, more applicable in vivo, and more easily validated in clinically relevant animal models.
Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity correlates closely with human telomerase reverse transcriptase(hTERT)expression. We constructed an attenuated adenovirus 5 vector(Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. We further modified the E3 region of OBP-301 to contain green fluorescent protein(GFP)gene for monitoring viral replication(TelomeScan, OBP-401). When TelomeScan was intratumorally injected into human tumors orthotopically implanted into the rectum in mice, para-aortic lymph node metastasis could be visualized at laparotomy with a three-chip color cooled charged-coupled device camera. This article reviews recent highlights in this rapidly evolving field of cancer therapeutic and diagnostic approaches using telomerase-specific oncolytic adenoviruses.
... Lucy* Yes — it is possible to get genital herpes from oral sex. Genital herpes is caused by the herpes ... Genital herpes is usually caused by HSV-2; oral herpes (cold sores) is usually caused by HSV-1. ...
Lambright, E S; Kang, E H; Force, S; Lanuti, M; Caparrelli, D; Kaiser, L R; Albelda, S M; Molnar-Kimber, K L
HSV-1716, a replicating nonneurovirulent herpes simplex virus type 1, has shown efficacy in treating multiple types of human tumors in immunodeficient mice. Since the majority of the human population has been previously exposed to herpes simplex virus, the efficacy of HSV-based oncolytic therapy was investigated in an immunocompetent animal tumor model. EJ-6-2-Bam-6a, a tumor cell line derived from h-ras-transformed murine fibroblast, exhibit a diffuse growth pattern in the peritoneal cavity of BALB/c mice and replicate HSV-1716 to titers observed in human tumors. An established intraperitoneal (ip) tumor model of EJ-6-2-Bam-6a in naive and HSV-immunized mice was used to evaluate the efficacy of single or multiple ip administrations of HSV-1716 (4 x 10(6) pfu/treatment) or of carrier cells, which are irradiated, ex vivo virally infected EJ-6-2-Bam-6a cells that can amplify the viral load in situ. All treated groups significantly prolonged survival versus media control with an approximately 40% long-term survival rate (cure) in the multiply treated, HSV-naive animals. Prior immunization of the mice with HSV did not significantly decrease the median survival of the single or multiply treated HSV-1716 or the carrier cell-treated groups. These studies support the development of replication-selective herpes virus mutants for use in localized intraperitoneal malignancies.
strategies are urgently needed. We proposed to develop a novel virotherapy for prostate cancer during the funding period. Our working hypothesis was...animals. The extension of this studies demonstrates that co-administration of fusogenic virotherapy with cyclophosphamide, an approved anticancer...chemotherapy drug that also has immunosuppressive activities, can significantly increase the therapeutic effect of virotherapy , possibly by inhibiting the
Guse, K; Dias, J D; Bauerschmitz, G J; Hakkarainen, T; Aavik, E; Ranki, T; Pisto, T; Särkioja, M; Desmond, R A; Kanerva, A; Hemminki, A
Oncolytic viruses kill cancer cells by tumor-selective replication. Clinical data have established the safety of the approach but also the need of improvements in potency. Efficacy of oncolysis is linked to effective infection of target cells and subsequent productive replication. Other variables include intratumoral barriers, access to target cells, uptake by non-target organs and immune response. Each of these aspects relates to the location and degree of virus replication. Unfortunately, detection of in vivo replication has been difficult, labor intensive and costly and therefore not much studied. We hypothesized that by coinfection of a luciferase expressing E1-deleted virus with an oncolytic virus, both viruses would replicate when present in the same cell. Photon emission due to conversion of D-Luciferin is sensitive and penetrates tissues well. Importantly, killing of animals is not required and each animal can be imaged repeatedly. Two different murine xenograft models were used and intratumoral coinjections of luciferase encoding virus were performed with eight different oncolytic adenoviruses. In both models, we found significant correlation between photon emission and infectious virus production. This suggests that the system can be used for non-invasive quantitation of the amplitude, persistence and dynamics of oncolytic virus replication in vivo, which could be helpful for the development of more effective and safe agents.
Simpson, Guy R; Relph, Kate; Harrington, Kevin; Melcher, Alan; Pandha, Hardev
Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.
Zainutdinov, Sergei S.; Tikunov, Artem Y.; Matveeva, Olga V.
We report here the complete genome sequence of Sendai virus Moscow strain. Anecdotal evidence for the efficacy of oncolytic virotherapy exists for this strain. The RNA genome of the Moscow strain is 15,384 nucleotides in length and differs from the nearest strain, BB1, by 18 nucleotides and 11 amino acids. PMID:27516510
Burke, Michael J
Seneca Valley Virus isolate 001 (SVV-001) is an oncolytic RNA virus of the Picornaviridae family. It is also the first picornavirus discovered of the novel genus Senecavirus. SVV-001 replicates through an RNA intermediate, bypassing a DNA phase, and is unable to integrate into the host genome. SVV-001 was originally discovered as a contaminant in the cell culture of fetal retinoblasts and has since been identified as a potent oncolytic virus against tumors of neuroendocrine origin. SVV-001 has a number of features that make it an attractive oncolytic virus, namely, its ability to target and penetrate solid tumors via intravenous administration, inability for insertional mutagenesis, and being a self-replicating RNA virus with selective tropism for cancer cells. SVV-001 has been studied in both pediatric and adult early phase studies reporting safety and some clinical efficacy, albeit primarily in adult tumors. This review summarizes the current knowledge of SVV-001 and what its future as an oncolytic virus may hold. PMID:27660749
Burke, Michael J
Seneca Valley Virus isolate 001 (SVV-001) is an oncolytic RNA virus of the Picornaviridae family. It is also the first picornavirus discovered of the novel genus Senecavirus. SVV-001 replicates through an RNA intermediate, bypassing a DNA phase, and is unable to integrate into the host genome. SVV-001 was originally discovered as a contaminant in the cell culture of fetal retinoblasts and has since been identified as a potent oncolytic virus against tumors of neuroendocrine origin. SVV-001 has a number of features that make it an attractive oncolytic virus, namely, its ability to target and penetrate solid tumors via intravenous administration, inability for insertional mutagenesis, and being a self-replicating RNA virus with selective tropism for cancer cells. SVV-001 has been studied in both pediatric and adult early phase studies reporting safety and some clinical efficacy, albeit primarily in adult tumors. This review summarizes the current knowledge of SVV-001 and what its future as an oncolytic virus may hold.
Msaouel, Pavlos; Opyrchal, Mateusz; Domingo Musibay, Evidio; Galanis, Evanthia
Introduction Replication-competent oncolytic measles virus (MV) strains preferentially infect and destroy a wide variety of cancer tissues. Clinical translation of engineered attenuated MV vaccine derivatives is demonstrating the therapeutic potential and negligible pathogenicity of these strains in humans. Areas covered The present review summarizes the mechanisms of MV tumor selectivity and cytopathic activity as well as the current data on the oncolytic efficacy and preclinical testing of MV strains. Investigational strategies to reprogram MV selectivity, escape antiviral immunity and modulate the immune system to enhance viral delivery and tumor oncolysis are also discussed. Expert Opinion Clinical viral kinetic data derived from non-invasive monitoring of reporter transgene expression will guide future protocols to enhance oncolytic MV efficacy. Anti-measles immunity is a major challenge of measles-based therapeutics and various strategies are being investigated to modulate immunity. These include the combination of MV therapy with immunosuppressive drugs such as cyclophosphamide, the use of cell carriers and the introduction of immunomodulatory transgenes and wild-type virulence genes. Available MV retargeting technologies can address safety considerations that may arise as more potent oncolytic MV vectors are being developed. PMID:23289598
Ahmad, Zeeshan; Kratzke, Robert A
Oncolytic virotherapy is the use of replication-competent viruses to treat malignancies. The potential of oncolytic virotherapy as an approach to cancer therapy is based on historical evidence that certain viral infections can cause spontaneous remission of both hematologic and solid tumor malignancies. Oncolytic virotherapy may eliminate cancer cells through either direct oncolysis of infected tumor cells or indirect immune-mediated oncolysis of uninfected tumor cells. Recent advances in oncolytic virotherapy include the development of a wide variety of genetically attenuated RNA viruses with precise cellular tropism and the identification of cell-surface receptors that facilitate viral transfer to the tissue of interest. Current research is also focused on targeting metastatic disease by sustaining the release of progeny viruses from infected tumor cells and understanding indirect tumor cell killing through immune-mediated mechanisms of virotherapy. The purpose of this review is to critically evaluate recent evidence on the clinical development of tissue-specific viruses capable of targeting tumor cells and eliciting secondary immune responses in lung cancers and mesothelioma. PMID:28053943
Swift, Stephanie L.; Stojdl, David F.
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
Tresilwised, Nittaya; Pithayanukul, Pimolpan; Mykhaylyk, Olga; Holm, Per Sonne; Holzmüller, Regina; Anton, Martina; Thalhammer, Stefan; Adigüzel, Denis; Döblinger, Markus; Plank, Christian
Oncolytic adenoviruses rank among the most promising innovative agents in cancer therapy. We examined the potential of boosting the efficacy of the oncolytic adenovirus dl520 by associating it with magnetic nanoparticles and magnetic-field-guided infection in multidrug-resistant (MDR) cancer cells in vitro and upon intratumoral injection in vivo. The virus was complexed by self-assembly with core-shell nanoparticles having a magnetite core of about 10 nm and stabilized by a shell containing 68 mass % lithium 3-[2-(perfluoroalkyl)ethylthio]propionate) and 32 mass % 25 kDa branched polyethylenimine. Optimized virus binding, sufficiently stable in 50% fetal calf serum, was found at nanoparticle-to-virus ratios of 5 fg of Fe per physical virus particle (VP) and above. As estimated from magnetophoretic mobility measurements, 3,600 to 4,500 magnetite nanocrystallites were associated per virus particle. Ultrastructural analysis by electron and atomic force microscopy showed structurally intact viruses surrounded by magnetic particles that occasionally bridged several virus particles. Viral uptake into cells at a given virus dose was enhanced 10-fold compared to nonmagnetic virus when infections were carried out under the influence of a magnetic field. Increased virus internalization resulted in a 10-fold enhancement of the oncolytic potency in terms of the dose required for killing 50% of the target cells (IC(50) value) and an enhancement of 4 orders of magnitude in virus progeny formation at equal input virus doses compared to nonmagnetic viruses. Furthermore, the full oncolytic effect developed within two days postinfection compared with six days in a nonmagnetic virus as a reference. Plotting target cell viability versus internalized virus particles for magnetic and nonmagnetic virus showed that the inherent oncolytic productivity of the virus remained unchanged upon association with magnetic nanoparticles. Hence, we conclude that the mechanism of boosting the
Rojas, Juan J; Sampath, Padma; Hou, Weizhou; Thorne, Steve H
Purpose Recent data from randomized clinical trials with oncolytic viral therapies and with cancer immunotherapies have finally recapitulated the promise these platforms demonstrated in pre-clinical models. Perhaps the greatest advance with oncolytic virotherapy has been the appreciation of the importance of activation of the immune response in therapeutic activity. Meanwhile, the understanding that blockade of immune checkpoints (with antibodies that block the binding of PD1 to PDL1 or CTLA4 to B7-2) is critical for an effective anti-tumor immune response has revitalized the field of immunotherapy. The combination of immune activation using an oncolytic virus and blockade of immune checkpoints is therefore a logical next step. Experimental Design Here we explore such combinations and demonstrate their potential to produce enhanced responses in mouse tumor models. Different combinations and regimens were explored in immunocompetent mouse models of renal and colorectal cancer. Bioluminescence imaging and immune assays were used to determine the mechanisms mediating synergistic or antagonistic combinations. Results Interaction between immune checkpoint inhibitors and oncolytic virotherapy was found to be complex, with correct selection of viral strain, antibody and timing of the combination being critical for synergistic effects. Indeed, some combinations produced antagonistic effects and loss of therapeutic activity. A period of oncolytic viral replication and directed targeting of the immune response against the tumor were required for the most beneficial effects, with CD8+ and NK, but not CD4+ cells mediating the effects. Conclusions These considerations will be critical in the design of the inevitable clinical translation of these combination approaches. PMID:26187615
Saito, Kengo; Shirasawa, Hiroshi; Isegawa, Naohisa; Shiiba, Masashi; Uzawa, Katsuhiro; Tanzawa, Hideki
Oncolytic virotherapy utilizes viruses that can selectively destroy cancer cells without harming normal tissues. Clinical trials of oncolytic viruses show that most oncolytic agents are well tolerated and safe. The virotherapeutic agents currently in use have limited potency when administered alone; however, combination therapy using virotherapeutic agents and conventional anticancer agents, such as chemotherapeutics, radiation, and gene therapy, exhibits encouraging levels of efficacy. Advances in recombinant DNA technology have allowed the development of viruses that are tumor-selective and armed with transgenes, increasing the application potential and efficacy of this novel anticancer therapy. Here, we review the development of oncolytic viruses and the clinical trials of oncolytic virotherapy for oral cancers. We discuss current issues and perspectives of this evolving anticancer therapy, highlighting the potential applications of a unique, naturally occurring oncolytic virus, Sindbis virus.
Choi, Won Suk
Herpes zoster and post-herpetic neuralgia deteriorate the quality of life because of severe pain and complications, and cause considerable social and economic burden of disease. In 2012, herpes zoster vaccine was released in Korea. The efficacy of herpes zoster vaccine is known to be 51.3-66.5% among the aged over 60 and 69.8-72.4% among adults between 50 and 59. It is also known that preventive efficacy is maintained for at least 5 years. Although there can be local reactions such as redness, pain and swelling at the site of injection and systemic reaction such as headache and eruption after herpes zoster vaccination, most of the adverse reactions are minor and disappear within days by themselves. As it is a live vaccine, persons with severe immune-suppression and pregnant women should not be vaccinated with the vaccine. Currently, Korean Society of Infectious Diseases recommended for the aged over 60 to be vaccinated with herpes zoster vaccine by subcutaneous route. In this article, clinical aspects and burden of disease of herpes zoster, efficacy and effects of herpes zoster vaccine, and herpes zoster vaccine recommendation by Korean Society of Infectious Diseases are discussed.
Herpes - genital - self-care; Herpes simplex - genital - self-care; Herpesvirus 2 - self-care; HSV-2 - self-care ... Call your health care provider if you have any of the following: Symptoms of an outbreak that worsen despite medicine and self-care ...
Bolyard, Chelsea; Meisen, W Hans; Banasavadi-Siddegowda, Yeshavanth; Hardcastle, Jayson; Yoo, Ji Young; Wohleb, Eric S; Wojton, Jeffrey; Yu, Jun-Ge; Dubin, Samuel; Khosla, Maninder; Xu, Bo; Smith, Jonathan; Alvarez-Breckenridge, Christopher; Pow-Anpongkul, Pete; Pichiorri, Flavia; Zhang, Jianying; Old, Matthew; Zhu, Dan; Van Meir, Erwin G; Godbout, Jonathan P; Caligiuri, Michael A; Yu, Jianhua; Kaur, Balveen
Purpose: Brain angiogenesis inhibitor (BAI1) facilitates phagocytosis and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here, we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV).Experimental Design: Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and Ingenuity Pathway Analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα-blocking antibodies and macrophages derived from Bai1(-/-) mice were used.Results: RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared with rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Furthermore, we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild-type/RAMBO virus in Bai1(-/-) or wild-type non-tumor-bearing mice revealed the safety of this approach.Conclusions: We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety. Clin Cancer Res; 23(7); 1809-19. ©2016 AACR.
Fillat, Cristina; Maliandi, Maria Victoria; Mato-Berciano, Ana; Alemany, Ramon
Oncolytic viruses (OV) are promising anti-cancer agents, capable of selectively replicating in tumour cells and killing them. Chemotherapy, on the other hand, remains the backbone of current cancer treatment, although it is limited by a narrow therapeutic index, significant toxicity, and frequent acquired resistance. There is an increasing body of evidence on a variety of chemotherapeutic agents that have been shown to be synergic with OV and result in increased response rates in preclinical studies. Several possible mechanisms have been proposed to mediate the enhanced anti-tumour activity of such combination treatment. Moreover, it has been shown how prodrug- activating enzymes armed oncolytic viruses promote synergy with prodrugs. In the present review we summarise the current knowledge concerning the benefits of the combination of OV and cytotoxic drug treatment and discuss the translational opportunities such therapeutic synergies have in the fight against cancer.
Ruiz, Autumn J.; Hadac, Elizabeth M.; Nace, Rebecca A.
ABSTRACT Mengovirus, a member of the Picornaviridae family, has a broad cell tropism and can cause encephalitis and myocarditis in multiple mammalian species. Attenuation has been achieved by shortening the polycytidine tract in the 5′ noncoding region (NCR). A poly(C)-truncated strain of mengovirus, vMC24, resulted in significant tumor regression in immunocompetent BALB/c mice bearing syngeneic MPC-11 plasmacytomas, but the associated toxicities were unacceptable. To enhance its safety profile, microRNA target sequences complementary to miR-124 or miR-125 (enriched in nervous tissue), miR-133 and miR-208 (enriched in cardiac tissue), or miR-142 (control; enriched in hematopoietic tissues) were inserted into the vMC24 NCRs. The microRNA-detargeted viruses showed reduced replication and cell killing specifically in cells expressing the cognate microRNAs, but certain insertions additionally were associated with nonspecific suppression of viral fitness in vivo. In vivo toxicity testing confirmed that miR-124 targets within the 5′ NCR suppressed virus replication in the central nervous system while miR-133 and miR-208 targets in the 3′ NCR suppressed viral replication in cardiac tissue. A dual-detargeted virus named vMC24-NC, with miR-124 targets in the 5′ NCR and miR-133 plus miR-208 targets in the 3′ NCR, showed the suppression of replication in both nervous and cardiac tissues but retained full oncolytic potency when administered by intratumoral (106 50% tissue culture infectious doses [TCID50]) or intravenous (107 to 108 TCID50) injection into BALB/c mice bearing MPC-11 plasmacytomas. Overall survival of vMC24-NC-treated tumor-bearing mice was significantly improved compared to that of nontreated mice. MicroRNA-detargeted mengoviruses offer a promising oncolytic virotherapy platform that merits further development for clinical translation. IMPORTANCE The clinical potential of oncolytic virotherapy for cancer treatment has been well demonstrated
Larson, Christopher; Oronsky, Bryan; Scicinski, Jan; Fanger, Gary R.; Stirn, Meaghan; Oronsky, Arnold; Reid, Tony R.
Oncolytic viruses have had a tumultuous course, from the initial anecdotal reports of patients having antineoplastic effects after natural viral infections a century ago to the development of current cutting-edge therapies in clinical trials. Adenoviruses have long been the workhorse of virotherapy, and we review both the scientific and the not-so-scientific forces that have shaped the development of these therapeutics from wild-type viral pathogens, turning an old foe into a new friend. After a brief review of the mechanics of viral replication and how it has been modified to engineer tumor selectivity, we give particular attention to ONYX-015, the forerunner of virotherapy with extensive clinical testing that pioneered the field. The findings from those as well as other oncolytic trials have shaped how we now view these viruses, which our immune system has evolved to vigorously attack, as promising immunotherapy agents. PMID:26280277
Ulasov, I.V.; Borovjagin, A.V.; Schroeder, B.A.; Baryshnikov, A.Y.
Glioblastoma Multiforme (GBM) is a rapidly progressing brain tumor. Despite the relatively low percentage of cancer patients with glioma diagnoses, recent statistics indicate that the number of glioma patients may have increased over the past decade. Current therapeutic options for glioma patients include tumor resection, chemotherapy, and concomitant radiation therapy with an average survival of approximately 16 months. The rapid progression of gliomas has spurred the development of novel treatment options, such as cancer gene therapy and oncolytic virotherapy. Preclinical testing of oncolytic adenoviruses using glioma models revealed both positive and negative sides of the virotherapy approach. Here we present a detailed overview of the glioma virotherapy field and discuss auxiliary therapeutic strategies with the potential for augmenting clinical efficacy of GBM virotherapy treatment. PMID:25685829
Bhat, Rauf; Rommelaere, Jean
Natural killer (NK) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. The ability of NK cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. Therapies with NK cells involve activation of endogenous NK cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. To exploit the diverse functional abilities of NK cells for cancer immunotherapy, it is important to understand NK cell biology and the underlying regulatory mechanisms. The state of immune suppression prevalent in malignancies creates the need for innovative therapies. Oncolytic viruses are novel anticancer agents showing selective tropism for tumor cells and lacking pathogenicity in humans, but the use of oncolytic virotherapy (OVT) presents multiple challenges. An increasing body of evidence suggests that the host immune response may critically influence the outcome of OVT. Classically, the immune system is thought to limit the efficacy of therapy through virus clearance mediated by innate immune effectors or through adaptive antiviral immune responses eliminating infected cells. Effective strategies do need to be designed in OVT to circumvent the early antiviral activity of NK cells and to augment late NK-cell-mediated antitumor responses. The intrinsic immunostimulating capacity of oncolytic viruses and the possibility of engineering them to express heterologous immunostimulatory molecules (eg, cytokines) support the use of these agents to enhance antitumor immune responses besides inducing direct oncolytic effects. OVT has indeed shown promising therapeutic outcomes in various clinical trials. Here, we review the biology of NK cells, strategies involving NK cells for achieving cancer therapy, and, more particularly, the emerging role of NK cells in OVT.
Jiang, Hong; Fueyo, Juan
We recently evaluated the capacity of Delta-24-RGD oncolytic adenovirus to trigger an antitumor immune response in a syngeneic mouse glioma model. This virotherapy elicited immunity against both tumor-associated antigens and viral antigens. An immunogenic cell death accompanied by pathogen- or damage- associated patterns (PAMPs and DAMPs) induced by the virus may be responsible for the adenoviral-mediated antitumor effect. PMID:25954598
Bhat, Rauf; Rommelaere, Jean
Natural killer (NK) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. The ability of NK cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. Therapies with NK cells involve activation of endogenous NK cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. To exploit the diverse functional abilities of NK cells for cancer immunotherapy, it is important to understand NK cell biology and the underlying regulatory mechanisms. The state of immune suppression prevalent in malignancies creates the need for innovative therapies. Oncolytic viruses are novel anticancer agents showing selective tropism for tumor cells and lacking pathogenicity in humans, but the use of oncolytic virotherapy (OVT) presents multiple challenges. An increasing body of evidence suggests that the host immune response may critically influence the outcome of OVT. Classically, the immune system is thought to limit the efficacy of therapy through virus clearance mediated by innate immune effectors or through adaptive antiviral immune responses eliminating infected cells. Effective strategies do need to be designed in OVT to circumvent the early antiviral activity of NK cells and to augment late NK-cell-mediated antitumor responses. The intrinsic immunostimulating capacity of oncolytic viruses and the possibility of engineering them to express heterologous immunostimulatory molecules (eg, cytokines) support the use of these agents to enhance antitumor immune responses besides inducing direct oncolytic effects. OVT has indeed shown promising therapeutic outcomes in various clinical trials. Here, we review the biology of NK cells, strategies involving NK cells for achieving cancer therapy, and, more particularly, the emerging role of NK cells in OVT. PMID:27471713
Aref, Sarah; Bailey, Katharine; Fielding, Adele
Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and “blinding” the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated. PMID:27782084
Beauman, John G
Genital herpes simplex virus infection is a recurrent, lifelong disease with no cure. The strongest predictor for infection is a person's number of lifetime sex partners. The natural history includes first-episode mucocutaneous infection, establishment of latency in the dorsal root ganglion, and subsequent reactivation. Most infections are transmitted via asymptomatic viral shedding. Classic outbreaks consist of a skin prodrome and possible constitutional symptoms such as headache, fever, and inguinal lymphadenopathy. As the infection progresses, papules, vesicles on an erythematous base, and erosions appear over hours to days. These lesions usually crust, re-epithelialize, and heal without scarring. First-episode infections are more extensive: primary lesions last two to six weeks versus approximately one week for lesions in recurrent disease. Atypical manifestations are common. Infected persons experience a median of four recurrences per year after their first episode, but rates vary greatly. Genital herpes simplex virus type 2 recurs six times more frequently than type 1. Viral culture is preferred over polymerase chain reaction testing for diagnosis. Serologic testing can be useful in persons with a questionable history. Effective oral antiviral medications are available for initial, episodic, and suppressive therapy but are not a cure. There is some evidence that alternative therapies such as L-lysine, zinc, and some herbal preparations may offer some benefit. Counseling patients about the risk of transmission is crucial and helps prevent the spread of disease and neonatal complications.
Jha, Babal K; Dong, Beihua; Nguyen, Carvell T; Polyakova, Irina; Silverman, Robert H
The use of lytic viruses to preferentially infect and eliminate cancer cells while sparing normal cells is a promising experimental therapeutic approach for treating cancer. However, the efficacy of oncolytic virotherapy is often limited by two innate immunity pathways, the protein kinase PKR and the 2'-5'-oligoadenylate (OAS)/RNase L systems, which are widely present in many but not all tumor cell types. Previously, we reported that the anticancer drug, sunitinib, an inhibitor of VEGF-R and PDGF-R, has off-target effects against both PKR and RNase L. Here we show that combining sunitinib treatments with infection by an oncolytic virus, vesicular stomatitis virus (VSV), led to the elimination of prostate, breast, and kidney malignant tumors in mice. In contrast, either virus or sunitinib alone slowed tumor progression but did not eliminate tumors. In prostate tumors excised from treated mice, sunitinib decreased levels of the phosphorylated form of translation initiation factor, eIF2-α, a substrate of PKR, by 10-fold while increasing median viral titers by 23-fold. The sunitinib/VSV regimen caused complete and sustained tumor regression in both immunodeficient and immunocompetent animals. Results indicate that transient inhibition of innate immunity with sunitinib enhances oncolytic virotherapy allowing the recovery of tumor-bearing animals.
Toro Bejarano, Marcela; Merchan, Jaime R
The oncolytic virotherapy field has made significant advances in the last decade, with a rapidly increasing number of early- and late-stage clinical trials, some of them showing safety and promising therapeutic efficacy. Targeting tumor vasculature by oncolytic viruses (OVs) is an attractive strategy that offers several advantages over nontargeted viruses, including improved tumor viral entry, direct antivascular effects, and enhanced antitumor efficacy. Current understanding of the biological mechanisms of tumor neovascularization, novel vascular targets, and mechanisms of resistance has allowed the development of oncolytic viral vectors designed to target tumor neovessels. While some OVs (such as vaccinia and vesicular stomatitis virus) can intrinsically target tumor vasculature and induce vascular disruption, the majority of reported vascular-targeted viruses are the result of genetic manipulation of their viral genomes. Such strategies include transcriptional or transductional endothelial targeting, "armed" viruses able to downregulate angiogenic factors, or to express antiangiogenic molecules. The above strategies have shown preclinical safety and improved antitumor efficacy, either alone, or in combination with standard or targeted agents. This review focuses on the recent efforts toward the development of vascular-targeted OVs for cancer treatment and provides a translational/clinical perspective into the future development of new generation biological agents for human cancers.
Haseley, Amy; Boone, Sean; Wojton, Jeffrey; Yu, Lianbo; Yoo, Ji Young; Yu, Jianhua; Kurozumi, Kazuhiko; Glorioso, Joseph C; Caligiuri, Michael A; Kaur, Balveen
Oncolytic viral therapy has been explored widely as an option for glioma treatment but its effectiveness has remained limited. Cysteine rich 61 (CCN1) is an extracellular matrix (ECM) protein elevated in cancer cells that modulates their adhesion and migration by binding cell surface receptors. In this study, we examined a hypothesized role for CCN1 in limiting the efficacy of oncolytic viral therapy for glioma, based on evidence of CCN1 induction that occurs in this setting. Strikingly, we found that exogenous CCN1 in glioma ECM orchestrated a cellular antiviral response that reduced viral replication and limited cytolytic efficacy. Gene expression profiling and real-time PCR analysis revealed a significant induction of type-I interferon responsive genes in response to CCN1 exposure. This induction was accompanied by activation of the Jak/Stat signaling pathway, consistent with induction of an innate antiviral cellular response. Both effects were mediated by the binding of CCN1 to the cell surface integrin α6β1, activating its signaling and leading to rapid secretion of interferon-α, which was essential for the innate antiviral effect. Together, our findings reveal how an integrin signaling pathway mediates activation of a type-I antiviral interferon response that can limit the efficacy of oncolytic viral therapy. Furthermore, they suggest therapeutic interventions to inhibit CCN1-integrin α6 interactions to sensitize gliomas to viral oncolysis.
Cheng, Pei-Hsin; Wechman, Stephen L.; McMasters, Kelly M.; Zhou, Heshan Sam
Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads) are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viral mRNA export, and cell cycle disruption. PMID:26561828
Singh, Prafull K.; Doley, Juwar; Kumar, G. Ravi; Sahoo, A.P.; Tiwari, Ashok K.
Cancer is one of the major causes of death worldwide. In spite of achieving significant successes in medical sciences in the past few decades, the number of deaths due to cancer remains unchecked. The conventional chemotherapy and radiotherapy have limited therapeutic index and a plethora of treatment related side effects. This situation has provided an impetus for search of novel therapeutic strategies that can selectively destroy the tumour cells, leaving the normal cells unharmed. Viral oncotherapy is such a promising treatment modality that offers unique opportunity for tumour targeting. Numerous viruses with inherent anti-cancer activity have been identified and are in different phases of clinical trials. In the era of modern biotechnology and with better understanding of cancer biology and virology, it has become feasible to engineer the oncolytic viruses (OVs) to increase their tumour selectivity and enhance their oncolytic activity. In this review, the mechanisms by which oncolytic viruses kill the tumour cells have been discussed as also the development made in virotherapy for cancer treatment with emphasis on their tumour specific targeting. PMID:23168697
Bartee, Mee Y; Dunlap, Katherine M; Bartee, Eric
Oncolytic virotherapy represents an attractive option for the treatment of a variety of aggressive or refractory tumors. While this therapy is effective at rapidly debulking directly injected tumor masses, achieving complete eradication of established disease has proven difficult. One method to overcome this challenge is to use oncolytic viruses to induce secondary anti-tumor immune responses. Unfortunately, while the initial induction of these immune responses is typically robust, their subsequent efficacy is often inhibited through a variety of immunoregulatory mechanisms, including the PD1/PDL1 T-cell checkpoint pathway. To overcome this inhibition, we generated a novel recombinant myxoma virus (vPD1) which inhibits the PD1/PDL1 pathway specifically within the tumor microenvironment by secreting a soluble form of PD1 from infected cells. This virus both induced and maintained anti-tumor CD8+ T-cell responses within directly treated tumors and proved safer and more effective than combination therapy using unmodified myxoma and systemic αPD1 antibodies. Localized vPD1 treatment combined with systemic elimination of regulatory T cells had potent synergistic effects against metastatic disease that was already established in secondary solid organs. These results demonstrate that tumor-localized inhibition of the PD1/PDL1 pathway can significantly improve outcomes during oncolytic virotherapy. Furthermore, they establish a feasible path to translate these findings against clinically relevant disease.
Muharemagic, Darija; Zamay, Anna; Ghobadloo, Shahrokh M; Evgin, Laura; Savitskaya, Anna; Bell, John C; Berezovski, Maxim V
Oncolytic viruses promise to significantly improve current cancer treatments through their tumor-selective replication and multimodal attack against cancer cells. However, one of the biggest setbacks for oncolytic virus therapy is the intravenous delivery of the virus, as it can be cleared from the bloodstream by neutralizing antibodies before it reaches the tumor cells. We have selected DNA aptamers against an oncolytic virus, vesicular stomatitis virus, using a competitive binding approach, as well as against the antigen binding fragment (Fab) of antivesicular stomatitis virus polyclonal antibodies, in order to shield the virus from nAbs and enhance its in vivo survival. We used flow cytometry to identify these aptamers and evaluated their efficiency to shield vesicular stomatitis virus in a cell-based plaque forming assay. These oligonucleotides were then modified to obtain multivalent binders, which led to a decrease of viral aggregation, an increase in its infectivity and an increase in its stability in serum. The aptamers were also incubated in nondiluted serum, showing their effectiveness under conditions mimicking those in vivo. With this approach, we were able to increase viral infectivity by more than 70% in the presence of neutralizing antibodies. Thus, this method has the potential to enhance the delivery of vesicular stomatitis virus through the bloodstream without compromising the patient's immune system. PMID:24892725
Pinninti, Swetha G; Kimberlin, David W
Neonatal herpes simplex virus infections are uncommon, but because of the morbidity and mortality associated with the infection they are often considered in the differential diagnosis of ill neonates. The use of polymerase chain reaction for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy has revolutionized the diagnosis and management of these infants. Initiation of long-term antiviral suppressive therapy in these infants has led to significant improvement in morbidity. This article summarizes the epidemiology of neonatal herpes simplex virus infections and discusses clinical presentation, diagnosis, management, and follow up of infants with neonatal herpes disease.
Cherpes, Thomas L; Matthews, Dean B; Maryak, Samantha A
Neonatal herpes, seen roughly in 1 of 3000 live births in the United States, is the most serious manifestation of herpes simplex virus (HSV) infection in the perinatal period. Although acyclovir therapy decreases infant mortality associated with perinatal HSV transmission, development of permanent neurological disabilities is not uncommon. Mother-to-neonate HSV transmission is most efficient when maternal genital tract HSV infection is acquired proximate to the time of delivery, signifying that neonatal herpes prevention strategies need to focus on decreasing the incidence of maternal infection during pregnancy and more precisely identifying infants most likely to benefit from prophylactic antiviral therapy.
Okamoto, Kenichi W; Amarasekare, Priyanga; Petty, Ian T D
The specific targeting of tumor cells by replication-competent oncolytic viruses is considered indispensable for realizing the potential of oncolytic virotherapy. Yet off-target infections by oncolytic viruses may increase virus production, further reducing tumor load. This ability may be critical when tumor-cell scarcity or the onset of an adaptive immune response constrain viral anti-tumoral efficacy. Here we develop a mathematical framework for assessing whether oncolytic viruses with reduced tumor-specificity can more effectively eliminate tumors while keeping losses to normal cell populations low. We find viruses that infect some normal cells can potentially balance the competing goals of tumor elimination and minimizing the effects on normal cell populations. Particularly when infected tissues can be regenerated, moderating rather than completely eliminating the ability of oncolytic viruses to infect and lyse normal cells could improve cancer treatment, with potentially fewer side-effects than conventional treatments such as chemotherapy.
... virus; Herpes simplex virus culture Images Viral lesion culture References Costello M, Sabatini LM, Yungbluth M. Viral infections. In: McPherson RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods . 22nd ed. Philadelphia, PA: Elsevier ...
Rogers, C. D.; Peters, Phyllis
The article presents the medical, psychological, and reading diagnoses of a 24-year-old man with herpes encephalitis, an acute neurological disease. Test results are reported and the client's response to learning disability remedial techniques are reviewed. (SBH)
Rodríguez-Menchaca, Aldo A; Adney, Scott K; Zhou, Lei; Logothetis, Diomedes E
inhibitory effect. The dual regulation of these very different ion channels, all of which are voltage-dependent, points to conserved mechanisms of regulation of these channels by PIP(2).
Herpes simplex is a common recurrent viral infection caused by the herpes simplex virus. The two closely related but distinct viruses that cause herpes simplex infections are herpes simplex 1 (HSV-1) and herpes simplex 2 (HSV-2). HSV-1 is commonly associated with infections around the oral mucosa and is the cause of herpes labialis, often referred…
Zawar, Vijay; Godse, Kiran
We describe recurrent acute right-sided facial urticaria associated with herpes labialis infection in a middle-aged female patient. Antiviral medications and antihistamines not only successfully cleared the herpes infection and urticaria but also prevented further recurrences.
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Pinninti, Swetha G; Kimberlin, David W
Genital herpes infections are extremely common worldwide and ~22% of pregnant women are infected with herpes simplex virus. Eighty percent of those affected with genital herpes are unaware of being infected. The most devastating consequence of maternal genital herpes is neonatal herpes disease. Fortunately, neonatal herpes simplex infections are uncommon but due to the morbidity and mortality associated with the infection are often considered in the differential diagnosis of ill neonates. The use of polymerase chain reaction assay for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy have revolutionized the diagnosis and management of these infants. Most recently, the initiation of long-term antiviral suppressive therapy in these infants has led to significant improvement in morbidity. This review will summarize the epidemiology of maternal and neonatal herpes infections and discuss clinical presentation, diagnosis, management, and follow-up of infants with neonatal herpes disease.
Ran, Li; Tan, Xiaohua; Li, Yanchun; Zhang, Huafeng; Ma, Ruihua; Ji, Tiantian; Dong, Wenqian; Tong, Tong; Liu, Yuying; Chen, Degao; Yin, Xiaonan; Liang, Xiaoyu; Tang, Ke; Ma, Jingwei; Zhang, Yi; Cao, Xuetao; Hu, Zhuowei; Qin, Xiaofeng; Huang, Bo
Oncolytic viruses have been utilized for the treatment of various cancers. However, delivery of the viral particles to tumor cells remains a major challenge. Microparticles (MP) are vesicle forms of plasma membrane fragments of 0.1-1 μm in size that are shed by cells. We have previously shown the delivery of chemotherapeutic drugs using tumor cell-derived MPs (T-MP). Here we report that T-MPs can be utilized as a unique carrier system to deliver oncolytic adenoviruses to human tumors, leading to highly efficient cytolysis of tumor cells needed for in vivo treatment efficacy. This T-MP-mediated oncolytic virotherapy approach holds multiple advantages, including: 1) delivery of oncolytic adenovirus by T-MPs is able to avoid the antiviral effect of host antibodies; 2) delivery of oncolytic adenovirus by T-MPs is not limited by virus-specific receptor that mediates the entry of virus into tumor cells; 3) T-MPs are apt at delivering oncolytic adenoviruses to the nucleus of tumor cells as well as to stem-like tumor-repopulating cells for the desired purpose of killing them. These findings highlight a novel oncolytic adenovirus delivery system with highly promising clinical applications.
Yuan, Ming; Webb, Eika; Lemoine, Nicholas Robert; Wang, Yaohe
The development of oncolytic viruses has led to an emerging new class of cancer therapeutics. Although the safety profile has been encouraging, the transition of oncolytic viruses to the clinical setting has been a slow process due to modifications. Therefore, a new generation of more potent oncolytic viruses needs to be exploited, following our better understanding of the complex interactions between the tumor, its microenvironment, the virus, and the host immune response. The conventional method for creation of tumor-targeted oncolytic viruses is based on homologous recombination. However, the creation of new mutant oncolytic viruses with large genomes remains a challenge due to the multi-step process and low efficiency of homologous recombination. The CRISPR-associated endonuclease Cas9 has hugely advanced the potential to edit the genomes of various organisms due to the ability of Cas9 to target a specific genomic site by a single guide RNA. In this review, we discuss the CRISPR-Cas9 system as an efficient viral editing method for the creation of new oncolytic viruses, as well as its potential future applications in the development of oncolytic viruses. Further, this review discusses the potential of off-target effects as well as CRISPR-Cas9 as a tool for basic research into viral biology.
Yuan, Ming; Webb, Eika; Lemoine, Nicholas Robert; Wang, Yaohe
The development of oncolytic viruses has led to an emerging new class of cancer therapeutics. Although the safety profile has been encouraging, the transition of oncolytic viruses to the clinical setting has been a slow process due to modifications. Therefore, a new generation of more potent oncolytic viruses needs to be exploited, following our better understanding of the complex interactions between the tumor, its microenvironment, the virus, and the host immune response. The conventional method for creation of tumor-targeted oncolytic viruses is based on homologous recombination. However, the creation of new mutant oncolytic viruses with large genomes remains a challenge due to the multi-step process and low efficiency of homologous recombination. The CRISPR-associated endonuclease Cas9 has hugely advanced the potential to edit the genomes of various organisms due to the ability of Cas9 to target a specific genomic site by a single guide RNA. In this review, we discuss the CRISPR-Cas9 system as an efficient viral editing method for the creation of new oncolytic viruses, as well as its potential future applications in the development of oncolytic viruses. Further, this review discusses the potential of off-target effects as well as CRISPR-Cas9 as a tool for basic research into viral biology. PMID:26959050
Brantley, Julie S; Hicks, Lindsey; Sra, Karan; Tyring, Stephen K
Genital herpes is the most prevalent sexually transmitted infection in the USA. While sometimes mild in severity, it can be a distressing and painful chronic condition. Likewise, herpes labialis and herpes zoster can be both physically and psychologically painful. While there is no cure for these conditions, treatment to alleviate symptoms, suppress recurrences and reduce transmission has been drastically improved over the past 20 years with the use of guanine nucleoside antivirals, such as valacyclovir hydrochloride (Valtrex), GlaxoSmithKline) the highly bioavailable prodrug of acyclovir (Zovirax((R)), GlaxoSmithKline), and famciclovir (Famvir, Novartis), a highly bioavailable prodrug of penciclovir (Denavir, Novartis). Clinical trials involving approximately 10,000 patients (including patients from nongenital herpes studies, such as herpes zoster) have assessed the safety and efficacy of valacyclovir in the treatment of initial genital herpes outbreaks, episodic treatment of recurrent episodes and daily suppressive therapy. It was shown that valacyclovir has similar efficacy to acyclovir in the episodic and suppressive treatment of genital herpes. Valacyclovir is the only antiviral drug approved for a once-daily dose of suppressive therapy for genital herpes, as well as the only antiviral drug US FDA approved for a 3-day regimen of episodic treatment of recurrent genital herpes. In addition, valacyclovir is also indicated in the reduction of the sexual transmission of herpes simplex virus infection and for the treatment of herpes labialis. In herpes zoster, valacyclovir is more effective than acyclovir or placebo (and as equally effective as famciclovir) in shortening the length and severity of herpes zoster-associated pain and postherpetic neuralgia. Valacyclovir has an acceptable safety profile in patients with herpes simplex and herpes zoster. The less frequent dosing regimen makes it an attractive option in the treatment of genital herpes and other viral
Sweeney, Katrina; Halldén, Gunnel
Prostate cancer is a leading cause of cancer-related death and morbidity in men in the Western world. Tumor progression is dependent on functioning androgen receptor signaling, and initial administration of antiandrogens and hormone therapy (androgen-deprivation therapy) prevent growth and spread. Tumors frequently develop escape mechanisms to androgen-deprivation therapy and progress to castration-resistant late-stage metastatic disease that, in turn, inevitably leads to resistance to all current therapeutics, including chemotherapy. In spite of the recent development of more effective inhibitors of androgen–androgen receptor signaling such as enzalutamide and abiraterone, patient survival benefits are still limited. Oncolytic adenoviruses have proven efficacy in prostate cancer cells and cause regression of tumors in preclinical models of numerous drug-resistant cancers. Data from clinical trials demonstrate that adenoviral mutants have limited toxicity to normal tissues and are safe when administered to patients with various solid cancers, including prostate cancer. While efficacy in response to adenovirus administration alone is marginal, findings from early-phase trials targeting local-ized and metastatic prostate cancer suggest improved efficacy in combination with cytotoxic drugs and radiation therapy. Here, we review recent progress in the development of multimodal oncolytic adenoviruses as biological therapeutics to improve on tumor elimination in prostate cancer patients. These optimized mutants target cancer cells by several mechanisms including viral lysis and by expression of cytotoxic transgenes and immune-stimulatory factors that activate the host immune system to destroy both infected and noninfected prostate cancer cells. Additional modifications of the viral capsid proteins may support future systemic delivery of oncolytic adenoviruses. PMID:27579296
Opstelten, Wim; Eekhof, Just; Neven, Arie Knuistingh; Verheij, Theo
OBJECTIVE To review the evidence regarding treatment of herpes zoster (HZ) in the short-term, focusing on the prevention of postherpetic neuralgia (PHN). QUALITY OF EVIDENCE The evidence relating to treatment of HZ is derived mainly from randomized controlled trials (level I evidence). MAIN MESSAGE Antiviral drugs might have some effect on the severity of acute pain and on the duration of skin lesions. Corticosteroids also alleviate acute pain. Oral antiviral medication reduces the risk of eye complications in patients with ophthalmic HZ. There is no convincing evidence that antiviral medication reduces the risk of PHN. Some studies, however, have shown that famciclovir and valacyclovir shorten the duration of PHN. The effectiveness of amitriptyline or cutaneous and percutaneous interventions in preventing PHN has not been proven. CONCLUSION Oral antiviral drugs should be prescribed to elderly HZ patients with high risk of PHN. Moreover, these drugs should be prescribed to all patients at the first signs of ophthalmic HZ, irrespective of age or severity of symptoms. PMID:18337531
Shah, Snehal; Singaraju, Sasidhar; Einstein, A; Sharma, Ashish
Herpes zoster or shingles is reactivation of the varicella zoster virus that had entered the cutaneous nerve endings during an earlier episode of chicken pox traveled to the dorsal root ganglia and remained in a latent form. This condition is characterized by occurrence of multiple, painful, unilateral vesicles and ulceration which shows a typical single dermatome involvement. In this case report, we present a patient with herpes zoster involving the mandibular division of the trigeminal nerve, with unilateral vesicles over the right side of lower third of face along the trigeminal nerve tract, with intraoral involvement of buccal mucosa, labial mucosa and the tongue of the same side. Cytopathology revealed classic features of herpes infection including inclusion bodies, perinuclear halo and multinucleated cells. PMID:27721631
Wollina, U; Machetanz, J
Herpes zoster develops by endogenous reactivation of varizella zoster virus (VZV). Incidence increases with age. Females are more frequently affected than males. The reactivation rate in seropositive individuals is about 20 %. After a short prodromal stage, herpetiform-grouped vesicles appear in segmental arrangement. Pain and paresthesia are typical zoster symptoms. Complications like bacterial superinfections, vasculopathy, paresis, and oculopathy may occur. During pregnancy herpes zoster is a threat for mother and child. Among elderly patients, cardiovascular risk is increased during the first week of herpes zoster infection. Postherpetic neuropathy is feared. Diagnosis can be made clinically and by the use of polymerase chain reaction. First-line treatment is systemic antiviral drug therapy with either acyclovir or brivudine. Adjuvant therapies consist of pain management and topical treatment.
Wollmann, Guido; Ozduman, Koray; van den Pol, Anthony N.
Twenty years of oncolytic virus (OV) development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding – over 20 viruses have been recognized as potential OVs – new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme (GBM). So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against GBM. In this review, we present an overview of viruses that have been developed or considered for GBM treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of OV application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results; next-generation OVs that are either “armed” with therapeutic genes or that are embedded in a multimodality treatment regimen should enhance the clinical results. PMID:22290260
Takagi-Kimura, M; Yamano, T; Tagawa, M; Kubo, S
Oncolytic virotherapy using adenoviruses has potential therapeutic benefits for a variety of cancers. We recently developed MOA5, a tumor-specific midkine promoter-regulated oncolytic vector based on human adenovirus serotype 5 (Ad5). We modified the binding tropism of MOA5 by replacing the cell-binding domain of the Ad5 fiber knob with that from another adenovirus serotype 35 (Ad35); the resulting vector was designated MOA35. Here we evaluated the therapeutic efficacies of MOA5 and MOA35 for human osteosarcoma. Midkine mRNA expression and its promoter activity was significantly high in five human osteosarcoma cell lines, but was restricted in normal cells. Very low levels of adenovirus cellular receptor coxsackievirus/adenovirus receptor (CAR) (Ad5 receptor) expression were observed in MNNG-HOS and MG-63 cells, whereas high levels of CAR expression were seen in the other osteosarcoma cell lines. By contrast, CD46 (Ad35 receptor) was highly expressed in all osteosarcoma cell lines. Infectivity and in vitro cytocidal effect of MOA35 was significantly enhanced in MNNG-HOS and MG-63 cells compared with MOA5, although the cytocidal effects of MOA5 were sometimes higher in high CAR-expressing cell lines. In MG-63 xenograft models, MOA35 significantly enhanced antitumor effects compared with MOA5. Our findings indicate that MOA5 and MOA35 allow tailored virotherapy and facilitate more effective treatments for osteosarcoma.
Paiva, L R; Martins, M L; Ferreira, S C
One of the most promising strategies to treat cancer is attacking it with viruses designed to exploit specific altered pathways. Here, the effects of oncolytic virotherapy on tumors having compact, papillary, and disconnected morphologies are investigated through computer simulations of a multiscale model coupling macroscopic reaction-diffusion equations for the nutrients with microscopic stochastic rules for the actions of individual cells and viruses. The interaction among viruses and tumor cells involves cell infection, intracellular virus replication, and the release of new viruses in the tissue after cell lysis. The evolution over time of both the viral load and cancer cell population, as well as the probabilities for tumor eradication, were evaluated for a range of multiplicities of infection, viral entries, and burst sizes. It was found that in immunosuppressed hosts, the antitumor efficacy of a virus is primarily determined by its entry efficiency, its replicative capacity within the tumor, and its ability to spread over the tissue. However, the optimal traits for oncolytic viruses depend critically on the tumor growth dynamics and do not necessarily include rapid replication, cytolysis, or spreading, currently assumed as necessary conditions for a successful therapeutic outcome. Our findings have potential implications on the design of new vectors for the viral therapy of cancer.
Paiva, L. R.; Martins, M. L.; Ferreira, S. C.
One of the most promising strategies to treat cancer is attacking it with viruses designed to exploit specific altered pathways. Here, the effects of oncolytic virotherapy on tumors having compact, papillary, and disconnected morphologies are investigated through computer simulations of a multiscale model coupling macroscopic reaction-diffusion equations for the nutrients with microscopic stochastic rules for the actions of individual cells and viruses. The interaction among viruses and tumor cells involves cell infection, intracellular virus replication, and the release of new viruses in the tissue after cell lysis. The evolution over time of both the viral load and cancer cell population, as well as the probabilities for tumor eradication, were evaluated for a range of multiplicities of infection, viral entries, and burst sizes. It was found that in immunosuppressed hosts, the antitumor efficacy of a virus is primarily determined by its entry efficiency, its replicative capacity within the tumor, and its ability to spread over the tissue. However, the optimal traits for oncolytic viruses depend critically on the tumor growth dynamics and do not necessarily include rapid replication, cytolysis, or spreading, currently assumed as necessary conditions for a successful therapeutic outcome. Our findings have potential implications on the design of new vectors for the viral therapy of cancer.
Hutzen, Brian; Raffel, Corey; Studebaker, Adam W
A successful oncolytic virus is one that selectively propagates and destroys cancerous tissue without causing excessive damage to the normal surrounding tissue. Oncolytic measles virus (MV) is one such virus that exhibits this characteristic and thus has rapidly emerged as a potentially useful anticancer modality. Derivatives of the Edmonston MV vaccine strain possess a remarkable safety record in humans. Promising results in preclinical animal models and evidence of biological activity in early phase trials contribute to the enthusiasm. Genetic modifications have enabled MV to evolve from a vaccine agent to a potential anticancer therapy. Specifically, alterations of the MV genome have led to improved tumor selectivity and delivery, therapeutic potency, and immune system modulation. In this article, we will review the advancements that have been made in the design and development of MV that have led to its use as a cancer therapy. In addition, we will discuss the evidence supporting its use, as well as the challenges associated with MV as a potential cancer therapeutic. PMID:27512675
Oncolytic and Imaging Approaches for Advanced Prostate Cancer PRINCIPAL INVESTIGATOR: Lily Wu, M.D., Ph.D. CONTRACTING ORGANIZATION...SUBTITLE Molecular Engineering of Vector-based Oncolytic and Imaging Approaches for 5a. CONTRACT NUMBER Advanced Prostate Cancer 5b. GRANT...reproductions will be in black and white. 14. ABSTRACT Hormone refractory and metastatic prostate cancer are not well understood. Better animal models
specific fashion. Ad ditionally, mutated form of Vesicular Stomatitis Virus (VSV), an oncolytic virus capable of replicating in interferon (IFN) response...Our results indicated that direct injection of VSV (AV3) intra-prostaticaly lead to selective infection, replication, and overall i ncrease i n ap...ully re plication-competent a nd r apidly s pread through a nd ki ll cancerous cells. Vesicular Stomatitis Virus (VSV) is an oncolytic virus which
Peters, Cole; Nigim, Fares; Chiocca, E Antonio; Rabkin, Samuel D
Boston, Massachusetts, was the site of the 9th International Conference on Oncolytic Virus Therapeutics held 13–16 June 2015. An overarching theme of the meeting was the continued development of combinatorial treatment regimens to bolster the therapeutic potential of oncolytic viruses (OVs). Several talks focused on combining OVs with immune checkpoint inhibitors in a wide array of tumors, signaling an experimental and thematic shift toward driving immune activation to clear a tumor versus relying on direct viral oncolysis. An important aspect of the meeting was the variety of ongoing OV clinical trials. Topics ranged from basic virology to clinical trials and from academic research to intellectual property and biotechnology. There was much excitement due to the US Food and Drug Administration’s recent consideration of talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma (T-VEC was approved in October, following the conference). Here, we summarize the meeting’s primary themes, which reflect the current state of the field.
Miller, Amber; Russell, Stephen J
Introduction: Oncolytic viruses are experimental cancer therapies being translated to the clinic. They are unique in their ability to amplify within the body, therefore requiring careful monitoring of viral replication and biodistribution. Traditional monitoring strategies fail to recapitulate the dynamic nature of oncolytic virotherapy. Consequently, clinically relevant, noninvasive, high resolution strategies are needed to effectively track virotherapy in real time. Areas covered: The expression of the sodium iodide symporter (NIS) reporter gene is tightly coupled to viral genome replication and mediates radioisotope concentration, allowing noninvasive molecular nuclear imaging of active viral infection with high resolution. This provides insight into replication kinetics, biodistribution, the impact of vector design, administration, and dosing on therapeutic outcomes, and highlights the heterogeneity of spatial distribution and temporal evolution of infection. NIS-mediated imaging in clinical trials confirms the feasibility of this technology to noninvasively and longitudinally observe oncolytic virus infection, replication, and distribution. Expert opinion: NIS-mediated imaging provides detailed functional and molecular information on the evolution of oncolytic virus infection in living animals. The use of NIS reporter gene imaging has rapidly advanced to provide unparalleled insight into the spatial and temporal context of oncolytic infection which will be integral to optimization of oncolytic treatment strategies. PMID:26457362
Braus, Judy, Ed.
Ranger Rick's NatureScope is a creative education series dedicated to inspiring in children an understanding and appreciation of the natural world while developing the skills they will need to make responsible decisions about the environment. The topic of this issue is "Let's Hear It for the Herps!" Contents are organized into the…
Glover, Elbert D.
Factual information dealing with the virus herpes is provided in hopes of allaying the public fears that have recently appeared because of misinformation presented by the media. Symptoms, types, and new developments in treatment are explored. Recommendations for obtaining additional information are offered. (DF)
Russell, Stephen J; Federspiel, Mark J; Peng, Kah-Whye; Tong, Caili; Dingli, David; Morice, William G; Lowe, Val; O'Connor, Michael K; Kyle, Robert A; Leung, Nelson; Buadi, Francis K; Rajkumar, S Vincent; Gertz, Morie A; Lacy, Martha Q; Dispenzieri, Angela
MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 10(11) TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer.
Forveille, Sabrina; Zhou, Heng; Sauvat, Allan; Bezu, Lucillia; Müller, Kevin; Liu, Peng; Zitvogel, Laurence; Pierron, Gérard; Rekdal, Øystein; Kepp, Oliver; Kroemer, Guido
The oncolytic peptide LTX-315 has been designed for killing human cancer cells and turned out to stimulate anti-cancer immune responses when locally injected into tumors established in immunocompetent mice. Here, we investigated the question whether LTX-315 induces apoptosis or necrosis. Transmission electron microscopy or morphometric analysis of chromatin-stained tumor cells revealed that LTX-315 failed to induce apoptotic nuclear condensation and rather induced a necrotic phenotype. Accordingly, LTX-315 failed to stimulate the activation of caspase-3, and inhibition of caspases by means of Z-VAD-fmk was unable to reduce cell killing by LTX-315. In addition, 2 prominent inhibitors of regulated necrosis (necroptosis), namely, necrostatin-1 and cycosporin A, failed to reduce LTX-315-induced cell death. In conclusion, it appears that LTX-315 triggers unregulated necrosis, which may contribute to its pro-inflammatory and pro-immune effects. PMID:26566869
Gutermann, Anja; Mayer, Elfriede; von Dehn-Rothfelser, Karin; Breidenstein, Claudia; Weber, Mihaela; Muench, Martina; Gungor, Denis; Suehnel, Juergen; Moebius, Ulrich; Lechmann, Martin
NV1020, an oncolytic herpes simplex virus type 1, can destroy colon cancer cells by selectively replicating within these cells, while sparing normal cells. NV1020 is currently under investigation in a clinical phase I/II trial as an agent for the treatment of colon cancer liver metastases, in combination with conventional chemotherapeutic agents such as 5-fluorouracil (5-FU), SN38 (the active metabolite of irinotecan), and oxaliplatin. To study the synergy of NV1020 and chemotherapy, cytotoxicity and viral replication were evaluated in vitro by treating various human and murine colon carcinoma cell lines, using a colorimetric viability assay, a clonogenic assay, and a plaque-forming assay. In vivo experiments, using a subcutaneous syngeneic CT-26 tumor model in BALB/c mice, were performed to determine the efficacy of combination therapy. In vitro studies showed that the efficacy of NV1020 on human colon carcinoma cell lines HT-29, WiDr, and HCT-116 was additively or synergistically enhanced in combination with 5-FU, SN38, or oxaliplatin. The sequence of application was not important and effects were still apparent after a 21-day incubation period. Three intra-tumoral treatments with NV1020 (1 x 10(7) plaque-forming units), followed by three subcutaneous treatments with 5-FU (50 mg/kg), resulted in substantially higher inhibition of tumor growth and prolongation of survival compared with monotherapies (NV1020/5-FU vs. NV1020, p = 0.027). On WiDr cells, reduced replication of NV1020, in combination with 5-FU, indicated that additive and synergistic effects of combination therapy must be independent from viral replication. These results suggest that NV1020, in combination with chemotherapy, is a promising therapy for treating patients with metastatic colorectal cancer of the liver. We hypothesize that infection of cells with NV1020 sensitizes the infected cells for the cytotoxic effect of the chemotherapeutics.
Wennier, Sonia Tusell; Liu, Jia; McFadden, Grant
Single agent therapies are rarely successful in treating cancer, particularly at metastatic or end stages, and survival rates with monotherapies alone are generally poor. The combination of multiple therapies to treat cancer has already driven significant improvements in the standard of care treatments for many types of cancers. The first combination treatments exploited for cancer therapy involved the use of several cytotoxic chemotherapy agents. Later, with the development of more targeted agents, the use of novel, less toxic drugs, in combination with the more classic cytotoxic drugs has proven advantageous for certain cancer types. Recently, the combination of oncolytic virotherapy with chemotherapy has shown that the use of these two therapies with very distinct anti-tumor mechanisms may also lead to synergistic interactions that ultimately result in increased therapeutic effects not achievable by either therapy alone. The mechanisms of synergy between oncolytic viruses (OVs) and chemotherapeutic agents are just starting to be elucidated. It is evident, however, that the success of these OV-drug combinations depends greatly on the particular O V, the drug(s) selected, and the cancer type targeted. This review summarizes the different OV-drug combinations investigated to date, including the use of second generation armed OVs, which have been studied with the specific purpose of generating synergistic interactions with particular chemotherapy agents. The known mechanisms of synergy between these OV-drug combinations are also summarized. The importance of further investigating these mechanisms of synergy will be critical in order to maximize the therapeutic efficacy of OV-drug combination therapies in the future. PMID:21740354
Wennier, Sonia Tusell; Liu, Jia; McFadden, Grant
Single agent therapies are rarely successful in treating cancer, particularly at metastatic or end stages, and survival rates with monotherapies alone are generally poor. The combination of multiple therapies to treat cancer has already driven significant improvements in the standard of care treatments for many types of cancers. The first combination treatments exploited for cancer therapy involved the use of several cytotoxic chemotherapy agents. Later, with the development of more targeted agents, the use of novel, less toxic drugs, in combination with the more classic cytotoxic drugs has proven advantageous for certain cancer types. Recently, the combination of oncolytic virotherapy with chemotherapy has shown that the use of these two therapies with very distinct anti-tumor mechanisms may also lead to synergistic interactions that ultimately result in increased therapeutic effects not achievable by either therapy alone. The mechanisms of synergy between oncolytic viruses (OVs) and chemotherapeutic agents are just starting to be elucidated. It is evident, however, that the success of these OV-drug combinations depends greatly on the particular OV, the drug(s) selected, and the cancer type targeted. This review summarizes the different OV-drug combinations investigated to date, including the use of second generation armed OVs, which have been studied with the specific purpose of generating synergistic interactions with particular chemotherapy agents. The known mechanisms of synergy between these OV-drug combinations are also summarized. The importance of further investigating these mechanisms of synergy will be critical in order to maximize the therapeutic efficacy of OV-drug combination therapies in the future.
Chiocca, EA; Rabkin, SD
Oncolytic viruses (OVs) selectively replicate in and kill cancer cells, and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer-selective or can be genetically-engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines, and can be armed with immune modulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy; they include: (i) innate immune responses and the degree of inflammation induced, (ii) types of virus-induced cell death, (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture, and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers (MHC, co-stimulatory, NK receptors), and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing GM-CSF, have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between anti-virus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs. PMID:24764576
As one of the most common sexually transmitted diseases, genital herpes is a global medical problem with significant physical and psychological morbidity. Genital herpes is caused by herpes simplex virus type 1 or type 2 and can manifest as primary and/or recurrent infection. This manuscript provides an overview about the fundamental knowledge on the virus, its epidemiology, and infection. Furthermore, the current possibilities of antiviral therapeutic interventions and laboratory diagnosis of genital herpes as well as the present situation and perspectives for the treatment by novel antivirals and prevention of disease by vaccination are presented. Since the medical management of patients with genital herpes simplex virus infection is often unsatisfactory, this review aims at all physicians and health professionals who are involved in the care of patients with genital herpes. The information provided would help to improve the counseling of affected patients and to optimize the diagnosis, treatment, and prevention of this particular disease. PMID:27358569
As one of the most common sexually transmitted diseases, genital herpes is a global medical problem with significant physical and psychological morbidity. Genital herpes is caused by herpes simplex virus type 1 or type 2 and can manifest as primary and/or recurrent infection. This manuscript provides an overview about the fundamental knowledge on the virus, its epidemiology, and infection. Furthermore, the current possibilities of antiviral therapeutic interventions and laboratory diagnosis of genital herpes as well as the present situation and perspectives for the treatment by novel antivirals and prevention of disease by vaccination are presented. Since the medical management of patients with genital herpes simplex virus infection is often unsatisfactory, this review aims at all physicians and health professionals who are involved in the care of patients with genital herpes. The information provided would help to improve the counseling of affected patients and to optimize the diagnosis, treatment, and prevention of this particular disease.
Stephenson-Famy, Alyssa; Gardella, Carolyn
Genital herpes in pregnancy continues to cause significant maternal morbidity, with an increasing number of infections being due to oral-labial transmission of herpes simplex virus (HSV)-1. Near delivery, primary infections with HSV-1 or HSV-2 carry the highest risk of neonatal herpes infection, which is a rare but potentially devastating disease for otherwise healthy newborns. Prevention efforts have been limited by lack of an effective intervention for preventing primary infections and the unclear role of routine serologic testing.
Kim, Janice; Hall, Robert R; Lesniak, Maciej S; Ahmed, Atique U
Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis-all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.
Kim, Janice; Hall, Robert R.; Lesniak, Maciej S.; Ahmed, Atique U.
Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis—all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting. PMID:26633462
Choi, Won Suk; Kwon, Soon Sun; Lee, Jacob; Choi, Su-Mi; Lee, Jin Soo; Eom, Joong Sik; Sohn, Jang Wook; Choeng, Hee Jin
The burden of herpes zoster may be related to patients' immunity, although this has not been studied extensively. This hypothesis was tested in a matched case-control study of patients with herpes zoster who sought treatment at one of seven university hospitals in Korea from January 1, 2007, to December 31, 2010. Patients diagnosed with herpes zoster were placed into three groups based on their immune status: severely immunocompromised, mild-to-moderately immunocompromised, and normal immunity. Each patient in the severely immunocompromised group was matched with one patient in the mild-to-moderately immunocompromised group and one patient in the normal immunity group in the same hospital based on age, sex, and date of herpes zoster onset. A total of 582 patients with herpes zoster were included in the analysis: 194 in each of the three groups. Patients in the severely immunocompromised group had the highest herpes zoster-related hospitalization rate as compared to patients in the mild-to-moderately immunocompromised and normal immune groups (P < 0.01). The length of hospital stay and herpes zoster-related medical cost increased significantly with the deterioration of patients' immunity (P < 0.01, respectively). Cutaneous complications occurred more frequently in the severely immunocompromised group than in the other two groups (P < 0.01). An increase in herpes zoster burden was observed as the patients' immunity decreased. Therefore, effective measures are necessary to prevent herpes zoster and reduce its burden in severely immunocompromised patients.
Au, Eugene; Sacks, Stephen L.
Herpes simplex viruses are responsible for a number of disease states in infected individuals. Capable of establishing latent infection, herpes simplex can reactivate, causing pain, discomfort, and psychosocial consequences. Because no cure is available, treatment modalities for herpes simplex infection are required, from both personal and public health standpoints. To date, therapy has centered around the use of antiviral drugs to control infection and suppress recurrences. To expand the scope of available treatments, efforts have focused on the development of vaccines against herpes simplex virus and new agents such as immune response modifiers. Recent data suggest that these new agents are promising in their therapeutic potential.
Shin, Haina; Iwasaki, Akiko
Genital herpes is an incurable, chronic disease that affects millions of people worldwide. Not only does genital herpes cause painful, recurrent symptoms, it is also a significant risk factor for the acquisition of other sexually transmitted infections such as HIV-1. Antiviral drugs are used to treat herpes simplex virus (HSV) infection, but they cannot stop viral shedding and transmission. Thus, developing a vaccine that can prevent or clear infection will be crucial in limiting the spread of disease. In this review we outline recent studies that improve our understanding of host responses against HSV infection, discuss past clinical vaccine trials, and highlight new strategies for vaccine design against genital herpes.
Hicks, Caitlin W; Lum, Ying Wei; Heller, Jennifer A
Herpes simplex virus infection following surgery is an unusual postoperative phenomenon. Many mechanisms have been suggested, with the most likely explanation related to latent virus reactivation due to a proinflammatory response in the setting of local trauma. Here, we present a case of herpes simplex virus reactivation in an immunocompetent female following a conventional right lower extremity stab phlebectomy. Salient clinical and physical examination findings are described, and management strategies for herpes simplex virus reactivation are outlined. This is the first known case report of herpes simplex virus reactivation following lower extremity phlebectomy.
Gaby, Alan R
Herpes simplex is a common viral infection of the skin or mucous membranes. The lesions caused by this infection are often painful, burning, or pruritic, and tend to recur in most patients. Short-term treatment with acyclovir can accelerate the healing of an acute outbreak, and continuous acyclovir therapy is often prescribed for people with frequent recurrences. While this drug can reduce the recurrence rate by 60-90 percent, it can also cause a wide array of side effects, including renal failure, hepatitis, and anaphylaxis. Safe and effective alternatives are therefore needed. There is evidence that certain dietary modifications and natural substances may be useful for treating active Herpes simplex lesions or preventing recurrences. Treatments discussed include lysine, vitamin C, zinc, vitamin E, adenosine monophosphate, and lemon balm (Melissa officinalis).
Handsfield, H H; Stone, K M; Wasserheit, J N
Few meeting participants envisioned a prevention and control program on the scale or scope of CDC's programs to prevent HIV infection, syphilis, gonorrhea, and chlamydial infection, but all agreed that the virtual absence of public health interventions to prevent genital herpes is no longer appropriate in light of evolving epidemiologic knowledge and other research advances. The ultimate scope of a national genital herpes prevention effort will depend in part on the results of the recommended research agenda, which probably will evolve over the better part of a decade. Numerous other STD prevention partners will also need to contribute to this effort and help to determine the makeup of future programs. Substantial new fiscal resources will be required both to implement the proposed research agenda and, depending on the results, to undertake the prevention efforts indicated by those studies. Competing STD prevention priorities and other national health needs will influence the availability of those resources. The consultants' meeting and the research and program activities summarized above are described in more detail in the full meeting report, which is posted on the Division's web site (www.cdc.gov/nchstp/dstd/dstdp.html) or may be requested directly from the Division. DSTDP is interested in receiving comments and suggestions about herpes prevention.
Park, Geon-Tae; Choi, Kyung-Chul
The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field.
Dey, Mahua; Auffinger, Brenda; Lesniak, Maciej S; Ahmed, Atique U
Initial observations from as early as the mid-1800s suggested that patients suffering from hematological malignancies would transiently go into remission upon naturally contracting viral infections laid the foundation for the oncolytic virotherapy research field. Since then, research focusing on anticancer oncolytic virotherapy has rapidly evolved. Today, oncolytic viral vectors have been engineered to stimulate and manipulate the host immune system, selectively targeting tumor tissues while sparing non-neoplastic cells. Glioblastoma multiforme, the most common adult primary brain tumor, has a disasterous history. It is one of the most deadly cancers known to humankind. Over the last century our understanding of this disease has grown exponentially. However, the median survival of patients suffering from this disease has only been extended by a few months. Even with the best, most aggressive modern therapeutic approaches available, malignant gliomas are still virtually 100% fatal. Motivated by the desperate need to find effective treatment strategies, more investments have been applied to oncolytic virotherapy preclinical and clinical studies. In this review we will discuss the antiglioma oncolytic virotherapy research field. We will survey its history and the principles laid down to serve as basis for preclinical works. We will also debate the variety of viral vectors used, their clinical applications, the lessons learned from clinical trials and possible future directions.
Tresilwised, Nittaya; Pithayanukul, Pimolpan; Holm, Per Sonne; Schillinger, Ulrike; Plank, Christian; Mykhaylyk, Olga
Limitations to adenovirus infectivity can be overcome by association with magnetic nanoparticles and enforced infection by magnetic field influence. Here we examined three core-shell-type iron oxide magnetic nanoparticles differing in their surface coatings, particle sizes and magnetic properties for their ability to enhance the oncolytic potency of adenovirus Ad520 and to stabilize it against the inhibitory effects of serum or a neutralizing antibody. It was found that the physicochemical properties of magnetic nanoparticles are critical determinants of the properties which govern the oncolytic productivities of their complexes with Ad520. Although high serum concentration during infection or a neutralizing antibody had strong inhibitory influence on the uptake or oncolytic productivity of the naked virus, one particle type was identified which conferred high protection against both inhibitory factors while enhancing the oncolytic productivity of the internalized virus. This particle type equipped with a silica coating and adsorbed polyethylenimine, displaying a high magnetic moment and high saturation magnetization, mediated a 50% reduction of tumor growth rate versus control upon intratumoral injection of its complex with Ad520 and magnetic field influence, whereas Ad520 alone was inefficient. The correlations between physical properties of the magnetic particles or virus complexes and oncolytic potency are described herein.
Kukla, Urszula; Chronowska, Justyna; Łabuzek, Krzysztof; Okopień, Bogusław
Despite the unceasing progression in chemotherapy, radiotherapy and surgery, neoplasms are still the second, after cardiovascular diseases, cause of death in the world. The creation of oncolytic viruses gives hope for increase of anticancer therapy effectiveness. Oncolytic viruses are the type of viruses that selectively infect and cause the lyse of tumor cells excluding normal cells. This mechanism allows to avoid the consequences of the possible replication of the virus, which having entered to the organism, replicates in organism's cells by using the DNA of host cells. The development of genetic engineering and molecular biology has enabled the creation of this kind of genetically modified viruses, which deprive them of their virulence. Currently, there are many clinical trials in progress including the use of oncolytic viruses in head and neck squamous cell carcinoma, thyroid cancer, colorectal cancer, liver cancer, melanoma and glioblastoma multiforme treatment. There are parallel studies in animals using the subsequent viruses. Oncolytic viruses treatment is generally well tolerated, without significant side effects. It is worth to point out that this method combined with chemotherapy and radiotherapy allows to reduce the use of therapeutic doses, which significantly reduces the toxicity of conventional treatment. Further clinical studies evaluating the efficacy and safety of oncolytic viruses will develop more effective and better tolerated therapeutic protocols in the future.
Park, Geon-Tae; Choi, Kyung-Chul
The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field. PMID:27494901
Nande, Rounak; Howard, Candace M; Claudio, Pier Paolo
The field of ultrasound (US) has changed significantly from medical imaging and diagnosis to treatment strategies. US contrast agents or microbubbles (MB) are currently being used as potential carriers for chemodrugs, small molecules, nucleic acids, small interfering ribonucleic acid, proteins, adenoviruses, and oncolytic viruses. Oncolytic viruses can selectively replicate within and destroy a cancer cell, thus making them a powerful therapeutic in treating late-stage or metastatic cancer. These viruses have been shown to have robust activity in clinical trials when injected directly into tumor nodules. However limitations in oncolytic virus’ effectiveness and its delivery approach have warranted exploration of ultrasound-mediated delivery. Gene therapy bearing adenoviruses or oncolytic viruses can be coupled with MBs and injected intravenously. Following application of US energy to the target region, the MBs cavitate, and the resulting shock wave enhances drug, gene, or adenovirus uptake. Though the underlying mechanism is yet to be fully understood, there is evidence to suggest that mechanical pore formation of cellular membranes allows for the temporary uptake of drugs. This delivery method circumvents the limitations due to stimulation of the immune system that prevented intravenous administration of viruses. This review provides insight into this intriguing new frontier on the delivery of oncolytic viruses to tumor sites. PMID:27512682
Cummings, Anne L.
Explores potential benefits of incorporating concepts and interventions from experimental therapy to help clients with psychosocial difficulties in learning to live with genital herpes. Recommends experimental counseling of two-chair dialog, empty chair, and metaphor for helping clients with emotional sequelae of genital herpes. Presents case…
Drob, Sanford; Bernard, Harold S.
Explores how dyadic relationships can be affected when one partner suffers from genital herpes. Six patterns are described: When One Partner Does Not Know, The Compromise Relationship, The Enraged Partner, The Mark of Guilt, Problems in Risk Management, and Herpes Used as Weapon. Treatment strategies for dealing with patterns are offered.…
Ghaziuddin, Mohammad; And Others
This paper presents two case studies of children who developed herpes virus infection in the intrauterine or early postnatal period and presented with features of autism around two years of age. Other research suggesting a link between herpes and autism is reviewed. (DB)
Longo, David J.; And Others
Assigned 21 individuals with recurrent genital herpes to psychosocial intervention, social support, or waiting-list control conditions. Those receiving psychosocial intervention (herpes simplex virus information, relaxation training, stress management instructions, and an imagery technique) reported significantly greater reductions in herpes…
Garrubba, Carl; Donkers, Kelly
Varicella zoster virus (VZV) causes chickenpox and herpes zoster. Herpes zoster is a common infection in older adults and can lead to potentially debilitating postherpetic neuralgia. This article reviews the diagnosis and management of herpes zoster, including strategies to reduce disease frequency and severity with the herpes zoster vaccine.
... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Herpes simplex virus serological assays. 866.3305... simplex virus serological assays. (a) Identification. Herpes simplex virus serological assays are devices... herpes simplex virus in serum. Additionally, some of the assays consist of herpes simplex virus...
Rupp, Richard; Rosenthal, Susan L; Stanberry, Lawrence R
This review explores the development of prophylactic genital herpes vaccines and their potential impact on perinatal and oral-facial disease. Vaccine strategies have included the use of whole killed virus, viral subunits, attenuated live virus, viral vectors, and bare DNA. To date, the recombinant subunit vaccine, truncated HSV-2 gD and alum/MPL, has been the most efficacious. The vaccine is 73 to 74 percent effective in preventing genital disease in herpes simplex virus seronegative women but is not effective in men or seropositive women. Models predict a significant impact on genital herpes if it limits viral shedding. Reductions in perinatal and oral-facial disease are likely to occur as well. Once an efficacious herpes vaccine is available, its effectiveness will depend ultimately on vaccine acceptance by professional organizations, healthcare professionals, and parents. Further research is required to improve on and fully understand the implications of prophylactic herpes simplex vaccines.
MacNeill, Amy L
Over 6 million dogs are diagnosed with cancer in the USA each year. Treatment options for many of these patients are limited. It is important that the veterinary and scientific communities begin to explore novel treatment protocols for dogs with cancer. Oncolytic viral therapy is a promising treatment option that may prove to be relatively inexpensive and effective against several types of cancer. The efficacy of oncolytic virus therapies has been clearly demonstrated in murine cancer models, but the positive outcomes observed in mice are not always seen in human cancer patients. These therapies should be thoroughly evaluated in dogs with spontaneously arising cancers to provide needed information about the potential effectiveness of virus treatment for human cancers and to promote the health of our companion animals. This article provides a review of the results of oncolytic virus treatment of canine cancers.
Belcaid, Zineb; Lamfers, Martine L M; van Beusechem, Victor W; Hoeben, Rob C
Viruses have two opposing faces. On the one hand, they can cause harm and disease. A virus may manifest directly as a contagious disease with a clinical pathology of varying significance. A viral infection can also have delayed consequences, and in rare cases may cause cellular transformation and cancer. On the other hand, viruses may provide hope: hope for an efficacious treatment of serious disease. Examples of the latter are the use of viruses as a vaccine, as transfer vector for therapeutic genes in a gene therapy setting, or, more directly, as therapeutic anticancer agent in an oncolytic-virus therapy setting. Already there is evidence for antitumor activity of oncolytic viruses. The antitumor efficacy seems linked to their capacity to induce a tumor-directed immune response. Here, we will provide an overview on the development of oncolytic viruses and their clinical evaluation from the Dutch perspective.
Jia, Chen; Chen, Ying
Tumors are a serious threat to human health. The oncolytic virus is a kind of tumor killer virus which can infect and lyse cancer cells and spread through the tumor, while leaving normal cells largely unharmed. Mathematical models can help us to understand the tumor-virus dynamics and find better treatment strategies. This paper gives a new mathematical model of tumor therapy with oncolytic virus and MEK inhibitor. Stable analysis was given. Because mitogen-activated protein kinase (MEK) can not only lead to greater oncolytic virus infection into cancer cells, but also limit the replication of the virus, in order to provide the best dosage of MEK inhibitors and balance the positive and negative effect of the inhibitors, we put forward an optimal control problem of the inhibitor. The optimal strategies are given by theory and simulation. PMID:28097139
Dhar, Debanjan; Toth, Karoly; Wold, William S M
Oncolytic (replicating) adenovirus (Ad) vectors are emerging as a promising form of a cancer therapy agent. There has been a need for an appropriate animal model to study oncolytic Ad since human Ad -replication is usually species specific. We have shown that Syrian (golden) hamsters are an appropriate animal model to study human Ad5-based vectors. Syrian hamsters are immunocompetent, and they allow human Ad5 replication in normal tissues as well as in Syrian hamster cancer cells. The development of the Syrian hamster as a model to study oncolytic Ad vectors has opened avenues to explore the role of host immune response and preexisting immunity in Ad vector efficacy and toxicity/biodistribution following Ad vector administration. Since most of the normal tissues in the Syrian hamster are permissive for human Ad5 replication, Ad vectors can be studied in the context of orthotopic cancer model developed in Syrian hamsters.
Huang, Fang; Wang, Bin-Rong; Wu, Ye-Qing; Wang, Fan-Chao; Zhang, Jian; Wang, Yi-Gang
Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged survival in patients with early cancer, yet tumor relapse and drug resistance still occurred, which is explained by the cancer stem cell (CSC) theory. Oncolytic virotherapy has attracted increasing interest in cancer because of its ability to infect and lyse CSCs. This paper reviews the basic knowledge, CSC markers and therapeutics of gastrointestinal cancer (liver, gastric, colon and pancreatic cancer), as well as research advances and possible molecular mechanisms of various oncolytic viruses against gastrointestinal CSCs. This paper also summarizes the existing obstacles to oncolytic virotherapy and proposes several alternative suggestions to overcome the therapeutic limitations. PMID:27672294
MacNeill, Amy L
Over 6 million dogs are diagnosed with cancer in the USA each year. Treatment options for many of these patients are limited. It is important that the veterinary and scientific communities begin to explore novel treatment protocols for dogs with cancer. Oncolytic viral therapy is a promising treatment option that may prove to be relatively inexpensive and effective against several types of cancer. The efficacy of oncolytic virus therapies has been clearly demonstrated in murine cancer models, but the positive outcomes observed in mice are not always seen in human cancer patients. These therapies should be thoroughly evaluated in dogs with spontaneously arising cancers to provide needed information about the potential effectiveness of virus treatment for human cancers and to promote the health of our companion animals. This article provides a review of the results of oncolytic virus treatment of canine cancers. PMID:27512674
Dong, Fengqin; Wang, Li; Davis, John J.; Hu, Wenxian; Zhang, Lidong; Guo, Wei; Teraishi, Fuminori; Ji, Lin; Fang, Bingliang
Purpose The tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) and oncolytic viruses have recently been investigated extensively for cancer therapy. However, preclinical and clinical studies have revealed that their clinical application is hampered by either weak anticancer activity or systemic toxicity. We examined whether the weaknesses of the two strategies can be overcome by integrating the TRAIL gene into an oncolytic vector. Experimental Design We constructed a TRAIL-expressing oncolytic adenovector designated Ad/TRAIL-E1. The expression of both the TRAIL and viral E1A genes is under the control of a synthetic promoter consisting of sequences from the human telomerase reverse transcriptase promoter and a minimal cytomegalovirus early promoter. The transgene expression, apoptosis induction, viral replication, antitumor activity and toxicity of Ad/TRAIL-E1 were determined in vitro and in vivo in comparison with control vectors. Results Ad/TRAIL-E1 elicited enhanced viral replication and/or stronger oncolytic effect in vitro in various human cancer cell lines than a TRAIL-expressing replication-defective adenovector or an oncolytic adenovector expressing green fluorescent protein. Intralesional administration of Ad/TRAIL-E1 eliminated all subcutaneous xenograft tumors established from a human non-small cell lung cancer cell line, H1299, on nu/nu nude mice, resulting in long-term tumor-free survival. Furthermore, we found no treatment-related toxicity. Conclusions Viral replication and antitumor activity of oncolytic adenovirus can be enhanced by the TRAIL gene and Ad/TRAIL-E1 could become a potent therapeutic agent for cancer therapy. PMID:16951242
Turnbull, Samantha; West, Emma J; Scott, Karen J; Appleton, Elizabeth; Melcher, Alan; Ralph, Christy
The last few years have seen an increased interest in immunotherapy in the treatment of malignant disease. In particular, there has been significant enthusiasm for oncolytic virotherapy, with a large amount of pre-clinical data showing promise in animal models in a wide range of tumour types. How do we move forward into the clinical setting and translate something which has such potential into meaningful clinical outcomes? Here, we review how the field of oncolytic virotherapy has developed thus far and what the future may hold.
Spencer, Drew A; Young, Jacob S; Kanojia, Deepak; Kim, Julius W; Polster, Sean P; Murphy, Jason P; Lesniak, Maciej S
Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.
Malhotra, Akshiv; Sendilnathan, Arun; Old, Matthew O; Wise-Draper, Trisha M
Head and neck cancer (HNC) is the sixth most common malignancy worldwide. Despite recent advancements in surgical, chemotherapy, and radiation treatments, HNC remains a highly morbid and fatal disease. Unlike many other cancers, local control rather than systemic control is important for HNC survival. Therefore, novel local therapy in addition to systemic therapy is urgently needed. Oncolytic virotherapy holds promise in this regard as viruses can be injected intratumorally as well as intravenously with excellent safety profiles. This review will discuss the recent advancements in oncolytic virotherapy, highlighting some of the most promising candidates and modifications to date.
Malhotra, Akshiv; Sendilnathan, Arun; Old, Matthew O; Wise-Draper, Trisha M
Head and neck cancer (HNC) is the sixth most common malignancy worldwide. Despite recent advancements in surgical, chemotherapy, and radiation treatments, HNC remains a highly morbid and fatal disease. Unlike many other cancers, local control rather than systemic control is important for HNC survival. Therefore, novel local therapy in addition to systemic therapy is urgently needed. Oncolytic virotherapy holds promise in this regard as viruses can be injected intratumorally as well as intravenously with excellent safety profiles. This review will discuss the recent advancements in oncolytic virotherapy, highlighting some of the most promising candidates and modifications to date. PMID:27512673
Turnbull, Samantha; West, Emma J.; Scott, Karen J.; Appleton, Elizabeth; Melcher, Alan; Ralph, Christy
The last few years have seen an increased interest in immunotherapy in the treatment of malignant disease. In particular, there has been significant enthusiasm for oncolytic virotherapy, with a large amount of pre-clinical data showing promise in animal models in a wide range of tumour types. How do we move forward into the clinical setting and translate something which has such potential into meaningful clinical outcomes? Here, we review how the field of oncolytic virotherapy has developed thus far and what the future may hold. PMID:26633468
Rintoul, Julia L; Lemay, Chantal G; Tai, Lee-Hwa; Stanford, Marianne M; Falls, Theresa J; de Souza, Christiano T; Bridle, Byram W; Daneshmand, Manijeh; Ohashi, Pamela S; Wan, Yonghong; Lichty, Brian D; Mercer, Andrew A; Auer, Rebecca C; Atkins, Harold L; Bell, John C
Replicating viruses for the treatment of cancer have a number of advantages over traditional therapeutic modalities. They are highly targeted, self-amplifying, and have the added potential to act as both gene-therapy delivery vehicles and oncolytic agents. Parapoxvirus ovis or Orf virus (ORFV) is the prototypic species of the Parapoxvirus genus, causing a benign disease in its natural ungulate host. ORFV possesses a number of unique properties that make it an ideal viral backbone for the development of a cancer therapeutic: it is safe in humans, has the ability to cause repeat infections even in the presence of antibody, and it induces a potent Th-1-dominated immune response. Here, we show that live replicating ORFV induces an antitumor immune response in multiple syngeneic mouse models of cancer that is mediated largely by the potent activation of both cytokine-secreting, and tumoricidal natural killer (NK) cells. We have also highlighted the clinical potential of the virus by demonstration of human cancer cell oncolysis including efficacy in an A549 xenograft model of cancer. PMID:22273579
Suryawanshi, Yogesh R; Zhang, Tiantian; Essani, Karim
Breast cancer (BC) is the most common type of cancer among women and is the second most common cause of cancer-related deaths, following lung cancer. Severe toxicity associated with a long-term use of BC chemo- and radiotherapy makes it essential to look for newer therapeutics. Additionally, molecular heterogeneity at both intratumoral and intertumoral levels among BC subtypes is known to result in a differential response to standard therapeutics. Oncolytic viruses (OVs) have emerged as one of the most promising treatment options for BC. Many preclinical and clinical studies have shown that OVs are effective in treating BC, both as a single therapeutic agent and as a part of combination therapies. Combination therapies involving multimodal therapeutics including OVs are becoming popular as they allow to achieve the synergistic therapeutic effects, while minimizing the associated toxicities. Here, we review the OVs for BC therapy in preclinical studies and in clinical trials, both as a monotherapy and as part of a combination therapy. We also briefly discuss the potential therapeutic targets for BC, as these are likely to be critical for the development of new OVs.
Marchini, Antonio; Bonifati, Serena; Scott, Eleanor M; Angelova, Assia L; Rommelaere, Jean
Accumulated evidence gathered over recent decades demonstrated that some members of the Parvoviridae family, in particular the rodent protoparvoviruses H-1PV, the minute virus of mice and LuIII have natural anticancer activity while being nonpathogenic to humans. These studies have laid the foundations for the launch of a first phase I/IIa clinical trial, in which the rat H-1 parvovirus is presently undergoing evaluation for its safety and first signs of efficacy in patients with glioblastoma multiforme. After a brief overview of the biology of parvoviruses, this review focuses on the studies which unraveled the antineoplastic properties of these agents and supported their clinical use as anticancer therapeutics. Furthermore, the development of novel parvovirus-based anticancer strategies with enhanced specificity and efficacy is discussed, in particular the development of second and third generation vectors and the combination of parvoviruses with other anticancer agents. Lastly, we address the key challenges that remain towards a more rational and efficient use of oncolytic parvoviruses in clinical settings, and discuss how a better understanding of the virus life-cycle and of the cellular factors involved in virus infection, replication and cytotoxicity may promote the further development of parvovirus-based anticancer therapies, open new prospects for treatment and hopefully improve clinical outcome.
Wojton, Jeffrey; Kaur, Balveen
Interactions between tumor cells and their microenvironment have been shown to play a very significant role in the initiation, progression, and invasiveness of cancer. These tumor-stromal interactions are capable of altering the delivery and effectiveness of therapeutics into the tumor and are also known to influence future resistance and re-growth after treatment. Here we review recent advances in the understanding of the tumor microenvironment and its response to oncolytic viral therapy. The multifaceted environmental response to viral therapy can influence viral infection, replication, and propagation within the tumor. Recent studies have unveiled the complicated temporal changes in the tumor vasculature post OV treatment, and their impact on tumor biology. Similarly, the secreted extracellular matrix in solid tumors can affect both infection and spread of the therapeutic virus. Together, these complex changes in the tumor microenvironment also modulate the activation of the innate antiviral host immune response, leading to quick and efficient viral clearance. In order to combat these detrimental responses, viruses have been combined with pharmacological adjuvants and “armed” with therapeutic genes in order to suppress the pernicious environmental conditions following therapy. In this review we will discuss the impact of the tumor environment on viral therapy and examine some of the recent literature investigating methods of modulating this environment to enhance oncolysis. PMID:20399700
Rubin, David; Fusfeld, Robert D.
Herpes zoster may, in some instances, cause motor paralysis as well as the usual sensory and cutaneous manifestations. It is suggested that the presence of electromyographic denervation potentials be used as the criterion of muscle paresis in order to avoid mistaking atrophy of disuse for true lower motor neuron disease. Use of the proper physical therapy procedures hastens the recovery of function and may serve to retard denervation atrophy and fibrosis in patients with muscle paralysis. ImagesFigure 1 (Case 1).Figure 1 (Case 1). PMID:5828175
Toussaint, Arnaud; Simonson, Colin; Valla, Christian
Herpetic lesions most frequently occur on oral and genital areas. However, herpes simplex virus (HSV) can be a rare cause of breast infection. In few published articles, the route of transmission is predominantly from infant to mother. We report two cases about simultaneous mammary and extramammary (oral and genital) herpetic infection in nonlactating women. In both cases, HSV breast lesions were acquired by sexual contacts with partners who were asymptomatic HSV carriers. Through a review of literature, we highlight clinical signs for an early diagnosis. We also emphasize the advantage of the valacyclovir for treating this uncommon pathology.
James, Scott H; Kimberlin, David W
Herpes simplex virus (HSV) 1 and HSV-2 infections are highly prevalent worldwide and are characterized by establishing lifelong infection with periods of latency interspersed with periodic episodes of reactivation. Acquisition of HSV by an infant during the peripartum or postpartum period results in neonatal HSV disease, a rare but significant infection that can be associated with severe morbidity and mortality, especially if there is dissemination or central nervous system involvement. Diagnostic and therapeutic advances have led to improvements in mortality and, to a lesser extent, neurodevelopmental outcomes, but room exists for further improvement.
Guerra, B; Puccetti, C; Cervi, F
Genital herpes is a common sexually transmitted infection. In reproductive age it involves the additional risk of vertical transmission to the neonate. Rates of transmission are affected by the viral type and whether the infection around delivery is primary or recurrent. Neonatal herpes is a rare but very severe complication of genital herpes infection and is caused by contact with infected genital secretions at the time of labor. Maternal acquisition of herpes simplex virus (HSV) in the third trimester of pregnancy carries the highest risk of neonatal transmission. Prevention of neonatal herpes depends on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. Uninfected woman should be counselled about the need of avoiding sexual contact during the third trimester. Elective caesarean section before the onset of labor is the choice mode of delivery for women with genital lesions or with prodromal symptoms near the term, even if it offers only a partial protection against neonatal infection. Antiviral suppressive therapy is used from 36 weeks of gestation until delivery in pregnant women with recurrences to prevent genital lesions at the time of labor so reducing the need of caesarean sections. Currently, routine maternal serologic screening is not yet recommended. Because most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes, researchers should focus on the recognition of asymptomatic primary genital HSV infections.
Ungerechts, Guy; Bossow, Sascha; Leuchs, Barbara; Holm, Per S; Rommelaere, Jean; Coffey, Matt; Coffin, Rob; Bell, John; Nettelbeck, Dirk M
Oncolytic viruses (OVs) are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention.
Ungerechts, Guy; Bossow, Sascha; Leuchs, Barbara; Holm, Per S; Rommelaere, Jean; Coffey, Matt; Coffin, Rob; Bell, John; Nettelbeck, Dirk M
Oncolytic viruses (OVs) are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention. PMID:27088104
Lim, Filip; Khalique, Hena; Ventosa, Maria; Baldo, Aline
The majority of humans have been infected with Herpes Simplex Virus Type 1 (HSV-1) and harbor its viral DNA in the latent form within neurons for lifetime. This, combined with the absence of serious adverse effects due to HSV-1 derived vectors in clinical trials so far, highlight the potential to use this virus to develop neuronal gene transfer vectors which are transparent to the host, allowing the effects of the transgene to act without interference from the transfer system eg., for functional genomics in basic neuroscience or gene therapy of neurological disorders. On the other hand, other HSV-1 derived vectors which also have a promising perspective in the clinic, are designed to have enhanced cytotoxicity in certain cell types, as in the case of oncolytic vectors. Understanding virus-host interactions is fundamental not only to the success of these gene therapy vectors but also with respect to identifying and minimizing biohazards associated with their use. In this review we discuss characteristics of HSV-1 and gene therapy vectors derived from this virus which are useful to consider in the context of biosafety risk assessment and risk management.
Thomas, Maria A; Spencer, Jacqueline F; Toth, Karoly; Sagartz, John E; Phillips, Nancy J; Wold, William SM
We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth. PMID:18665155
Thomas, Maria A; Spencer, Jacqueline F; Toth, Karoly; Sagartz, John E; Phillips, Nancy J; Wold, William S M
We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth.
Wei, Ding; Sun, Na; Nan, Gang; Wang, Yuan; Liu, Hong-Qi; Peeters, Ben; Chen, Zhi-Nan; Bian, Huijie
Newcastle disease virus (NDV) is a naturally oncolytic virus that has been shown to be safe and effective for cancer therapy. Tumor virotherapy using NDV emerged in the 1950s and has advanced more recently by the increased availability of reverse genetics technology. In this study, we constructed a reverse genetics system based on the virulent and oncolytic NDV Italien strain, and generated two recombinant NDVs carrying a gene encoding either enhanced green fluorescent protein or firefly luciferase. We evaluated the replication and antitumor characteristics of these viruses in vitro and in vivo. Our data showed that the insertion of exogenous reporter genes did not affect NDV replication and sensitivity to type I interferon. The recombinant NDVs kept the property of tumor-selective replication both in vitro and in vivo and strongly induced syncytium formation leading to cell death. Moreover, the recombinant NDVs significantly prolonged the survival of tumor-bearing athymic mice (p=0.017) and suppressed the loss of body weight after intratumoral injection. Taken together, our study provides a novel platform to develop recombinant oncolytic viruses based on the NDV Italien strain and shows the efficiency of recombinant NDV Italien for oncolytic virotherapy of tumors.
Ulasov, Ilya V.; Shah, Nameeta; Kaverina, Natalya V.; Lee, Hwahyang; Lin, Biaoyang; Lieber, Andre; Kadagidze, Zaira G.; Yoon, Jae-Guen; Schroeder, Brett; Hothi, Parvinder; Ghosh, Dhimankrishna; Baryshnikov, Anatoly Y.; Cobbs, Charles S.
Oncolytic gene therapy using viral vectors may provide an attractive therapeutic option for malignant gliomas. These viral vectors are designed in a way to selectively target tumor cells and spare healthy cells. To determine the translational impact, it is imperative to assess the factors that interfere with the anti-glioma effects of the oncolytic adenoviral vectors. In the current study, we evaluated the efficacy of survivin-driven oncolytic adenoviruses pseudotyping with adenoviral fiber knob belonging to the adenoviral serotype 3, 11 and 35 in their ability to kill glioblastoma (GBM) cells selectively without affecting normal cells. Our results indicate that all recombinant vectors used in the study can effectively target GBM in vitro with high specificity, especially the 3 knob-modified vector. Using intracranial U87 and U251 GBM xenograft models we have also demonstrated that treatment with Conditionally Replicative Adenovirus (CRAd-S-5/3) vectors can effectively regress tumor. However, in several patient-derived GBM cell lines, cells exhibited resistance to the CRAd infection as evident from the diminishing effects of autophagy. To improve therapeutic response, tumor cells were pretreated with tamoxifen. Our preliminary data suggest that tamoxifen sensitizes glioblastoma cells towards oncolytic treatment with CRAd-S-5/3, which may prove useful for GBM in future experimental therapy. PMID:25738357
Price, Daniel L.; Li, Pingdong; Chen, Chun-Hao; Wong, Danni; Yu, Zhenkun; Chen, Nanhai G.; Yu, Yong A.; Szalay, Aladar A.; Cappello, Joseph; Fong, Yuman; Wong, Richard J.
Background Oncolytic viral efficacy may be limited by the penetration of the virus into tumors. This may be enhanced by intraoperative application of virus immediately after surgical resection. Methods Oncolytic vaccinia virus GLV-1h68 was delivered in silk-elastin-like protein polymer (SELP) in vitro and in vivo in anaplastic thyroid carcinoma cell line 8505c in nude mice. Results GLV-1h68 in SELP infected and lysed anaplastic thyroid cancer cells in vitro equally as effectively as in phosphate-buffered saline (PBS), and at 1 week retains a thousand fold greater infectious plaque-forming units. In surgical resection models of residual tumor, GLV-1h68 in SELP improves tumor control and shows increased viral β-galactosidase expression as compared to PBS. Conclusion The use of SELP matrix for intraoperative oncolytic viral delivery protects infectious viral particles from degradation, facilitates sustained viral delivery and transgene expression, and improves tumor control. Such optimization of methods of oncolytic viral delivery may enhance therapeutic outcomes. PMID:25244076
Rahman, Masmudur M; Madlambayan, Gerard J; Cogle, Christopher R; McFadden, Grant
High-dose chemotherapy and radiation followed by autologous blood and marrow transplantation (ABMT) has been used for the treatment of certain cancers that are refractory to standard therapeutic regimes. However, a major challenge with ABMT for patients with hematologic malignancies is disease relapse, mainly due to either contamination with cancerous hematopoietic stem and progenitor cells (HSPCs) within the autograft or the persistence of residual therapy-resistant disease niches within the patient. Oncolytic viruses represent a promising therapeutic approach to prevent cancer relapse by eliminating tumor-initiating cells that contaminate the autograft. Here we summarize an ex vivo "purging" strategy with oncolytic Myxoma virus (MYXV) to remove cancer-initiating cells from patient autografts prior to transplantation. MYXV, a novel oncolytic poxvirus with potent anti-cancer properties in a variety of in vivo tumor models, can specifically eliminate cancerous stem and progenitor cells from samples obtained from acute myelogenous leukemia (AML) patients, while sparing normal CD34+ hematopoietic stem and progenitor cells capable of rescuing hematopoiesis following high dose conditioning. We propose that a broader subset of patients with intractable hematologic malignancies who have failed standard therapy could become eligible for ABMT when the treatment schema is coupled with ex vivo oncolytic therapy.
Liu, Jia; Wennier, Sonia; McFadden, Grant
Myxoma virus (MYXV) is a poxvirus with a strict rabbit-specific host-tropism for pathogenesis. The immunoregulatory factors encoded by MYXV can suppress some functions of immune effectors from other species. We review their mechanisms of action, implications in therapeutics and the potential to improve MYXV as an oncolytic agent in humans.
Tong, Jessica G; Valdes, Yudith Ramos; Barrett, John W; Bell, John C; Stojdl, David; McFadden, Grant; McCart, J Andrea; DiMattia, Gabriel E; Shepherd, Trevor G
Epithelial ovarian cancer is unique among most carcinomas in that metastasis occurs by direct dissemination of malignant cells traversing throughout the intraperitoneal fluid. Accordingly, we test new therapeutic strategies using an in vitro three-dimensional spheroid suspension culture model that mimics key steps of this metastatic process. In the present study, we sought to uncover the differential oncolytic efficacy among three different viruses—Myxoma virus, double-deleted vaccinia virus, and Maraba virus—using three ovarian cancer cell lines in our metastasis model system. Herein, we demonstrate that Maraba virus effectively infects, replicates, and kills epithelial ovarian cancer (EOC) cells in proliferating adherent cells and with slightly slower kinetics in tumor spheroids. Myxoma virus and vaccinia viruses infect and kill adherent cells to a much lesser extent than Maraba virus, and their oncolytic potential is almost completely attenuated in spheroids. Myxoma virus and vaccinia are able to infect and spread throughout spheroids, but are blocked in the final stages of the lytic cycle, and oncolytic-mediated cell killing is reactivated upon spheroid reattachment. Alternatively, Maraba virus has a remarkably reduced ability to initially enter spheroid cells, yet rapidly infects and spreads throughout spheroids generating significant cell killing effects. We show that low-density lipoprotein receptor expression in ovarian cancer spheroids is reduced and this controls efficient Maraba virus binding and entry into infected cells. Taken together, these results are the first to implicate the potential impact of differential viral oncolytic properties at key steps of ovarian cancer metastasis. PMID:27119108
Rahman, Masmudur M.; Madlambayan, Gerard J.; Cogle, Christopher R.; McFadden, Grant
High-dose chemotherapy and radiation followed by autologous blood and marrow transplantation (ABMT) has been extensively used for the treatment of certain cancers that are refractory to standard therapeutic regimes. However, a major challenge with ABMT for patients with hematologic malignancies is disease relapse, mainly due to either contamination with cancerous hematopoietic stem and progenitor cells (HSPCs) within the autograft or the persistence of residual therapy-resistant disease niches within the patient. Oncolytic viruses represent a promising therapeutic approach to prevent cancer relapse by eliminating tumor-initiating cells that contaminate the autograft. Here we summarize an ex vivo “purging” strategy with oncolytic myxoma virus (MYXV) to remove cancer-initiating cells from patient autografts prior to transplantation. MYXV, a novel oncolytic poxvirus with potent anti-cancer properties in a variety of in vivo tumor models, can specifically eliminate cancerous stem and progenitor cells from samples obtained from acute myelogenous leukemia (AML) patients, while sparing normal CD34+ hematopoietic stem and progenitor cells capable of rescuing hematopoiesis following high dose conditioning. We propose that a broader subset of patients with intractable hematologic malignancies who have failed standard therapy could become eligible for ABMT when the treatment schema is coupled with ex vivo oncolytic therapy. PMID:20211576
Taipale, Kristian; Liikanen, Ilkka; Juhila, Juuso; Turkki, Riku; Tähtinen, Siri; Kankainen, Matti; Vassilev, Lotta; Ristimäki, Ari; Koski, Anniina; Kanerva, Anna; Diaconu, Iulia; Cerullo, Vincenzo; Vähä-Koskela, Markus; Oksanen, Minna; Linder, Nina; Joensuu, Timo; Lundin, Johan; Hemminki, Akseli
Despite many clinical trials conducted with oncolytic viruses, the exact tumor-level mechanisms affecting therapeutic efficacy have not been established. Currently there are no biomarkers available that would predict the clinical outcome to any oncolytic virus. To assess the baseline immunological phenotype and find potential prognostic biomarkers, we monitored mRNA expression levels in 31 tumor biopsy or fluid samples from 27 patients treated with oncolytic adenovirus. Additionally, protein expression was studied from 19 biopsies using immunohistochemical staining. We found highly significant changes in several signaling pathways and genes associated with immune responses, such as B-cell receptor signaling (P < 0.001), granulocyte macrophage colony-stimulating factor (GM-CSF) signaling (P < 0.001), and leukocyte extravasation signaling (P < 0.001), in patients surviving a shorter time than their controls. In immunohistochemical analysis, markers CD4 and CD163 were significantly elevated (P = 0.020 and P = 0.016 respectively), in patients with shorter than expected survival. Interestingly, T-cell exhaustion marker TIM-3 was also found to be significantly upregulated (P = 0.006) in patients with poor prognosis. Collectively, these data suggest that activation of several functions of the innate immunity before treatment is associated with inferior survival in patients treated with oncolytic adenovirus. Conversely, lack of chronic innate inflammation at baseline may predict improved treatment outcome, as suggested by good overall prognosis.
Miller, Amber; Nace, Rebecca; Ayala-Breton C, Camilo; Steele, Michael; Bailey, Kent; Peng, Kah Whye; Russell, Stephen J
Antitumor efficacy of oncolytic virotherapy is determined by the density and distribution of infectious centers within the tumor, which may be heavily influenced by the permeability and blood flow in tumor microvessels. Here, we investigated whether systemic perfusion pressure, a key driver of tumor blood flow, could influence the intratumoral extravasation of systemically administered oncolytic vesicular stomatitis virus (VSV) in myeloma tumor-bearing mice. Exercise was used to increase mean arterial pressure, and general anesthesia to decrease it. A recombinant VSV expressing the sodium iodide symporter (NIS), which concentrates radiotracers at sites of infection, was administered intravenously to exercising or anesthetized mice, and nuclear NIS reporter gene imaging was used to noninvasively track the density and spatial distribution of intratumoral infectious centers. Anesthesia resulted in decreased intratumoral infection density, while exercise increased the density and uniformity of infectious centers. Perfusion state also had a significant impact on the antitumor efficacy of the VSV therapy. In conclusion, quantitative dynamic radiohistologic imaging was used to noninvasively interrogate delivery of oncolytic virotherapy, highlighting the critical importance of perfusion pressure as a driver of intratumoral delivery and efficacy of oncolytic viruses. PMID:26647825
Oncolytic viruses (OVs) comprise an emerging cancer therapeutic modality whose activity involves both direct tumor cell lysis and the induction of immunogenic cell death (ICD). Cellular proteins released from the OV-lysed tumor cells, known as damage-associated molecular patterns and tumor-associated antigens, activate dendritic cells and elicit adaptive antitumor immunity. Interaction with the innate immune system and the development of long-lasting immune memory also contribute to OV-induced cell death. The degree to which the ICD component contributes to the clinical efficacy of OV therapy is still unclear. Modulation of a range of immune interactions may be beneficial or detrimental in nature and the interactions depend on the specific tumor, the site and extent of the disease, the immunosuppressive tumor microenvironment, the OV platform, the dose, time, and delivery conditions, as well as individual patient responses. To enhance the contribution of ICD, OVs have been engineered to express immunostimulatory genes and strategies have been developed to combine OV therapy with chemo- and immune-based therapeutic regimens. However, these approaches carry the risk that they may also be tolerogenic depending on their levels and the presence of other cytokines, their direct antiviral effects, and the timing and conditions of their expression. The contribution of autophagy to adaptive immunity, the ability of the OVs to kill cancer stem cells, and the patient’s baseline immune status are additional considerations. This review focuses on the complex and as yet poorly understood balancing act that dictates the outcome of OV therapy. We summarize current understanding of the OVs’ function in eliciting antitumor immunity and its relationship to therapeutic efficacy. Also discussed are the criteria involved in restraining antiviral immune responses and minimizing pathology while promoting antitumor immunity to override immune tolerance. PMID:27226725
Blondeau, Joseph M.; Embil, Juan A.
The authors provide a careful review of the characteristics of the herpes simplex virus and its various manifestations. They offer suggestions for its diagnosis and treatment, in various forms, and outline an approach to physician counselling of infected persons.
Herpes genitalis is caused by the herpes simplex virus type 1 or type 2 and can manifest as primary or recurrent infection. It is one of the most common sexually transmitted infections and due to associated physical and psychological morbidity it constitutes a considerable, often underestimated medical problem. In addition to providing the reader with basic knowledge of the pathogen and clinical presentation of herpes genitalis, this review article discusses important aspects of the laboratory diagnostics, antiviral therapy and prophylaxis. The article is aimed at all health-care workers managing patients with herpes genitalis and attempts to improve the often suboptimal counselling, targeted use of laboratory diagnostics, treatment and preventive measures provided to patients. PMID:28017972
Herpes genitalis is caused by the herpes simplex virus type 1 or type 2 and can manifest as primary or recurrent infection. It is one of the most common sexually transmitted infections and due to associated physical and psychological morbidity it constitutes a considerable, often underestimated medical problem. In addition to providing the reader with basic knowledge of the pathogen and clinical presentation of herpes genitalis, this review article discusses important aspects of the laboratory diagnostics, antiviral therapy and prophylaxis. The article is aimed at all health-care workers managing patients with herpes genitalis and attempts to improve the often suboptimal counselling, targeted use of laboratory diagnostics, treatment and preventive measures provided to patients.
Huber, Michaell A
Oral infection caused by the herpes simplex virus represents one of the more common conditions the dental practitioner will be called upon to manage. Unique in its ability to establish latency and undergo subsequent recurrence, it is an ubiquitous infectious agent for which a cure does not exist. For the immunocompetent patient, herpes virus simplex infection typically represents nothing more than a nuisance. However, for the immunocompromised patient, this infection is associated with increased morbidity and mortality. Recently introduced antiviral drug regimens may reduce the morbidity and potential mortality of the herpes simplex virus, especially in immunocompromised patients. The value of antiviral therapy in the management of recurrent herpes simplex virus infection in the immunocompetent patient remains an area of contentious debate.
Moon, Chang Yoon; Choi, Joung-Woo; Kasala, Dayananda; Jung, Soo-Jung; Kim, Sung Wan; Yun, Chae-Ok
Oncolytic adenoviruses (Ads) have shown great promise in cancer gene therapy but their efficacy has been compromised by potent immunological, biochemical, and specific tumor-targeting limitations. To take full advantage of the innate cancer-specific killing potency of oncolytic Ads but also exploit the subtleties of the tumor microenvironment, we have generated a pH-sensitive and bio-reducible polymer (PPCBA)-coated oncolytic Ad. Ad-PPCBA complexes showed higher cellular uptake at pH 6.0 than pH 7.4 in both high and low coxsackie and adenovirus receptor-(CAR)-expressing cells, thereby demonstrating Ad-PPCBA's ability to target the low pH hypoxic tumor microenvironment and overcome CAR dependence for target cell uptake. Endocytic mechanism studies indicated that Ad-PPCBA internalization is mediated by macropinocytosis instead of the CAR-dependent endocytic pathway that internalizes naked Ad. VEGF-specific shRNA-expressing oncolytic Ad complexed with PPCBA (RdB/shVEGF-PPCBA) elicited much more potent suppression of U87 human brain cancer cell VEGF gene expression in vitro, and human breast cancer MCF7 cell/Matrigel plug vascularization in a mouse model, when cancer cells had been previously infected at pH 6.0 versus pH 7.4. Moreover, intratumorally and intravenously injected RdB/shVEGF-PPCBA nanocomplexes elicited significantly higher therapeutic efficacy than naked virus in U87-tumor mouse xenograft models, reducing IL-6, ALT, and AST serum levels. These data demonstrated PPCBA's biocompatibility and capability to shield the Ad surface to prevent innate immune response against Ad after both intratumoral and systemic administration. Taken together, these results demonstrate that smart, tumor-specific, oncolytic Ad-PPCBA complexes can be exploited to treat both primary and metastatic tumors.
Fernández-Ulibarri, Inés; Hammer, Katharina; Arndt, Michaela A E; Kaufmann, Johanna K; Dorer, Dominik; Engelhardt, Sarah; Kontermann, Roland E; Hess, Jochen; Allgayer, Heike; Krauss, Jürgen; Nettelbeck, Dirk M
Antibody therapy of solid cancers is well established, but suffers from unsatisfactory tumor penetration of large immunoglobulins or from low serum retention of antibody fragments. Oncolytic viruses are in advanced clinical development showing excellent safety, but suboptimal potency due to limited virus spread within tumors. Here, by developing an immunoRNase-encoding oncolytic adenovirus, we combine viral oncolysis with intratumoral genetic delivery of a small antibody-fusion protein for targeted bystander killing of tumor cells (viro-antibody therapy). Specifically, we explore genetic delivery of a small immunoRNase consisting of an EGFR-binding scFv antibody fragment fused to the RNase Onconase (ONC(EGFR)) that induces tumor cell death by RNA degradation after cellular internalization. Onconase is a frog RNase that combines lack of immunogenicity and excellent safety in patients with high tumor killing potency due to its resistance to the human cytosolic RNase inhibitor. We show that ONC(EGFR) expression by oncolytic adenoviruses is feasible with an optimized, replication-dependent gene expression strategy. Virus-encoded ONC(EGFR) induces potent and EGFR-dependent bystander killing of tumor cells. Importantly, the ONC(EGFR)-encoding oncolytic adenovirus showed dramatically increased cytotoxicity specifically to EGFR-positive tumor cells in vitro and significantly enhanced therapeutic activity in a mouse xenograft tumor model. The latter demonstrates that ONC(EGFR) is expressed at levels sufficient to trigger tumor cell killing in vivo. The established ONC(EGFR)-encoding oncolytic adenovirus represents a novel agent for treatment of EGFR-positive tumors. This viro-antibody therapy platform can be further developed for targeted/personalized cancer therapy by exploiting antibody diversity to target further established or emerging tumor markers or combinations thereof.
Yeung-Yue, Kimberly A; Brentjens, Mathijs H; Lee, Patricia C; Tyring, Stephen K
Herpes simplex virus persists in a latent form for the life of its host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently no cure is available. Antiviral therapy is the main treatment modality, used either orally, intravenously, or topically to prohibit further replication of the virus and thereby minimize cellular destruction. However, immunologic advances in the treatment and prevention of herpes simplex infections are promising and continue to be studied.
Elish, Diana; Singh, Fiza; Weinberg, Jeffrey M
Herpes labialis, a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin, causes pain and discomfort for millions of adults each year. Over the past several years, the major focus of herpes research has been on the treatment of genital herpes. However, several studies have been conducted to evaluate the efficacy of therapies specifically for herpes labialis. Last year in Cutis, we reviewed oral and topical therapies for herpes labialis. In this final part of the series, we review experimental and natural treatments that are available for herpes labialis and its associated symptoms.
Tétrault, I.; Boivin, G.
OBJECTIVE: To provide an update on new diagnostic tests and antiviral strategies for managing genital herpes. QUALITY OF EVIDENCE: Treatment guidelines are based on randomized clinical trials and recommendations from the Expert Working Group on Canadian Guidelines for Sexually Transmitted Diseases. Recommendations concerning other aspects of managing genital herpes (e.g., indications for using type-specific serologic tests) are mainly based on expert opinion. MAIN MESSAGE: Genital herpes is one of the most common sexually transmitted diseases, affecting about 20% of sexually active people; up to 80% of cases are undiagnosed. Because of frequent atypical presentation and the emotional burden associated with genital herpes, clinical diagnosis should be confirmed by viral culture. Type-specific serologic assays are now available, but their use is often restricted to special situations and requires adequate counseling. New antivirals (valacyclovir and famciclovir) with improved pharmacokinetic profiles have now been approved for episodic treatment of recurrences and suppressive therapy. CONCLUSION: Wise use of new diagnostic assays for herpes simplex coupled with more convenient treatment regimens should provide better management of patients with genital herpes. Images Figure 1 PMID:10955181
... medlineplus.gov/news/fullstory_163137.html Genital Herpes Vaccine Shows Promise in Animal Trials Two-pronged approach ... THURSDAY, Jan. 19, 2017 (HealthDay News) -- A new vaccine for genital herpes could be nearing human clinical ...
Pica, Francesca; Volpi, Antonio
Between 20% and 40% of the population is estimated to suffer from episodes of recurrent herpes labialis, although few reports in the literature have addressed the public awareness of this infection in the general population. The aims of this study were to determine the existing level of awareness and knowledge of this disease and to assess the source of this knowledge, the ability of the public to recognize the characteristics of the disease and the behavior of patients with clinical cases of disease manifestation. To this end, 2,000 individuals (961 male and 1,039 female) of 14 years of age and older were surveyed using the ECOcapi system [Eurisko Consumer Omnibus-CAPI (computer-assisted personal interviewing) version]. Eighty-nine percent of those surveyed had some knowledge of herpes labialis; 92% were able to refer to at least one symptom of herpes labialis, 91% were able to identify correctly his infection from pictures, and 45% had experienced personally at least one episode of herpes labialis infection. The majority of the individuals suffering from herpes labialis self-medicated using a topical therapy. Women were found to be affected more commonly by herpes labialis than men [OR 1.42 (1.18-1.70)], and women were also more likely to recognize the disease [OR 1.65 (1.30-2.08)] and to seek medical advice for the condition [OR 1.38 (1.12-1.70)]. In conclusion, herpes labialis is a common and well-known condition, and it is often self-diagnosed correctly, as the prodromal phase and the use of self-medication are very common.
Underwood, M A; Wartell, A E; Borghese, R A
Herpes encephalitis is a rare but devastating infection in premature infants. We report a 29 week gestation infant with severe intrauterine cutaneous and central nervous system herpes accompanied by hyperleukocytosis. Leukemoid reactions are not uncommon in this population, but the association of herpes encephalitis and a leukemoid reaction or hyperleukocytosis has not been reported previously.
Opstelten, Wim; Neven, Arie Knuistingh; Eekhof, Just
ABSTRACT OBJECTIVE To review the evidence regarding the treatment and prevention of herpes labialis. QUALITY OF EVIDENCE The evidence relating to treatment and prevention of herpes labialis is derived from randomized controlled trials (level I evidence). MAIN MESSAGE Treatment with an indifferent cream (zinc oxide or zinc sulfate), an anesthetic cream, or an antiviral cream has a small favourable effect on the duration of symptoms, if applied promptly. This is also the case with oral antiviral medication. If antiviral medicine (cream or oral) is started before exposure to the triggering factor (sunlight), it will provide some protection. Research on sunscreens has shown mixed results: some protection has been reported under experimental conditions that could not be replicated under natural conditions. In the long term, the number of relapses of herpes labialis can be limited with oral antiviral medication. CONCLUSION Only prompt topical or oral therapy will alleviate symptoms of herpes labialis. Both topical and oral treatment can contribute to the prevention of herpes labialis. PMID:19074705
Al-Hussaini, Abdulrahman A; Fagih, Mosa A
Herpes simplex virus is a common cause of ulcerative esophagitis in the immunocompromised or debilitated host. Despite a high prevalence of primary and recurrent Herpes simplex virus infection in the general population, Herpes simplex virus esophagitis (HSVE) appears to be rare in the immunocompetent host. We report three cases of endoscopically-diagnosed HSVE in apparently immunocompetent children; the presentation was characterized by acute onset of fever, odynophagia, and dysphagia. In two cases, the diagnosis was confirmed histologically by identification of herpes viral inclusions and culture of the virus in the presence of inflammation. The third case was considered to have probable HSVE based on the presence of typical cold sore on his lip, typical endoscopic finding, histopathological evidence of inflammation in esophageal biopsies and positive serologic evidence of acute Herpes simplex virus infection. Two cases received an intravenous course of acyclovir and one had self-limited recovery. All three cases had normal immunological workup and excellent health on long-term follow-up.
Orsini, G; Loizzi, P; Morelli, L; Chiechi, L M; Sabatini, R; Distante, G
We report a very severe form of herpers gestationis that arose at the 26(th) week of pregnancy and reached us for observation at the 30(th) week. Herpes gestationis in an autoimmune vesicobullous dermatosis characterised by skin eruptions, intense itching and consequent increase in fetal morbility, with delayed intrauterine growth and prematurity. Owing to its particular severity (involvement of the entire body surface including the face), between the 30th and the 32(nd) weeks we had to address a severe clinical condition characterised by anaemia, marked hypoproteinaemia, hypoalbuminaemia, hupertension and hyperglycaemia which led us to resort to the maximum dose of oral corticotherapy in association with topical therapy using clobetasol propionate. In our opinion the results obtained were highly statisfactory with the result that at the end of the 37(th) week, in consideration of the patient's obstetric history, podalic presentation and parity, we performed a Caesarean delivering a newborn of 3000 g in excellent condition. The patient was discharged symptom-free on the 6(th) day and the newborn was in full healt.
Guan, Mingxu; Romano, Gaetano; Coroniti, Roberta; Henderson, Earl E
Thyroid malignant neoplasm develops from follicular or parafollicular thyroid cells. A higher proportion of anaplastic thyroid cancer has an adverse prognosis. New drugs are being used in clinical treatment. However, for advanced thyroid malignant neoplasm such as anaplastic thyroid carcinoma, the major impediment to successful control of the disease is the absence of effective therapies. Oncolytic virotherapy has significantly progressed as therapeutics in recent years. The advance is that oncolytic viruses can be designed with biological specificity to infect, replicate and lyse tumor cells. Significant advances in virotherapy have being achieved to improve the accessibility, safety and efficacy of the treatment. Therefore, it is necessary to summarize and bring together the main areas covered by these investigations for the virotherapy of thyroid malignant neoplasm. We provide an overview of the progress in virotherapy research and clinical trials, which employ virotherapy for thyroid malignant neoplasm as well as the future prospect for virotherapy of thyroid malignant neoplasms.
Bailey, Kent; Kirk, Amber; Naik, Shruthi; Nace, Rebecca; Steele, Michael B; Suksanpaisan, Lukkana; Li, Xing; Federspiel, Mark J; Peng, Kah-Whye; Kirk, David; Russell, Stephen J
Simple, inductive mathematical models of oncolytic virotherapy are needed to guide protocol design and improve treatment outcomes. Analysis of plasmacytomas regressing after a single intravenous dose of oncolytic vesicular stomatitis virus in myeloma animal models revealed that intratumoral virus spread was spatially constrained, occurring almost exclusively through radial expansion of randomly distributed infectious centers. From these experimental observations we developed a simple model to calculate the probability of survival for any cell within a treated tumor. The model predicted that small changes to the density of initially infected cells or to the average maximum radius of infected centers would have a major impact on treatment outcome, and this was confirmed experimentally. The new model provides a useful and flexible tool for virotherapy protocol optimization.
Cerullo, Vincenzo; Koski, Anniina; Vähä-Koskela, Markus; Hemminki, Akseli
Adenovirus is one of the most commonly used vectors for gene therapy and two products have already been approved for treatment of cancer in China (Gendicine(R) and Oncorine(R)). An intriguing aspect of oncolytic adenoviruses is that by their very nature they potently stimulate multiple arms of the immune system. Thus, combined tumor killing via oncolysis and inherent immunostimulatory properties in fact make these viruses in situ tumor vaccines. When further engineered to express cytokines, chemokines, tumor-associated antigens, or other immunomodulatory elements, they have been shown in various preclinical models to induce antigen-specific effector and memory responses, resulting both in full therapeutic cures and even induction of life-long tumor immunity. Here, we review the state of the art of oncolytic adenovirus, in the context of their capability to stimulate innate and adaptive arms of the immune system and finally how we can modify these viruses to direct the immune response toward cancer.
Introduction: Herpes zoster is an acute, cutaneous viral infection caused by the reactivation of varicella-zoster virus (VZV) that is the cause of varicella. It is an acute neurological disease which can often lead to serious postherpetic neuralgia (PHN). Different nerves can be included with the skin rash in the area of its enervation especially cranial nerves (CV) and intercostal nerves. Case report: In this report we present a patient with herpes zoster which involved ulnar nerve with skin rash in the region of ulnar innervations in women with no disease previously diagnosed. The failure of her immune system may be explained by great emotional stress and overwork she had been exposed to with neglecting proper nutrition in that period. Conclusion: Herpes zoster may involve any nerve with characteristic skin rash in the area of its innervations, and failure in immune system which leads reactivation of VZV may be caused by other factors besides the underlying illness. PMID:26980938
Retamal-Díaz, Angello R; Suazo, Paula A; Garrido, Ignacio; Kalergis, Alexis M; González, Pablo A
Herpes simplex viruses and humans have co-existed for tens of thousands of years. This long relationship has translated into the evolution and selection of viral determinants to evade the host immune response and reciprocally the evolution and selection of host immune components for limiting virus infection and damage. Currently there are no vaccines available to avoid infection with these viruses or therapies to cure them. Herpes simplex viruses are neurotropic and reside latently in neurons at the trigeminal and dorsal root ganglia, occasionally reactivating. Most viral recurrences are subclinical and thus, unnoticed. Here, we discuss the initial steps of infection by herpes simplex viruses and the molecular mechanisms they have developed to evade innate and adaptive immunity. A better understanding of the molecular mechanisms evolved by these viruses to evade host immunity should help us envision novel vaccine strategies and therapies that limit infection and dissemination.
Marchini, Antonio; Scott, Eleanor M; Rommelaere, Jean
Oncolytic viruses (OVs) target and destroy cancer cells while sparing their normal counterparts. These viruses have been evaluated in numerous studies at both pre-clinical and clinical levels and the recent Food and Drug Administration (FDA) approval of an oncolytic herpesvirus-based treatment raises optimism that OVs will become a therapeutic option for cancer patients. However, to improve clinical outcome, there is a need to increase OV efficacy. In addition to killing cancer cells directly through lysis, OVs can stimulate the induction of anti-tumour immune responses. The host immune system thus represents a "double-edged sword" for oncolytic virotherapy: on the one hand, a robust anti-viral response will limit OV replication and spread; on the other hand, the immune-mediated component of OV therapy may be its most important anti-cancer mechanism. Although the relative contribution of direct viral oncolysis and indirect, immune-mediated oncosuppression to overall OV efficacy is unclear, it is likely that an initial period of vigorous OV multiplication and lytic activity will most optimally set the stage for subsequent adaptive anti-tumour immunity. In this review, we consider the use of histone deacetylase (HDAC) inhibitors as a means of boosting virus replication and lessening the negative impact of innate immunity on the direct oncolytic effect. We also discuss an alternative approach, aimed at potentiating OV-elicited anti-tumour immunity through the blockade of immune checkpoints. We conclude by proposing a two-phase combinatorial strategy in which initial OV replication and spread is maximised through transient HDAC inhibition, with anti-tumour immune responses subsequently enhanced by immune checkpoint blockade.
Bramante, Simona; Koski, Anniina; Liikanen, Ilkka; Vassilev, Lotta; Oksanen, Minna; Siurala, Mikko; Heiskanen, Raita; Hakonen, Tiina; Joensuu, Timo; Kanerva, Anna; Pesonen, Sari; Hemminki, Akseli
Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules to boost virus triggered antitumoral immune responses. Cyclophosphamide (CP) is a chemotherapy drug that is associated with cytotoxicity and immunosuppression at higher doses, whereas immunostimulatory and anti-angiogenic properties are observed at low continuous dosage. Therefore, the combination of oncolytic immuno-virotherapy with low-dose CP is an appealing approach. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a TNBC cell line and in vivo in an orthotopic xenograft mouse model, in combination with low-dose CP or its main active metabolite 4-hydroperoxycyclophosphamide (4-HP-CP). Furthermore, we summarized the breast cancer-specific human data on this virus from the Advanced Therapy Access Program (ATAP). Low-dose CP increased the efficacy of Ad5/3-D24-GMCSF in vitro and in a TNBC mouse model. In ATAP, treatments appeared safe and well-tolerated. Thirteen out of 16 breast cancer patients treated were evaluable for possible benefits with modified RECIST 1.1 criteria: 1 patient had a minor response, 2 had stable disease (SD), and 10 had progressive disease (PD). One patient is alive at 1,771 d after treatment. Ad5/3-D24-GMCSF in combination with low-dose CP showed promising efficacy in preclinical studies and possible antitumor activity in breast cancer patients refractory to other forms of therapy. This preliminary data supports continuing the clinical development of oncolytic adenoviruses for treatment of breast cancer, including TNBC.
Marchini, Antonio; Scott, Eleanor M.; Rommelaere, Jean
Oncolytic viruses (OVs) target and destroy cancer cells while sparing their normal counterparts. These viruses have been evaluated in numerous studies at both pre-clinical and clinical levels and the recent Food and Drug Administration (FDA) approval of an oncolytic herpesvirus-based treatment raises optimism that OVs will become a therapeutic option for cancer patients. However, to improve clinical outcome, there is a need to increase OV efficacy. In addition to killing cancer cells directly through lysis, OVs can stimulate the induction of anti-tumour immune responses. The host immune system thus represents a “double-edged sword” for oncolytic virotherapy: on the one hand, a robust anti-viral response will limit OV replication and spread; on the other hand, the immune-mediated component of OV therapy may be its most important anti-cancer mechanism. Although the relative contribution of direct viral oncolysis and indirect, immune-mediated oncosuppression to overall OV efficacy is unclear, it is likely that an initial period of vigorous OV multiplication and lytic activity will most optimally set the stage for subsequent adaptive anti-tumour immunity. In this review, we consider the use of histone deacetylase (HDAC) inhibitors as a means of boosting virus replication and lessening the negative impact of innate immunity on the direct oncolytic effect. We also discuss an alternative approach, aimed at potentiating OV-elicited anti-tumour immunity through the blockade of immune checkpoints. We conclude by proposing a two-phase combinatorial strategy in which initial OV replication and spread is maximised through transient HDAC inhibition, with anti-tumour immune responses subsequently enhanced by immune checkpoint blockade. PMID:26751469
Prostate cancer is the most commonly diagnosed non- skin carcinoma, and one of the leading causes of cancerrelated deaths in North American men. Presently...primary and metastatic cancer cells while sparing normal cells. Vesicular Stomatitis Virus (VSV) is an oncolytic virus which is able to replicate in...capable of selectively infecting and killing malignant prostate cells while sparing normal cells. This cancer-specific cell death was not due to
Ady, Justin W; Heffner, Jacqueline; Klein, Elizabeth; Fong, Yuman
The development of targeted agents and chemotherapies for pancreatic cancer has only modestly affected clinical outcome and not changed 5-year survival. Fortunately the genetic and molecular mechanisms underlying pancreatic cancer are being rapidly uncovered and are providing opportunities for novel targeted therapies. Oncolytic viral therapy is one of the most promising targeted agents for pancreatic cancer. This review will look at the current state of the development of these self-replicating nanoparticles in the treatment of pancreatic cancer. PMID:27512661
Sosnovtseva, A O; Lipatova, A V; Grinenko, N F; Baklaushev, V P; Chumakov, P M; Chekhonin, V P
A humanized line of rat C6 glioma cells expressing human poliovirus receptor was obtained and tested for the sensitivity to oncolytic effects of vaccine strains of type 1, 2, and 3 polioviruses. Presentation of the poliovirus receptor on the surface of C6 glioma cells was shown to be a necessary condition for the interaction of cells with polioviruses, but insufficient for complete poliovirus oncolysis.
Elish, Diana; Singh, Fiza; Weinberg, Jeffrey M
Given the prevalence of herpes labialis, effective therapy has the potential to affect the lives of many and presents a challenge for clinicians. Over the last several years, most of the focus of herpes research has been on the treatment of genital herpes. Recently, however, several studies have been published examining the efficacy of therapies specifically for herpes labialis. Several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In this series of articles, we review oral and topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. This article will review oral treatment options.
Wongthida, Phonphimon; Diaz, Rosa M; Galivo, Feorillo; Kottke, Timothy; Thompson, Jill; Melcher, Alan; Vile, Richard
We show here, for the first time to our knowledge, that the antitumor therapy of oncolytic vesicular stomatitis virus (VSV) in the B16ova model depends upon signaling through myeloid differentiation primary response gene 88 (MyD88) in host cells. VSV-mediated therapy of B16ova tumors was abolished in MyD88(-/-) mice despite generation of antigen-specific T cell responses similar to those in immune-competent mice. Mice defective in only toll-like receptor 4 (TLR4), TLR7, or interleukin 1 (IL-1) signaling retained VSV-induced therapy, suggesting that multiple, redundant pathways of innate immune activation by the virus contribute to antitumor immune reactivity. Lack of MyD88 signaling was associated with decreased expression of proinflammatory cytokines and neutrophil infiltration in response to intratumoral virus, as well as decreased infiltration of draining lymph nodes (LN) with plasmacytoid dendritic cells (pDCs) (CD11b(-)GR1(+)B220(+)) and myeloid-derived suppressor cells (CD11b(+)GR1(+)F4/80(+)). MyD88 signaling in response to VSV was also closely associated with a type I interferon (IFN) response. This inhibited virus replication within the tumor but also protected the host from viral dissemination from the tumor. Therefore, the innate immune response to oncolytic viruses can be, simultaneously, protherapeutic, antioncolytic, and systemically protective. These paradoxically conflicting roles need to be carefully considered in future strategies designed to improve the efficacy of oncolytic virotherapy.
Zhang, Lianwen; Steele, Michael B; Jenks, Nathan; Grell, Jacquelyn; Behrens, Marshall; Nace, Rebecca; Naik, Shruthi; Federspiel, Mark J; Russell, Stephen J; Peng, Kah-Whye
Tumor-selective oncolytic vesicular stomatitis viruses (VSVs) are being evaluated in clinical trials. Here, we report that the MPC-11 murine plasmacytoma model is so extraordinarily susceptible to oncolytic VSVs that a low dose of virus leads to extensive intratumoral viral replication, sustained viremia, intravascular coagulation, and a rapidly fatal tumor lysis syndrome (TLS). Rapid softening, shrinkage and hemorrhagic necrosis of flank tumors was noted within 1-2 days after virus administration, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, increase in plasma cell free DNA, lymphopenia, consumptive coagulopathy, increase in fibrinogen degradation products, decreased liver function tests, dehydration, weight loss, and euthanasia or death after 5-8 days. Secondary viremia was observed but viral replication in normal host tissues was not detected. Toxicity could be mitigated by using VSVs with slowed replication kinetics, and was less marked in animals with smaller flank tumors. The MPC-11 tumor represents an interesting model to further study the complex interplay of robust intratumoral viral replication, tumor lysis, and associated toxicities in cases where tumors are highly responsive to oncolytic virotherapy.
Nosaki, Kaname; Hamada, Katsuyuki; Takashima, Yuto; Sagara, Miyako; Matsumura, Yumiko; Miyamoto, Shohei; Hijikata, Yasuki; Okazaki, Toshihiko; Nakanishi, Yoichi; Tani, Kenzaburo
Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL) and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future. PMID:27847861
Nguyen, Andrew; Ho, Louisa; Wan, Yonghong
Cancer is a traitorous archenemy that threatens our survival. Its ability to evade detection and adapt to various cancer therapies means that it is a moving target that becomes increasingly difficult to attack. Through technological advancements, we have developed sophisticated weapons to fight off tumor growth and invasion. However, if we are to stand a chance in this war against cancer, advanced tactics will be required to maximize the use of our available resources. Oncolytic viruses (OVs) are multi-functional cancer-fighters that can be engineered to suit many different strategies; in particular, their retooling can facilitate increased capacity for direct tumor killing (oncolytic virotherapy) and elicit adaptive antitumor immune responses (oncolytic immunotherapy). However, administration of these modified OVs alone, rarely induces successful regression of established tumors. This may be attributed to host antiviral immunity that acts to eliminate viral particles, as well as the capacity for tumors to adapt to therapeutic selective pressure. It has been shown that various chemotherapeutic drugs with distinct functional properties can potentiate the antitumor efficacy of OVs. In this review, we summarize the chemotherapeutic combinatorial strategies used to optimize virally induced destruction of tumors. With a particular focus on pharmaceutical immunomodulators, we discuss how specific therapeutic contexts may alter the effects of these synergistic combinations and their implications for future clinical use.
Workenhe, Samuel T; Mossman, Karen L
Oncolytic viruses are novel immunotherapeutics with increasingly promising outcomes in cancer patient clinical trials. Preclinical and clinical studies have uncovered the importance of virus-induced activation of antitumor immune responses for optimal therapeutic efficacy. Recently, several classes of chemotherapeutics have been shown to cause immunogenic cancer cell death characterized by the release of immunomodulatory molecules that activate antigen-presenting cells and thus trigger the induction of more potent anticancer adaptive immune responses. In preclinical models, several oncolytic viruses induce immunogenic cell death, which is associated with increased cross-priming of tumor-associated antigens. In this review, we discuss the recent advances in immunogenic cancer cell death as induced by chemotherapeutic treatments, including the roles of relevant danger-associated molecular patterns and signaling pathways, and highlighting the significance of the endoplasmic reticulum (ER) stress response. As virtually all viruses modulate both ER stress and cell death responses, we provide perspectives on future research directions that can be explored to optimize oncolytic viruses, alone or in combination with targeted drug therapies, as potent immunogenic cancer cell death-inducing agents. We propose that such optimized virus-drug synergistic strategies will improve the therapeutic outcomes for many currently intractable cancers.
Guan, Mingxu; Ma, Yanping; Shah, Sahil Rajesh; Romano, Gaetano
Biomarkers associated with thyroid malignant neoplasm (TMN) have been widely applied in clinical diagnosis and in research oncological programs. The identification of novel TMN biomarkers has greatly improved the efficacy of clinical diagnosis. A more accurate diagnosis may lead to better clinical outcomes and effective treatments. However, the major deficiency of conventional chemotherapy and radiotherapy is lack of specificity. Due to the macrokinetic interactions, adverse side effects will occur, including chemotherapy and radiotherapy resistance. Therefore, a new treatment is urgently needed. As an alternative approach, oncolytic virotherapy may represent an opportunity for treatment strategies that can more specifically target tumor cells. In most cases, viral entry requires the expression of specific receptors on the surface of the host cell. Currently, molecular virologists and gene therapists are working on engineering oncolytic viruses with altered tropism for the specific targeting of malignant cells. This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
Nosaki, Kaname; Hamada, Katsuyuki; Takashima, Yuto; Sagara, Miyako; Matsumura, Yumiko; Miyamoto, Shohei; Hijikata, Yasuki; Okazaki, Toshihiko; Nakanishi, Yoichi; Tani, Kenzaburo
Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL) and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.
Farzad, Lisa; Cerullo, Vincenzo; Yagyu, Shigeki; Bertin, Terry; Hemminki, Akseli; Rooney, Cliona; Lee, Brendan; Suzuki, Masataka
Oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Investigators have therefore incorporated sequences into these vectors that encode immunomodulatory molecules to enhance antitumor immunity. Successful implementation of this strategy requires multiple tumor immune inhibitory mechanisms to be overcome, and insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. HDAds, however, lack replicative capacity. Since HDAds encode the adenoviral packaging signal, we hypothesized that the coadministration of Onc.Ad with HDAd would allow to be amplified and packaged during replication of Onc.Ad in transduced cancer cells. This combination could provide immunostimulation without losing oncolytic activity. We now show that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy. PMID:27119096
Nguyen, Andrew; Ho, Louisa; Wan, Yonghong
Cancer is a traitorous archenemy that threatens our survival. Its ability to evade detection and adapt to various cancer therapies means that it is a moving target that becomes increasingly difficult to attack. Through technological advancements, we have developed sophisticated weapons to fight off tumor growth and invasion. However, if we are to stand a chance in this war against cancer, advanced tactics will be required to maximize the use of our available resources. Oncolytic viruses (OVs) are multi-functional cancer-fighters that can be engineered to suit many different strategies; in particular, their retooling can facilitate increased capacity for direct tumor killing (oncolytic virotherapy) and elicit adaptive antitumor immune responses (oncolytic immunotherapy). However, administration of these modified OVs alone, rarely induces successful regression of established tumors. This may be attributed to host antiviral immunity that acts to eliminate viral particles, as well as the capacity for tumors to adapt to therapeutic selective pressure. It has been shown that various chemotherapeutic drugs with distinct functional properties can potentiate the antitumor efficacy of OVs. In this review, we summarize the chemotherapeutic combinatorial strategies used to optimize virally induced destruction of tumors. With a particular focus on pharmaceutical immunomodulators, we discuss how specific therapeutic contexts may alter the effects of these synergistic combinations and their implications for future clinical use. PMID:24967214
Steel, Jason C.; Morrison, Brian J.; Mannan, Poonam; Abu-Asab, Mones S.; Wildner, Oliver; Miles, Brian K.; Yim, Kevin C.; Ramanan, Vijay; Prince, Gregory A.; Morris, John C.
Oncolytic adenoviruses as a treatment for cancer have demonstrated limited clinical activity. Contributing to this may be the relevance of preclinical animal models used to study these agents. Syngeneic mouse tumor models are generally non-permissive for adenoviral replication, whereas human tumor xenograft models exhibit attenuated immune responses to the vector. The cotton rat (Sigmodon hispidus) is susceptible to human adenovirus infection, permissive for viral replication and exhibits similar inflammatory pathology to humans with adenovirus replicating in the lungs, respiratory passages and cornea. We evaluated three transplantable tumorigenic cotton rat cell lines, CCRT, LCRT and VCRT as models for the study of oncolytic adenoviruses. All three cells lines were readily infected with adenovirus type-5-based vectors and exhibited high levels of transgene expression. The cell lines supported viral replication demonstrated by the induction of cytopathogenic effect (CPE) in tissue culture, increase in virus particle numbers and assembly of virions seen on transmission electron microscopy. In vivo, LCRT and VCRT tumors demonstrated delayed growth after injection with replicating adenovirus. No in vivo antitumor activity was seen in CCRT tumors despite in vitro oncolysis. Adenovirus was also rapidly cleared from the CCRT tumors compared to LCRT and VCRT tumors. The effect observed with the different cotton rat tumor cell lines mimics the variable results of human clinical trials highlighting the potential relevance of this model for assessing the activity and toxicity of oncolytic adenoviruses.
Kristian, Taipale; Ilkka, Liikanen; Juuso, Juhila; Aila, Karioja-Kallio; Minna, Oksanen; Riku, Turkki; Nina, Linder; Johan, Lundin; Ari, Ristimäki; Anna, Kanerva; Anniina, Koski; Timo, Joensuu; Markus, Vähä-Koskela; Akseli, Hemminki
The quality of the antitumor immune response is decisive when developing new immunotherapies for cancer. Oncolytic adenoviruses cause a potent immunogenic stimulus and arming them with costimulatory molecules reshapes the immune response further. We evaluated peripheral blood T-cell subsets of 50 patients with refractory solid tumors undergoing treatment with oncolytic adenovirus. These data were compared to changes in antiviral and antitumor T cells, treatment efficacy, overall survival, and T-cell subsets in pre- and post-treatment tumor biopsies. Treatment caused a significant (P < 0.0001) shift in T-cell subsets in blood, characterized by a proportional increase of CD8(+) cells, and decrease of CD4(+) cells. Concomitant treatment with cyclophosphamide and temozolomide resulted in less CD4(+) decrease (P = 0.041) than cyclophosphamide only. Interestingly, we saw a correlation between T-cell changes in peripheral blood and the tumor site. This correlation was positive for CD8(+) and inverse for CD4(+) cells. These findings give insight to the interconnections between peripheral blood and tumor-infiltrating lymphocyte (TIL) populations regarding oncolytic virotherapy. In particular, our data suggest that induction of T-cell response is not sufficient for clinical response in the context of immunosuppressive tumors, and that peripheral blood T cells have a complicated and potentially misleading relationship with TILs.
Wechman, Stephen L.; Rao, Xiao-Mei; Cheng, Pei-Hsin; Gomez-Gutierrez, Jorge G.; McMasters, Kelly M.; Zhou, H. Sam
Oncolytic adenoviruses (Ads) have been shown to be safe and have great potential for the treatment of solid tumors. However, the therapeutic efficacy of Ads is antagonized by limited spread within solid tumors. To develop Ads with enhanced spread, viral particles of an E1-wildtype Ad5 dl309 was repeatedly treated with UV type C irradiation and selected for the efficient replication and release from cancer cells. After 72 cycles of treatment and cancer selection, AdUV was isolated. This vector has displayed many favorable characteristics for oncolytic therapy. AdUV was shown to lyse cancer cells more effectively than both E1-deleted and E1-wildtype Ads. This enhanced cancer cell lysis appeared to be related to increased AdUV replication in and release from infected cancer cells. AdUV-treated A549 cells displayed greater expression of the autophagy marker LC3-II during oncolysis and formed larger viral plaques upon cancer cell monolayers, indicating increased virus spread among cancer cells. This study indicates the potential of this approach of irradiation of entire viral particles for the development of oncolytic viruses with designated therapeutic properties. PMID:27314377
Angelova, Assia L.; Geletneky, Karsten; Nüesch, Jürg P. F.; Rommelaere, Jean
Oncolytic virotherapy of cancer is among the innovative modalities being under development and especially promising for targeting tumors, which are resistant to conventional treatments. Presently, at least a dozen of viruses, belonging to nine different virus families, are being tested within the frames of various clinical studies in cancer patients. Continuously growing preclinical evidence showing that the autonomous rat parvovirus H-1 (H-1PV) is able to kill tumor cells that resist conventional treatments and to achieve a complete cure of various human tumors in animal models argues for its inclusion in the arsenal of oncolytic viruses with an especially promising bench to bedside translation potential. Oncolytic parvovirus safe administration to humans relies on the intrinsic preference of these agents for quickly proliferating, metabolically, and biochemically disturbed tumor versus normal cells (tumor selectivity or oncotropism). The present review summarizes and discusses (i) preclinical evidence of H-1PV innocuousness for normal cells and healthy tissues in vitro and in animals, respectively, (ii) toxicological assessments of H-1PV mono- or combined therapy in tumor-bearing virus-permissive animal models, as well as (iii) historical results of experimental infection of human cancer patients with H-1PV. Altogether, these data argue against a risk of H-1PV inducing significant toxic effects in human patients. This highly favorable safety profile allowed the translation of H-1PV preclinical research into a Phase I/IIa clinical trial being currently in progress. PMID:25954743
Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing; Reilly, Karlyne M; McFadden, Grant; Yong, V Wee; Forsyth, Peter A
Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation.
Josupeit, Rafael; Rudolph, Stephan; Ehrig, Klaas; Donat, Ulrike; Weibel, Stephanie; Chen, Nanhai G.; Yu, Yong A.; Zhang, Qian; Heisig, Martin; Thamm, Douglas; Stritzker, Jochen; MacNeill, Amy; Szalay, Aladar A.
Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS) using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS. PMID:22615950
Cerullo, Vincenzo; Diaconu, Iulia; Kangasniemi, Lotta; Rajecki, Maria; Escutenaire, Sophie; Koski, Anniina; Romano, Valentina; Rouvinen, Noora; Tuuminen, Tamara; Laasonen, Leena; Partanen, Kaarina; Kauppinen, Satu; Joensuu, Timo; Oksanen, Minna; Holm, Sirkka-Liisa; Haavisto, Elina; Karioja-Kallio, Aila; Kanerva, Anna; Pesonen, Sari; Arstila, Petteri T; Hemminki, Akseli
Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T(regs)) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.
Pinninti, Swetha G; Kimberlin, David W
Genital herpes simplex virus (HSV) infections are very common worldwide. Approximately 22% of pregnant women are infected genitally with HSV, and most of them are unaware of this. The most devastating consequence of maternal genital herpes is HSV disease in the newborn. Although neonatal HSV infections remain uncommon, due to the significant morbidity and mortality associated with the infection, HSV infection in the newborn is often considered in the differential diagnosis of ill neonates. This review summarizes the epidemiology and management of neonatal HSV infections and discusses strategies to prevent HSV infection in the newborn.
Giurcăneanu, F; Crişan, I; Eşanu, V; Cioca, V; Cajal, N
The results obtained at the Dermatological service of the Colentina Hospital show that the product NIVCRISOL-D, containing propolis, has a significant therapeutical effect against recurrent herpes and zona zoster.
Cassady, Kevin A; Saunders, Ute; Shimamura, Masako
The chimeric herpes simplex viruses (HSV) are Δγ₁34.5 vectors encoding the human cytomegalovirus (HCMV) IRS1 or TRS1 genes. They are capable of late viral protein synthesis and are superior to Δγ₁34.5 HSVs in oncolytic activity. The interferon (IFN) response limits efficient HSV gene expression and replication. HCMV TRS1 and IRS1 restore one γ₁34.5 gene function: evasion of IFN-inducible protein kinase R, allowing late viral protein synthesis. Here we show that, unlike wild-type HSV, the chimeric HSV do not restore another γ₁34.5 function, the suppression of early IFN signaling mediated by IFN regulatory factor 3 (IRF3).
Ramírez, Manuel; García-Castro, Javier; Melen, Gustavo J; González-Murillo, África; Franco-Luzón, Lidia
Oncolytic virotherapy is gaining interest in the clinic as a new weapon against cancer. In vivo administration of oncolytic viruses showed important limitations that decrease their effectiveness very significantly: the antiviral immune response causes the elimination of the therapeutic effect, and the poor natural ability of oncolytic viruses to infect micrometastatic lesions significantly minimizes the effective dose of virus. This review will focus on updating the technical and scientific foundations of one of the strategies developed to overcome these limitations, ie, using cells as vehicles for oncolytic viruses. Among many candidates, a special type of adult stem cell, mesenchymal stem cells (MSCs), have already been used in the clinic as cell vehicles for oncolytic viruses, partly due to the fact that these cells are actively being evaluated for other indications. MSC carrier cells are used as Trojan horses loaded with oncoviruses, are administered systemically, and release their cargos at the right places. MSCs are equipped with an array of molecules involved in cell arrest in the capillaries (integrins and selectins), migration toward specific parenchymal locations within tissues (chemokine receptors), and invasion and degradation of the extracellular matrix (proteases). In addition to anatomical targeting capacity, MSCs have a well-recognized role in modulating immune responses by affecting cells of the innate (antigen-presenting cells, natural killer cells) and adaptive immune system (effector and regulatory lymphocytes). Therefore, carrier MSCs may also modulate the immune responses taking place after therapy, ie, the antiviral and the antitumor immune responses.
Puig-Saus, C; Laborda, E; Rodríguez-García, A; Cascalló, M; Moreno, R; Alemany, R
Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.
Chalikonda, S; Kivlen, M H; O'Malley, M E; Eric Dong, X D; McCart, J A; Gorry, M C; Yin, X-Y; Brown, C K; Zeh, H J; Guo, Z S; Bartlett, D L
In this study, we assessed the ability of a highly tumor-selective oncolytic vaccinia virus armed with a yeast cytosine deaminase gene to infect and lyse human and murine ovarian tumors both in vitro and in vivo. The virus vvDD-CD could infect, replicate in and effectively lyse both human and mouse ovarian cancer cells in vitro. In two different treatment schedules involving either murine MOSEC or human A2780 ovarian carcinomatosis models, regional delivery of vvDD-CD selectively targeted tumor cells and ovarian tissue, effectively delaying the development of either tumor or ascites and leading to significant survival advantages. Oncolytic virotherapy using vvDD-CD in combination with the prodrug 5-fluorocytosine conferred an additional long-term survival advantage upon tumor-bearing immunocompetent mice. These findings demonstrate that a tumor-selective oncolytic vaccinia combined with gene-directed enzyme prodrug therapy is a highly effective strategy for treating advanced ovarian cancers in both syngeneic mouse and human xenograft models. Given the biological safety, tumor selectivity and oncolytic potency of this armed oncolytic virus, this dual therapy merits further investigation as a promising new treatment for metastatic ovarian cancer.
Nakano, K; Todo, T; Chijiiwa, K; Tanaka, M
Gallbladder cancer is an extremely difficult disease to cure once metastases occur. In this paper, we explored the potential of G207, an oncolytic, replication-competent herpes simplex virus type 1 mutant, as a new therapeutic means for gallbladder cancer. Gallbladder carcinoma cell lines (four human and one hamster) showed nearly total cell killing within 72 h of G207 infection at a m.o.i. of 0.25 to 2.5 in vitro. The susceptibility to G207 cytopathic activity correlated with the infection efficiency demonstrated by lacZ expression. Intraneoplastic inoculation of G207 (1 x 10(7) pfu) in immunocompetent hamsters bearing established subcutaneous KIGB-5 tumors caused a significant inhibition of tumor growth and prolongation of survival. Repeated inoculations (three times with 4-day intervals) were significantly more efficacious than a single inoculation. In hamsters with bilateral subcutaneous KIGB-5 tumors, inoculation of one tumor alone with G207 caused regression or growth reduction of uninoculated tumors as well as inoculated tumors. In athymic mice, however, the anti-tumor effect was largely reduced in inoculated tumors and completely abolished in remote tumors, suggesting large contribution of T-cell-mediated immune responses to both local and systemic anti-tumor effect of G207. These results indicate that G207 may be useful as a new strategy for gallbladder cancer treatment.
George, G. C. W.
Studies of patients suffering from anorexia nervosa appear to show an increased immunity to certain infections, as well as immunological deficiencies. This is the report of a patient with anorexia nervosa who developed herpes simplex encephalitis, a condition associated with lowered immunological defence mechanisms. PMID:7301681
Eymard, D; Martin, L; Doummar, G; Piché, J
Over four months, three cases of biopsy-proven herpes simplex esophagitis were seen at Centre hospitalier Pierre-Boucher, Longueuil, in young adult males with no evidence of immunosuppression and negative serological testing for antibody against the human immunodeficiency virus. Clinical presentation consisted of odynophagia, fever and retrosternal chest pain. All patients rapidly improved with acyclovir therapy.
Eymard, Daniel; Martin, Luc; Doummar, Gilbert; Piché, Jean
Over four months, three cases of biopsy-proven herpes simplex esophagitis were seen at Centre hospitalier Pierre-Boucher, Longueuil, in young adult males with no evidence of immunosuppression and negative serological testing for antibody against the human immunodeficiency virus. Clinical presentation consisted of odynophagia, fever and retrosternal chest pain. All patients rapidly improved with acyclovir therapy. PMID:22346532
Naude, H.; Pretorius, E.
Aphasia implies the loss or impairment of language caused by brain damage. The key to understanding the nature of aphasic symptoms is the neuro-anatomical site of brain damage, and not the causative agent. However, because "Herpes simplex" virus (HSV) encephalitis infection usually affects the frontal and temporal lobes, subcortical…
Van Epps, Puja; Schmader, Kenneth E; Canaday, David H
Herpes zoster, clinically referred to as shingles, is an acute, cutaneous viral infection caused by reactivation of the varicella zoster virus, the same virus that causes chickenpox. The incidence of herpes zoster and its complications increase with decline in cell-mediated immunity, including age-associated decline. The most effective management strategy for herpes zoster is prevention of the disease through vaccination in those who are most vulnerable. Despite the demonstrated efficacy in reducing the incidence and severity of herpes zoster, the uptake of vaccine remains low. Here, we will discuss the controversies that surround the live herpes zoster vaccine and address the common clinical questions that arise. We will also discuss the new adjuvanted herpes zoster vaccine currently under investigation.
Mamdani, F. S.
Herpes zoster is an infection caused by reactivation of dormant varicella-zoster virus. The acute course of herpes zoster is generally benign; however, some patients will experience postherpetic neuralgia characterized by severe, relentless, and at times disabling pain that is often refractory to treatment. While herpes zoster responds to acyclovir, cost-benefit considerations limit the drug's usefulness to only a select group. Postherpetic neuralgia requires a holistic approach, including pharmacologic therapy using several different classes of drugs. PMID:7907508
Patel, Raj; Green, John; Clarke, Emily; Seneviratne, Kanchana; Abbt, Naomi; Evans, Ceri; Bickford, Jane; Nicholson, Marian; O'Farrell, Nigel; Barton, Simon; FitzGerald, Mark; Foley, Elizabeth
These guidelines concern the management of anogenital herpes simplex virus infections in adults and give advice on diagnosis, management, and counselling of patients. This guideline replaces the 2007 BASHH herpes guidelines and includes new sections on herpes proctitis, key points to cover with patients regarding transmission and removal of advice on the management of HSV in pregnancy which now has a separate joint BASHH/RCOG guideline.
Chentoufi, Aziz Alami; BenMohamed, Lbachir
Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 & HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed. PMID:23320014
Awasthi, Sita; Shaw, Carolyn; Friedman, Harvey
No vaccines are approved for prevention or treatment of genital herpes. The focus of genital herpes vaccine trials has been on prevention using herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) alone or combined with glycoprotein B. These prevention trials did not achieve their primary end points. However, subset analyses reported some positive outcomes in each study. The most recent trial was the Herpevac Trial for Women that used gD2 with monophosphoryl lipid A and alum as adjuvants in herpes simplex virus type 1 (HSV-1) and HSV-2 seronegative women. Unexpectedly, the vaccine prevented genital disease by HSV-1 but not HSV-2. Currently, HSV-1 causes more first episodes of genital herpes than HSV-2, highlighting the importance of protecting against HSV-1. The scientific community is conflicted between abandoning vaccine efforts that include gD2 and building upon the partial successes of previous trials. We favor building upon success and present approaches to improve outcomes of gD2-based subunit antigen vaccines.
Lee, Nam Hee; Kim, Mikyung; Oh, Sung Yong; Kim, Seong-Geun; Kwon, Hyuk-Chan; Hwang, Tae-Ho
Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec. PMID:27901484
Ylösmäki, Erkko; Lavilla-Alonso, Sergio; Jäämaa, Sari; Vähä-Koskela, Markus; af Hällström, Taija; Hemminki, Akseli; Arola, Johanna; Mäkisalo, Heikki; Saksela, Kalle
MicroRNAs (miRNAs) are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3′ untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5) in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver. PMID:23349911
Ylösmäki, Erkko; Lavilla-Alonso, Sergio; Jäämaa, Sari; Vähä-Koskela, Markus; af Hällström, Taija; Hemminki, Akseli; Arola, Johanna; Mäkisalo, Heikki; Saksela, Kalle
MicroRNAs (miRNAs) are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5) in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver.
Janelle, Valérie; Brassard, Frédérick; Lapierre, Pascal; Lamarre, Alain; Poliquin, Laurent
Vesicular stomatitis virus (VSV) has been widely used to characterize cellular processes, viral resistance, and cytopathogenicity. Recently, VSV has also been used for oncolytic virotherapy due to its capacity to selectively lyse tumor cells. Mutants of the matrix (M) protein of VSV have generally been preferred to the wild-type virus for oncolysis because of their ability to induce type I interferon (IFN) despite causing weaker cytopathic effects. However, due to the large variability of tumor types, it is quite clear that various approaches and combinations of multiple oncolytic viruses will be needed to effectively treat most cancers. With this in mind, our work focused on characterizing the cytopathogenic profiles of four replicative envelope glycoprotein (G) VSV mutants. In contrast to the prototypic M mutant, VSV G mutants are as efficient as wild-type virus at inhibiting cellular transcription and host protein translation. Despite being highly cytopathic, the mutant G(6R) triggers type I interferon secretion as efficiently as the M mutant. Importantly, most VSV G mutants are more effective at killing B16 and MC57 tumor cells in vitro than the M mutant or wild-type virus through apoptosis induction. Taken together, our results demonstrate that VSV G mutants retain the high cytopathogenicity of wild-type VSV, with G(6R) inducing type I IFN secretion at levels similar to that of the M mutant. VSV G protein mutants could therefore prove to be highly valuable for the development of novel oncolytic virotherapy strategies that are both safe and efficient for the treatment of various types of cancer.
Irwin, Chad R; Favis, Nicole A; Agopsowicz, Kate C; Hitt, Mary M; Evans, David H
Myxoma virus (MYXV) is one of many animal viruses that exhibit oncolytic properties in transformed human cells. Compared to orthopoxviruses like vaccinia (VACV), MYXV spreads inefficiently, which could compromise its use in treating tumors and their associated metastases. The VACV F11 protein promotes virus exit and rapid spread by inhibiting Rho signalling, which results in a disruption of cortical actin. We have previously shown that although MYXV lacks an F11 homolog, the F11L gene can be introduced into MYXV promoting the spread of this Leporipoxvirus in natural host cells. Here we show that the F11-encoding (F11L(+)) MYXV strain replicates to higher levels in a number of human cancer cells. We also show that F11L(+) MYXV induces better tumor control and prolonged survival of mice bearing MDA-MB-231 cancer cells. Furthermore, we show that this virus also spreads more efficiently from the site of growth in one injected tumor, to a second untreated tumor. While we focused mostly on the use of a modified MYXV we were able to show that the effects of F11 on MYXV growth in cancer cells could be mimicked through the use of pharmacological inhibition or siRNA-mediated silencing of key regulators of cortical actin (RhoA, RhoC, mDia1, or LIMK2). These data suggest that it may be possible to increase the oncolytic efficacy of wild-type MYXV using chemical inhibitors of RhoA/C or their downstream targets. Furthermore, since all viruses must overcome barriers to exit posed by structures like cortical actin, these findings suggest that the oncolytic activity of other viruses may be enhanced through similar strategies.
Zemp, Franz J.; McKenzie, Brienne A.; Lun, Xueqing; Reilly, Karlyne M.; McFadden, Grant; Yong, V. Wee; Forsyth, Peter A.
Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the patient's immune response to the virus infection limits the therapy's utility, investigations into the specific cell type(s) involved in this response have been performed using non-specific pharmacological inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumours, and robust monocyte, T and NK cell infiltration 3 days following MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumour-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumour-resident macrophage population. Virotherapy of CPA-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multi-faceted cellular immune response that can be overcome with CPA-mediated lymphoablation. PMID:25336188
Irwin, Chad R.; Favis, Nicole A.; Agopsowicz, Kate C.; Hitt, Mary M.; Evans, David H.
Myxoma virus (MYXV) is one of many animal viruses that exhibit oncolytic properties in transformed human cells. Compared to orthopoxviruses like vaccinia (VACV), MYXV spreads inefficiently, which could compromise its use in treating tumors and their associated metastases. The VACV F11 protein promotes virus exit and rapid spread by inhibiting Rho signalling, which results in a disruption of cortical actin. We have previously shown that although MYXV lacks an F11 homolog, the F11L gene can be introduced into MYXV promoting the spread of this Leporipoxvirus in natural host cells. Here we show that the F11-encoding (F11L+) MYXV strain replicates to higher levels in a number of human cancer cells. We also show that F11L+ MYXV induces better tumor control and prolonged survival of mice bearing MDA-MB-231 cancer cells. Furthermore, we show that this virus also spreads more efficiently from the site of growth in one injected tumor, to a second untreated tumor. While we focused mostly on the use of a modified MYXV we were able to show that the effects of F11 on MYXV growth in cancer cells could be mimicked through the use of pharmacological inhibition or siRNA-mediated silencing of key regulators of cortical actin (RhoA, RhoC, mDia1, or LIMK2). These data suggest that it may be possible to increase the oncolytic efficacy of wild-type MYXV using chemical inhibitors of RhoA/C or their downstream targets. Furthermore, since all viruses must overcome barriers to exit posed by structures like cortical actin, these findings suggest that the oncolytic activity of other viruses may be enhanced through similar strategies. PMID:24391902
Yumul, Roma; Richter, Maximilian; Lu, Zhuo-Zhuang; Saydaminova, Kamola; Wang, Hongjie; Wang, Chung-Huei Katherine; Carter, Darrick; Lieber, André
A central resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. Human adenoviruses (Ads) have evolved mechanisms to breach epithelial barriers. For example, during Ad serotype 3 (Ad3) infection of epithelial tumor cells, massive amounts of subviral penton-dodecahedral particles (PtDd) are produced and released from infected cells to trigger the transient opening of epithelial junctions, thus facilitating lateral virus spread. We show here that an Ad3 mutant that is disabled for PtDd production is significantly less effective in killing of epithelial human xenograft tumors than the wild-type Ad3 virus. Intratumoral spread and therapeutic effect of the Ad3 mutant was enhanced by co-administration of a small recombinant protein (JO; produced in Escherichia coli) that incorporated the minimal junction opening domains of PtDd. We then demonstrated that co-administration of JO with replication-competent Ads that do not produce PtDd (Ad5, Ad35) resulted in greater attenuation of tumor growth than virus injection alone. Furthermore, we genetically modified a conditionally replicating Ad5-based oncolytic Ad (Ad5Δ24) to express a secreted form of JO upon replication in tumor cells. The JO-expressing virus had a significantly greater antitumor effect than the unmodified AdΔ24 version. Our findings indicate that epithelial junctions limit the efficacy of oncolytic Ads and that this problem can be address by co-injection or expression of JO. JO has also the potential for improving cancer therapy with other types of oncolytic viruses. PMID:26993072
Nasatzky, E; Katz, J
Bell's palsy is a sudden, isolated, peripheral facial paralysis caused by various known and sometimes unknown factors. The case of an 18-year-old man who developed Bell's palsy after onset of primary herpetic gingivostomatitis is presented. Although Bell's palsy has already been associated with herpes simplex virus type 1, the described case is the first in the literature in which enzyme-linked immunosorbent assays for immunoglobulin G to herpes simplex virus type 1 and herpes simplex virus type 1 culture were both positive. The recent literature regarding the possible relationship between herpes simplex virus type 1 and Bell's palsy is reviewed and discussed.
Calvo-Mosquera, G; González-Cal, A; Calvo-Rodríguez, D; Primucci, C Y; Plamenov-Dipchikov, P
Shingles is a painful rash that results from reactivation of latent varicella-zoster virus in the dorsal root ganglia or cranial nerves. In this article an update is presented on the prevention and pharmacological treatment of the secondary pain from the virus infection. The most effective way to prevent post-herpetic neuralgia and its consequences is the prevention of herpes itself. A live attenuated vaccine (the Oka strain varicella zoster virus) has been available for several years, and is approved in adults aged 50 years old. Although this vaccine has shown to be effective against herpes zoster and post-herpetic neuralgia, its effectiveness decreases with age and is contraindicated in patients with some form of immunosuppression. Today the recombinant vaccines provide an alternative, and may be administered to immunocompromised persons.
Burcea, M; Avram, Corina-Ioana; Stamate, Alina-Cristina; Malciolu, R; Oprea, S; Zemba, M
The herpes simplex virus is one of the most common pathogens in humans, who are seropositive for the virus in 90% of the cases at the adult age. It determines reccurent infections in more than a third of the population and these infections depend on the immune response of the host. Ocular infections of newborns are due to the herpes simplex virus type 2, meanwhile type 1 is found predominantly at adults; almost all ocular structures can be affected. HSV-1 in the most frequent etiologic agent in infectious anterior uveitis (with the varicelo-zosterian virus) and it is responsible for 6-10% of all cases of anterior uveitis. More than half of the keratouveitides due to HSV will develop intraocular hypertension and open-angle secondary glaucoma, during reccurences and most of them will resolve after proper control of inflammation.
Philpot, Stephen J; Archer, John S
A 74-year-old woman developed vertigo and jerk nystagmus to the left with normal cerebral imaging. Three days later she developed fever, altered mental state and left medial temporal lobe hypodensity, confirmed on lumbar puncture to be due to herpes simplex type 1 encephalitis. We propose that the patient had vestibular neuronitis caused by HSV-1 that progressed to ipsilateral temporal lobe encephalitis.
Koski, Anniina; Bramante, Simona; Kipar, Anja; Oksanen, Minna; Juhila, Juuso; Vassilev, Lotta; Joensuu, Timo; Kanerva, Anna; Hemminki, Akseli
In clinical trials with oncolytic adenoviruses, there has been no mortality associated with treatment vectors. Likewise, in the Advanced Therapy Access Program (ATAP), where 290 patients were treated with 10 different viruses, no vector-related mortality was observed. However, as the patient population who received adenovirus treatments in ATAP represented heavily pretreated patients, often with very advanced disease, some patients died relatively soon after receiving their virus treatment mandating autopsy to investigate cause of death. Eleven such autopsies were performed and confirmed disease progression as the cause of death in each case. The regulatory requirement for investigating the safety of advanced therapy medical products presented a unique opportunity to study tissue samples collected as a routine part of the autopsies. Oncolytic adenoviral DNA was recovered in a wide range of tissues, including injected and noninjected tumors and various normal tissues, demonstrating the ability of the vector to disseminate through the vascular route. Furthermore, we recovered and cultured viable virus from samples of noninjected brain metastases of an intravenously treated patient, confirming that oncolytic adenovirus can reach tumors through the intravascular route. Data presented here give mechanistic insight into mode of action and biodistribution of oncolytic adenoviruses in cancer patients. PMID:26156245
Gil, Margaret; Seshadri, Mukund; Komorowski, Marcin P; Abrams, Scott I; Kozbor, Danuta
Oncolytic viruses hold promise for the treatment of cancer, but their interaction with the tumor microenvironment needs to be elucidated for optimal tumor cell killing. Because the CXCR4 receptor for the stromal cell-derived factor-1 (SDF-1/CXCL12) chemokine is one of the key stimuli involved in signaling interactions between tumor cells and their stromal microenvironment, we used oncolytic virotherapy with a CXCR4 antagonist to target the CXCL12/CXCR4 signaling axis in a triple-negative 4T1 breast carcinoma in syngeneic mice. We show here that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intravenously to mice with orthotopic tumors attains higher intratumoral concentration than its soluble counterpart and exhibits increased efficacy over that mediated by oncolysis alone. A systemic delivery of the armed virus after resection of the primary tumor was efficacious in inhibiting the development of spontaneous metastasis and increased overall tumor-free survival. Inhibition of tumor growth with the armed virus was associated with destruction of tumor vasculature, reductions in expression of CXCL12 and VEGF, and decrease in intratumoral numbers of bone marrow-derived endothelial and myeloid cells. These changes led to induction of antitumor antibody responses and resistance to tumor rechallenge. Engineering an oncolytic virus armed with a CXCR4 antagonist represents an innovative strategy that targets multiple elements within the tumor microenvironment. As such, this approach could have a significant therapeutic impact against primary and metastatic breast cancer.
Kim, Chung Kwon; Ahmed, Atique U; Auffinger, Brenda; Ulasov, Ilya V; Tobias, Alex L; Moon, Kyung-Sub; Lesniak, Maciej S
Current research has evaluated the intrinsic tumor-tropic properties of stem cell carriers for targeted anticancer therapy. Our laboratory has been extensively studying in the preclinical setting, the role of neural stem cells (NSCs) as delivery vehicles of CRAd-S-pk7, a gliomatropic oncolytic adenovirus (OV). However, the mediated toxicity of therapeutic payloads, such as oncolytic adenoviruses, toward cell carriers has significantly limited this targeted delivery approach. Following this rationale, in this study, we assessed the role of a novel antioxidant thiol, N-acetylcysteine amide (NACA), to prevent OV-mediated toxicity toward NSC carriers in an orthotropic glioma xenograft mouse model. Our results show that the combination of NACA and CRAd-S-pk7 not only increases the viability of these cell carriers by preventing reactive oxygen species (ROS)-induced apoptosis of NSCs, but also improves the production of viral progeny in HB1.F3.CD NSCs. In an intracranial xenograft mouse model, the combination treatment of NACA and NSCs loaded with CRAd-S-pk7 showed enhanced CRAd-S-pk7 production and distribution in malignant tissues, which improves the therapeutic efficacy of NSC-based targeted antiglioma oncolytic virotherapy. These data demonstrate that the combination of NACA and NSCs loaded with CRAd-S-pk7 may be a desirable strategy to improve the therapeutic efficacy of antiglioma oncolytic virotherapy.
Dold, Catherine; Rodriguez Urbiola, Carles; Wollmann, Guido; Egerer, Lisa; Muik, Alexander; Bellmann, Lydia; Fiegl, Heidelinde; Marth, Christian; Kimpel, Janine; von Laer, Dorothee
Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection. This is in stark contrast to published data for other cancer cell lines, which were mostly found to be interferon incompetent. We showed that in vitro this antiviral state could be reverted by combining VSV-GP with the JAK1/2-inhibitor ruxolitinib. In addition, for the first time, we report the in vivo enhancement of oncolytic virus treatment by ruxolitinib, both in subcutaneous as well as in orthotopic xenograft mouse models, without causing significant additional toxicity. In conclusion, VSV-GP has the potential to be a potent and safe oncolytic virus to treat ovarian cancer, especially when combined with an inhibitor of the interferon response. PMID:27738655
Cun, Biyun; Song, Xin; Jia, Renbing; Zhao, Xiaoping; Wang, Haibo; Ge, Shengfang; Fan, Xianqun
Uveal melanoma is the most common primary intraocular malignancy in adults; however, current therapeutic modalities, including chemotherapy, have not been successful. Oncolytic viruses serve as an emerging gene therapy tool for cancer treatment because they specifically kill tumor cells while sparing normal cells. The oncolytic virus H101 has been approved by the Chinese State Food and Drug Administration for the treatment of certain malignancies. Unfortunately, the monotherapy of adenovirus has demonstrated limited efficacy in a clinical setting. Thus, novel treatment strategies in which an oncolytic virus is combined with existing chemicals are advancing toward potential clinical use. In this study, we chose the combination of oncolytic virus H101 and the alkylating agent dacarbazine (DTIC) to treat uveal melanoma cells in vitro. Our results demonstrated that the combination exerted a synergistic antitumor effect without enhanced toxicity to normal cells via a type of cell cycle block other than the induction of apoptosis. Further investigation is warranted to elucidate the specific underlying mechanisms of this co-treatment therapy. Our study suggests the viro-chemo combination therapy is feasible and is a potentially promising approach for the treatment of uveal melanoma.
Deng, Lili; Fan, Jun; Guo, Mingming; Huang, Biao
Targeted oncolytic vaccinia viruses are being developed as a novel strategy in cancer therapy. Arming vaccinia viruses with immunostimulatory cytokines can enhance antitumor efficacy. Such engineered oncolytic viruses, like JX-594, a Wyeth strain vaccinia virus modified with human granulocyte-macrophage colony-stimulating factor (GM-CSF), have shown promising results and have proceeded rapidly in clinical trials. However, the oncolytic potential of the Chinese vaccine strain Tian Tan (VTT) has not been explored. In this study, we constructed a targeted oncolytic vaccinia virus of Tian Tan strain Guang9 (VG9) expressing murine GM-CSF (VG9-GMCSF) and evaluated the antitumor effect of this recombinant vaccinia virus in a murine melanoma model. In vitro, viral replication and cytotoxicity of VG9-GMCSF was as potent as VG9; in vivo, VG9-GMCSF significantly inhibited the growth of subcutaneously implanted melanoma tumors, prolonged the survival of tumor-bearing mice, and produced an antitumor cytotoxic response. Such antitumor effect may be due to the lytic nature of virus as well as the stimulation of immune activity by GM-CSF production. Our results indicate that VG9-GMCSF induces strong tumoricidal activity, providing a potential therapeutic strategy for combating cancer.
Goaster, Jacqueline Le; Bourée, Patrice; Ifergan, Charles; Tangy, Frederic; Olivier, René; Haenni, Anne-Lise
In 2012, a 50 year-old athletic male presented with weakness, pain and unilateral phrenic paralysis, followed by bilateral phrenic paralysis with deep dyspnea. In 2013, the Parsonage-Turner syndrome was diagnosed. When the patient was seen in September 2014 for the first time, he was facing phrenic neuromuscular failure, which led to the hypothesis of neurotropic herpes viruses. A control of the global serological anti-Herpes immunity to analyze his antibody (Ab) levels confirmed herpes immune genetic deficiency. An appropriate herpes chemotherapy treatment was proposed. Immediately, a spectacular recovery of the patient was observed, and after a few weeks, the respiratory function tests showed normal values. The hypothesis of the inductive role of viruses of the herpes family in the Parsonage-Turner syndrome was thus substantiated. The patient's immune deficiency covers the HSV2, HHV3, HHV4, HHV5 and HHV6 Ab levels. This led to the control of herpes in the family lineage: indeed, his daughter presented alterations of her serological herpes Ab levels.
Myers, Rachel; Coviello, Christian; Erbs, Philippe; Foloppe, Johann; Rowe, Cliff; Kwan, James; Crake, Calum; Finn, Seán; Jackson, Edward; Balloul, Jean-Marc; Story, Colin; Coussios, Constantin; Carlisle, Robert
Oncolytic viruses (OV) could become the most powerful and selective cancer therapies. However, the limited transport of OV into and throughout tumors following intravenous injection means their clinical administration is often restricted to direct intratumoral dosing. Application of physical stimuli, such as focused ultrasound, offers a means of achieving enhanced mass transport. In particular, shockwaves and microstreaming resulting from the instigation of an ultrasound-induced event known as inertial cavitation can propel OV hundreds of microns. We have recently developed a polymeric cup formulation which, when delivered intravenously, provides the nuclei for instigation of sustained inertial cavitation events within tumors. Here we report that exposure of tumors to focused ultrasound after intravenous coinjection of cups and oncolytic vaccinia virus , leads to substantial and significant increases in activity. When cavitation was instigated within SKOV-3 or HepG2 xenografts, reporter gene expression from vaccinia virus was enhanced 1,000-fold (P < 0.0001) or 10,000-fold (P < 0.001), respectively. Similar increases in the number of vaccinia virus genomes recovered from tumors were also observed. In survival studies, the application of cup mediated cavitation to a vaccinia virus expressing a prodrug converting enzyme provided significant (P < 0.05) retardation of tumor growth. This technology could improve the clinical utility of all biological therapeutics including OV. PMID:27375160
Auffinger, Brenda; Ahmed, Atique U; Lesniak, Maciej S
Glioblastoma multiforme, one of the most common and aggressive brain tumors in adults, is highly resistant to currently available therapies and often recurs. Due to its poor prognosis and difficult management, there is an urgent need for the development and translation of new anti-glioma therapeutic approaches into the clinic. In this context, oncolytic virotherapy arises as an exciting treatment option for glioma patients. These natural or genetically engineered viruses are able to effectively infect cancer cells, inducing a specific anti-tumor cytotoxic effect. In addition, some viruses have been redesigned to modulate glioma microenvironment, to express cytokines to boost a systemic anti-glioma immune response and to incorporate angiostatic genes to decrease glioma vasculature. Although recent clinical trials have confirmed the safety of oncolytic virotherapies in the brain, their moderate clinical efficacy has not yet matched the encouraging preclinical laboratory results. In this review, we will discuss the leading anti-glioma virotherapy approaches that are presently under preclinical and clinical evaluation. We will also review different delivery methods, in vivo virus behavior, fate, replication, intratumoral spread, activation of anti-tumor immune response, and targeting of glioma stem cells. We will focus on the advantages and limitations of each therapeutic approach and how to overcome these hurdles to effectively translate exciting laboratory results into promising clinical trials.
Sampath, Padma; Thorne, Steve H
Results from randomized clinical trials over the last several years have finally begun to demonstrate the potential of oncolytic viral therapies to treat a variety of cancers. One reason for these successes has been the realization that this platform is most effective when considered primarily as an immunotherapy. Cancer immunotherapy has also made dramatic strides recently with antibodies capable of blocking immune checkpoint inhibitors and adoptive T-cell therapies, notably CAR T-cells, leading a panel of novel and highly clinically effective therapies. It is clear therefore that an understanding of how and when these complementary approaches can most effectively be combined offers the real hope of moving beyond simply treating the disease and toward starting to talk about curative therapies. In this review we discuss approaches to combining these therapeutic platforms, both through engineering the viral vectors to more beneficially interact with the host immune response during therapy, as well as through the direct combinations of different therapeutics. This primarily, but not exclusively focuses on strains of oncolytic vaccinia virus. Some of the results reported to date, primarily in pre-clinical models but also in early clinical trials, are dramatic and hold great promise for the future development of similar therapies and their translation into cancer therapies.
Zamarin, Dmitriy; Holmgaard, Rikke B; Subudhi, Sumit K; Park, Joon Seok; Mansour, Mena; Palese, Peter; Merghoub, Taha; Wolchok, Jedd D; Allison, James P
Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, we explored the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses, leading to lymphocytic infiltrates and antitumor effect in distant (nonvirally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4(+) and CD8(+) T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.
Kottke, Timothy; Chester, John; Ilett, Elizabeth; Thompson, Jill; Diaz, Rosa; Coffey, Matt; Selby, Peter; Nuovo, Gerard; Pulido, Jose; Mukhopadhyay, Debabrata; Pandha, Hardev; Harrington, Kevin; Melcher, Alan; Vile, Richard
We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro- and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses.
Peng, K-W; Myers, R; Greenslade, A; Mader, E; Greiner, S; Federspiel, MJ; Dispenzieri, A; Russell, SJ
Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies whose titers increase progressively with each exposure, resulting in faster virus inactivation and further reductions in efficacy with each successive dose. A single dose of cyclophosphamide (CPA) at 370 mg m−2 was not sufficient to control the primary antiviral immune responses in mice, squirrel monkeys and humans. We therefore tested clinically approved multidose CPA regimens, which are known to kill proliferating lymphocytes, to determine if more intensive CPA therapy can more effectively suppress antiviral antibody responses during virotherapy. In virus-susceptible mice, primary antibody responses to intravenously (i.v.) administered oncolytic measles virus (MV) or vesicular stomatitis virus (VSV) were partially or completely suppressed, respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) CPA regimens initiated 1 day before virus. When MV- or VSV-immune mice were re-challenged with the respective viruses and concurrently treated with four daily systemic doses of CPA, their anamnestic antibody responses were completely suppressed and antiviral antibody titers fell significantly below pre-booster levels. We conclude that the CPA regimen of four daily doses at 370 mg m−2 should be evaluated clinically with i.v. virotherapy to control the antiviral antibody response and facilitate effective repeat dosing. PMID:22476202
Peng, K-W; Myers, R; Greenslade, A; Mader, E; Greiner, S; Federspiel, M J; Dispenzieri, A; Russell, S J
Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies whose titers increase progressively with each exposure, resulting in faster virus inactivation and further reductions in efficacy with each successive dose. A single dose of cyclophosphamide (CPA) at 370 mg m(-2) was not sufficient to control the primary antiviral immune responses in mice, squirrel monkeys and humans. We therefore tested clinically approved multidose CPA regimens, which are known to kill proliferating lymphocytes, to determine if more intensive CPA therapy can more effectively suppress antiviral antibody responses during virotherapy. In virus-susceptible mice, primary antibody responses to intravenously (i.v.) administered oncolytic measles virus (MV) or vesicular stomatitis virus (VSV) were partially or completely suppressed, respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) CPA regimens initiated 1 day before virus. When MV- or VSV-immune mice were re-challenged with the respective viruses and concurrently treated with four daily systemic doses of CPA, their anamnestic antibody responses were completely suppressed and antiviral antibody titers fell significantly below pre-booster levels. We conclude that the CPA regimen of four daily doses at 370 mg m(-2) should be evaluated clinically with i.v. virotherapy to control the antiviral antibody response and facilitate effective repeat dosing.
Kaliberov, Sergey A.; Kaliberova, Lyudmila N.; Buchsbaum, Donald J.; Curiel, David T.
Pancreatic cancer is a significant clinical problem and novel therapeutic approaches are desperately needed. Recent advances in conditionally replicative adenovirus-based (CRAd) oncolytic virus design allow the application of CRAd vectors as a therapeutic strategy to efficiently target and eradicate chemoresistant pancreatic cancer cells thereby improving the efficacy of pancreatic cancer treatment. The goal of this study was to construct and validate the efficacy of an infectivity-enhanced, liver-untargeted, tumor-specific CRAd vector. A panel of CRAds has been derived which embody the C-X-C chemokine receptor type 4 promoter for conditional replication, two fiber complex mosaicism for targeting expansion, and hexon hypervariable region 7 (HVR7) modification for liver untargeting. We evaluated CRAds for cancer virotherapy using a human pancreatic tumor xenograft model. Employment of the fiber mosaic approach improved CRAd replication in pancreatic tumor xenografts. Substitution of the HVR7 of the Ad5 hexon for Ad serotype 3 hexon resulted in decreased liver tropism of systemically administrated CRAd. Obtained data demonstrated that employment of complex mosaicism increased efficacy of the combination of oncolytic virotherapy with chemotherapy in a human pancreatic tumor xenograft model. PMID:24903014
El-Andaloussi, Nazim; Bonifati, Serena; Kaufmann, Johanna K; Mailly, Laurent; Daeffler, Laurent; Deryckère, François; Nettelbeck, Dirk M; Rommelaere, Jean; Marchini, Antonio
In this study, our goal was to generate a chimeric adenovirus-parvovirus (Ad-PV) vector that combines the high-titer and efficient gene transfer of adenovirus with the anticancer potential of rodent parvovirus. To this end, the entire oncolytic PV genome was inserted into a replication-defective E1- and E3-deleted Ad5 vector genome. As we found that parvoviral NS expression inhibited Ad-PV chimera production, we engineered the parvoviral P4 early promoter, which governs NS expression, by inserting into its sequence tetracycline operator elements. As a result of these modifications, P4-driven expression was blocked in the packaging T-REx-293 cells, which constitutively express the tetracycline repressor, allowing high-yield chimera production. The chimera effectively delivered the PV genome into cancer cells, from which fully infectious replication-competent parvovirus particles were generated. Remarkably, the Ad-PV chimera exerted stronger cytotoxic activities against various cancer cell lines, compared with the PV and Ad parental viruses, while being still innocuous to a panel of tested healthy primary human cells. This Ad-PV chimera represents a novel versatile anticancer agent which can be subjected to further genetic manipulations in order to reinforce its enhanced oncolytic capacity through arming with transgenes or retargeting into tumor cells.
Callegari, Elisa; Elamin, Bahaeldin K.; D’Abundo, Lucilla; Falzoni, Simonetta; Donvito, Giovanna; Moshiri, Farzaneh; Milazzo, Maddalena; Altavilla, Giuseppe; Giacomelli, Luciano; Fornari, Francesca; Hemminki, Akseli; Di Virgilio, Francesco; Gramantieri, Laura; Negrini, Massimo; Sabbioni, Silvia
The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR-199 target sites within the 3’ UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity. PMID:24069256
Villa, Nancy Y.; Wasserfall, Clive H.; Meacham, Amy M.; Wise, Elizabeth; Chan, Winnie; Wingard, John R.; McFadden, Grant
Allogeneic hematopoietic cell transplant (allo-HCT) can be curative for certain hematologic malignancies, but the risk of graft-versus-host disease (GVHD) is a major limitation for wider application. Ideally, strategies to improve allo-HCT would involve suppression of T lymphocytes that drive GVHD while sparing those that mediate graft-versus-malignancy (GVM). Recently, using a xenograft model, we serendipitously discovered that myxoma virus (MYXV) prevented GVHD while permitting GVM. In this study, we show that MYXV binds to resting, primary human T lymphocytes but will only proceed into active virus infection after the T cells receive activation signals. MYXV-infected T lymphocytes exhibited impaired proliferation after activation with reduced expression of interferon-γ, interleukin-2 (IL-2), and soluble IL-2Rα, but did not affect expression of IL-4 and IL-10. MYXV suppressed T-cell proliferation in 2 patterns (full vs partial) depending on the donor. In terms of GVM, we show that MYXV-infected activated human T lymphocytes effectively deliver live oncolytic virus to human multiple myeloma cells, thus augmenting GVM by transfer of active oncolytic virus to residual cancer cells. Given this dual capacity of reducing GVHD plus increasing the antineoplastic effectiveness of GVM, ex vivo virotherapy with MYXV may be a promising clinical adjunct to allo-HCT regimens. PMID:25904246
Villa, Nancy Y; Wasserfall, Clive H; Meacham, Amy M; Wise, Elizabeth; Chan, Winnie; Wingard, John R; McFadden, Grant; Cogle, Christopher R
Allogeneic hematopoietic cell transplant (allo-HCT) can be curative for certain hematologic malignancies, but the risk of graft-versus-host disease (GVHD) is a major limitation for wider application. Ideally, strategies to improve allo-HCT would involve suppression of T lymphocytes that drive GVHD while sparing those that mediate graft-versus-malignancy (GVM). Recently, using a xenograft model, we serendipitously discovered that myxoma virus (MYXV) prevented GVHD while permitting GVM. In this study, we show that MYXV binds to resting, primary human T lymphocytes but will only proceed into active virus infection after the T cells receive activation signals. MYXV-infected T lymphocytes exhibited impaired proliferation after activation with reduced expression of interferon-γ, interleukin-2 (IL-2), and soluble IL-2Rα, but did not affect expression of IL-4 and IL-10. MYXV suppressed T-cell proliferation in 2 patterns (full vs partial) depending on the donor. In terms of GVM, we show that MYXV-infected activated human T lymphocytes effectively deliver live oncolytic virus to human multiple myeloma cells, thus augmenting GVM by transfer of active oncolytic virus to residual cancer cells. Given this dual capacity of reducing GVHD plus increasing the antineoplastic effectiveness of GVM, ex vivo virotherapy with MYXV may be a promising clinical adjunct to allo-HCT regimens.
Mao, Li-jun; Zhang, Jie; Liu, Ning; Fan, Li; Yang, Dong-rong; Xue, Bo-xin; Shan, Yu-xi; Zheng, Jun-nian
Recent studies suggest that SATB1 is a promising therapeutic target for prostate cancer. To develop novel SATB1-based therapeutic agents for prostate cancer, in this study, we aimed to construct ZD55-SATB1, an oncolytic adenovirus ZD55 carrying shRNA targeting SATB1, and investigate its effects on the inhibition of prostate cancer growth and metastasis. ZD55-SATB1 was constructed and used to infect human prostate cancer cell lines DU145 and LNCaP. The inhibitory effect of ZD55-SATB1 on SATB1 expression was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The cytotoxicity of ZD55-SATB1 was detected by MTT assay. Cell invasion was detected by Matrigel invasion assay. The in vivo antitumor activities of ZD55-SATB1 were evaluated in xenograft mouse model. We found that ZD55-SATB1 selectively replicated and significantly reduced SATB1 expression in DU145 and LNCaP cells. ZD55-SATB1 effectively inhibited the viability and invasion of DU145 and LNCaP cells in vitro and inhibited prostate cancer growth and metastasis in xenograft nude mice. In conclusion, replicative oncolytic adenovirus armed with SATB1 shRNA exhibits effective antitumor effect in human prostate cancer. Our study provides the basis for the development of ZD55-SATB1 for the treatment of prostate cancer.
Msaouel, Pavlos; Dispenzieri, Angela; Galanis, Evanthia
Viruses have adapted through millennia of evolution to effectively invade and lyse cells through diverse mechanisms. Strains of the attenuated measles virus Edmonston (MV-Edm) vaccine lineage can preferentially infect and destroy cancerous cells while sparing the surrounding tissues. This specificity is predominantly due to overexpression of the measles virus receptor CD46 in tumor cells. To facilitate in vivo monitoring of viral gene expression and replication, these oncolytic strains have been engineered to either express soluble marker peptides, such as the human carcinoembryonic antigen (CEA; MV-CEA virus), or genes that facilitate imaging and therapy, such as the human thyroidal sodium iodide symporter (NIS) gene (MV-NIS). Preclinical efficacy and safety data for engineered oncolytic MV-Edm derivatives that led to their clinical translation are discussed in this review, and an overview of the early experience in three ongoing clinical trials of patients with ovarian cancer, glioblastoma multiforme and multiple myeloma is provided. The information obtained from these ongoing trials will guide the future clinical application and further development of MV strains as anticancer agents. PMID:19169959
Bartee, Eric; Bartee, Mee Y; Bogen, Bjarne; Yu, Xue-Zhong
Multiple myeloma is an incurable malignancy of plasma B-cells. Traditional chemotherapeutic regimes often induce initial tumor regression; however, virtually all patients eventually succumb to relapse caused by either reintroduction of disease during autologous transplant or expansion of chemotherapy resistant minimal residual disease. It has been previously demonstrated that an oncolytic virus known as myxoma can completely prevent myeloma relapse caused by reintroduction of malignant cells during autologous transplant. The ability of this virus to treat established residual disease in vivo, however, remained unknown. Here we demonstrate that intravenous administration of myxoma virus into mice bearing disseminated myeloma results in the elimination of 70–90% of malignant cells within 24 hours. This rapid debulking was dependent on direct contact of myxoma virus with residual myeloma and did not occur through destruction of the hematopoietic bone marrow niche. Importantly, systemic myxoma therapy also induced potent antimyeloma CD8+ T cell responses which localized to the bone marrow and were capable of completely eradicating established myeloma in some animals. These results demonstrate that oncolytic myxoma virus is not only effective at preventing relapse caused by reinfusion of tumor cells during stem cell transplant, but is also potentially curative for patients bearing established minimal residual disease. PMID:27933316
Wei, Na; Fan, Jun Kai; Gu, Jin Fa; He, Ling Feng; Tang, Wen Hao; Cao, Xin; Liu, Xin Yuan
Safety and efficiency are equally important to be considered in developing oncolytic adenovirus. Previously, we have reported that ZD55, an oncolytic adenovirus with the deletion of E1B-55K gene, exhibited potent antitumor activity. In this study, to improve the safety of ZD55, we utilized MUC1 promoter to replace the native promoter of E1A on the basis of ZD55, and generated a double-regulated adenovirus, named MUD55. Our data demonstrated that the expression of early and late genes of MUD55 was both reduced in MUC1-negative cells, resulting in its stricter glandular-tumor selective progeny production. The cytopathic effect of MUD55 was about 10-fold lower than mono-regulated adenovirus ZD55 or Ad.MUC1 in normal cells and not obviously attenuated in glandular tumor cells. Moreover, MUD55 showed the least liver toxicity when administrated by intravenous injection in nude mice. These results indicate that MUD55 could be a promising candidate for the treatment of adenocarcinoma.
Hirvinen, Mari; Rajecki, Maria; Kapanen, Mika; Parviainen, Suvi; Rouvinen-Lagerström, Noora; Diaconu, Iulia; Nokisalmi, Petri; Tenhunen, Mikko; Hemminki, Akseli; Cerullo, Vincenzo
For long it has been recognized that tumor necrosis factor alpha (TNFa) has anticancer characteristics, and its use as a cancer therapeutic was proposed already in the 1980s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency, and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore, the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene-mediated direct effect such as TNFa-mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa-expressing adenovirus showed increased cancer-eradicating potency, which was shown to be because of elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24-hTNFa-treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and antitumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy.
Levinson, Rebecca T.; Hulgan, Todd; Kalams, Spyros A.; Fessel, Joshua P.; Samuels, David C.
Background. Herpes zoster, or shingles, is a common, painful reactivation of latent varicella zoster virus infection. Understanding host factors that predispose to herpes zoster may permit development of more effective prevention strategies. Our objective was to examine mitochondrial haplogroups as a potential host factor related to herpes zoster incidence. Methods. Study participants were drawn from BioVU, a deoxyribonucleic acid (DNA) biobank connected to deidentified electronic medical records (EMRs) from Vanderbilt University Medical Center. Our study used 9691 Caucasian individuals with herpes zoster status determined by International Classification of Diseases, Ninth Revision codes 053–053.9. Cases and controls were matched on sex and date of birth within 5 years. Mitochondrial haplogroups were defined from mitochondrial DNA variants genotyped on the Illumina 660W or Illumina Infinium Human-Exome Beadchip. Sex and date of birth were extracted from the EMR. Results. European mitochondrial haplogroup H had a protective association with herpes zoster status (odds ratio [OR] = .82; 95% confidence interval [CI], .71–.94; P = .005), whereas haplogroup clade IWX was a risk factor for herpes zoster status (OR = 1.38; 95% CI, 1.07–1.77; P = .01). Conclusions. Mitochondrial haplogroup influences herpes zoster risk. Knowledge of a patient's mitochondrial haplogroup could allow for a precision approach to the management of herpes zoster risk through vaccination strategies and management of other modifiable risk factors. PMID:27807590
Hales, Craig M; Harpaz, Rafael; Ortega-Sanchez, Ismael; Bialek, Stephanie R
Herpes zoster vaccine (Zostavax [Merck & Co., Inc.]) was licensed in 2006 and recommended by the Advisory Committee on Immunization Practices (ACIP) in 2008 for prevention of herpes zoster (shingles) and its complications among adults aged ≥60 years. The Food and Drug Administration (FDA) approved the use of Zostavax in 2011 for adults aged 50 through 59 years based on a large study of safety and efficacy in this age group. ACIP initially considered the use of herpes zoster vaccine among adults aged 50 through 59 years in June 2011, but declined to recommend the vaccine in this age group, citing shortages of Zostavax and limited data on long-term protection afforded by herpes zoster vaccine. In October 2013, ACIP reviewed the epidemiology of herpes zoster and its complications, herpes zoster vaccine supply, short-term vaccine efficacy in adults aged 50 through 59 years, short- and long- term vaccine efficacy and effectiveness in adults aged ≥60 years, an updated cost-effectiveness analysis, and deliberations of the ACIP herpes zoster work group, all of which are summarized in this report. No vote was taken, and ACIP maintained its current recommendation that herpes zoster vaccine be routinely recommended for adults aged ≥60 years. Meeting minutes are available at http://www.cdc.gov/vaccines/acip/meetings/meetings-info.html.
Levinson, Rebecca T; Hulgan, Todd; Kalams, Spyros A; Fessel, Joshua P; Samuels, David C
Background. Herpes zoster, or shingles, is a common, painful reactivation of latent varicella zoster virus infection. Understanding host factors that predispose to herpes zoster may permit development of more effective prevention strategies. Our objective was to examine mitochondrial haplogroups as a potential host factor related to herpes zoster incidence. Methods. Study participants were drawn from BioVU, a deoxyribonucleic acid (DNA) biobank connected to deidentified electronic medical records (EMRs) from Vanderbilt University Medical Center. Our study used 9691 Caucasian individuals with herpes zoster status determined by International Classification of Diseases, Ninth Revision codes 053-053.9. Cases and controls were matched on sex and date of birth within 5 years. Mitochondrial haplogroups were defined from mitochondrial DNA variants genotyped on the Illumina 660W or Illumina Infinium Human-Exome Beadchip. Sex and date of birth were extracted from the EMR. Results. European mitochondrial haplogroup H had a protective association with herpes zoster status (odds ratio [OR] = .82; 95% confidence interval [CI], .71-.94; P = .005), whereas haplogroup clade IWX was a risk factor for herpes zoster status (OR = 1.38; 95% CI, 1.07-1.77; P = .01). Conclusions. Mitochondrial haplogroup influences herpes zoster risk. Knowledge of a patient's mitochondrial haplogroup could allow for a precision approach to the management of herpes zoster risk through vaccination strategies and management of other modifiable risk factors.
Chernakova, G M; Kleshcheva, E A; Semenova, T B
Approximately a quarter of the world's population at some point in life is at risk of developing shingles (Herpes Zoster). In 10-20% of cases the first branch of the trigeminal nerve gets involved (Herpes Zoster Ophthalmicus, HZO). Ophthalmic complications of HZO are able to cause a significant reduction in visual function.
Li, De-Kun; Raebel, Marsha A; Cheetham, T Craig; Hansen, Craig; Avalos, Lyndsay; Chen, Hong; Davis, Robert
To examine the risks of genital herpes and antiherpes treatment during pregnancy in relation to preterm delivery (PTD), we conducted a multicenter, member-based cohort study within 4 Kaiser Permanente regions: northern and southern California, Colorado, and Georgia. The study included 662,913 mother-newborn pairs from 1997 to 2010. Pregnant women were classified into 3 groups based on genital herpes diagnosis and treatment: genital herpes without treatment, genital herpes with antiherpes treatment, and no herpes diagnosis or treatment (unexposed controls). After controlling for potential confounders, we found that compared with being unexposed, having untreated genital herpes during first or second trimester was associated with more than double the risk of PTD (odds ratio (OR) = 2.23, 95% confidence interval (CI): 1.80, 2.76). The association was stronger for PTD due to premature rupture of membrane (OR = 3.57, 95% CI: 2.53, 5.06) and for early PTD (≤35 weeks gestation) (OR = 2.87, 95% CI: 2.22, 3.71). In contrast, undergoing antiherpes treatment during pregnancy was associated with a lower risk of PTD compared with not being treated, and the PTD risk was similar to that observed in the unexposed controls (OR = 1.11, 95% CI: 0.89, 1.38). The present study revealed increased risk of PTD associated with genital herpes infection if left untreated and a potential benefit of antiherpes medications in mitigating the effect of genital herpes infection on the risk of PTD.
Rigamonti, Andrea; Lauria, Giuseppe; Mantero, Vittorio; Salmaggi, Andrea
Late relapse of herpes simplex encephalitis, defined as recurrence more than 3 months after the first initial encephalitic episode, is a rare condition. We describe the case of an adult patient who presented a relapse of herpes simplex encephalitis 8 years after the first episode occurred at the age of 57 years and review the literature of this topic.
Mell, Howard K
The epidemiology of oral and genital herpes has dramatically changed over the past decade. Herpes simplex virus-1, traditionally associated with oral herpes, is now implicated in an increasing percentage of genital herpes cases. The possibility of "autoinoculation" (or self-infection) of anatomic sites other than that of the primary infection has been recognized. New methods of suppression therapy are being examined. These changes have led to a revision in the recommendations by the Centers for Disease Control and Prevention (CDC). This review discusses herpes infections of the oral and genital mucosa and the suggested approach to the infected patient who presents in the emergency department. Specific attention is given to the CDC's 2006 guidelines for the treatment of sexually transmitted diseases.
Mark, Hayley D; Lucea, Marguerite; Nanda, Joy P; Farley, Jason E; Gilbert, Lisa
This cross-sectional survey explored the frequency of genital herpes testing among 110 people living with HIV (PLWH) and reported barriers and facilitators related to testing. Forty-four percent of the respondents had not been tested for genital herpes since receiving an HIV diagnosis, 34% had been tested, and 22% preferred not to say. Respondents' most frequently cited factors affecting a decision to not be tested were: (a) testing not being recommended by a provider, (b) not having herpes symptoms, and (c) not thinking they had herpes. Data from this study indicated that PLWH were not frequently tested for genital herpes; there was a limited understanding of the frequently subclinical nature of infection; and provider recommendations for testing, or lack thereof, affected testing decisions.
Awasthi, Sita; Friedman, Harvey M
A half billion people have genital herpes infections worldwide. Approximately one-fifth of American women between ages 14 and 49 are HSV-2 seropositive. The development of an effective genital herpes vaccine is a global health necessity based on the mental anguish genital herpes causes for some individuals, the fact that pregnant women with genital herpes risk transmitting infection to their newborn children, and the observation that HSV-2 infection is associated with a 3-fold to 4-fold increased probability of HIV acquisition. We review the strengths and limitations of preclinical animal models used to assess genital herpes vaccine candidates and the goals of prophylactic and therapeutic vaccines. We also discuss the current pipeline of vaccine candidates and lessons learned from past clinical trials that serve as a stimulus for new strategies, study designs and endpoint determinations.
Lavery, Eric A; Coyle, Walter J
Herpes simplex virus (HSV) infection is well known as a sexually transmitted disease. However, relatively little has been published concerning the presentations and treatment of HSV infection within the gastrointestinal tract, where HSV most commonly affects the esophagus in both immunocompromised and immunocompetent patients. HSV proctitis is not uncommon and occurs primarily in males having sex with males. In patients with normal immune systems, gastrointestinal HSV infections are generally self-limited and rarely require antiviral therapy. Treatment of infection is suggested for immunocompromised patients, though no large randomized controlled trials have been performed. This article reviews the manifestations of HSV infection within the luminal gastrointestinal tract and options for diagnosis and treatment.
Jha, S; Jose, M; Kumar, V
Herpes Simplex Encephalitis (HSE) is the most common cause of fatal viral encephalitis. A high index of suspicion is mandatory for early diagnosis and successful therapy to restrict morbidity and mortality. We report 4 patients of HSE, with interesting presentations, viz. brainstem involvement in an immunosuppressed patient, Kluver-Bucy Syndrome-a consequence of untreated HSE, HSE in the postpartum period mistaken as cortical venous thrombosis, and response to inadequate treatment. They demonstrate the wide spectrum of clinical features, pitfalls in diagnosis, and a variable response to therapy in HSE.
Balasubramaniam, Ramesh; Kuperstein, Arthur S; Stoopler, Eric T
Oral herpes virus infections (OHVIs) are among the most common mucosal disorders encountered by oral health care providers. These infections can affect individuals at any age, from infants to the elderly, and may cause significant pain and dysfunction. Immunosuppressed patients may be at increased risk for serious and potential life-threatening complications caused by OHVIs. Clinicians may have difficulty in diagnosing these infections because they can mimic other conditions of the oral mucosa. This article provides oral health care providers with clinically relevant information regarding etiopathogenesis, diagnosis, and management of OHVIs.
Pizzuto, Matteo S.; Silic-Benussi, Micol; Pavone, Silvia; Ciminale, Vincenzo; Capua, Ilaria
ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3- and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCE Despite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These
Laudes, Matthias; Bilkovski, Roman; Oberhauser, Frank; Droste, Andrea; Gomolka, Matthias; Leeser, Uschi; Udelhoven, Michael; Krone, Wilhelm
Generation of new adipocytes plays a major role in the development of obesity. We previously have shown that transcriptional repressor factor that binds to IST (FBI)-1 exerts a dual effect in the process of adipogenesis by inhibiting proliferation and promoting differentiation of preadipocytes. The aim of the present study was to identify FBI-1 regulated molecular effectors that could account for these effects. Overexpressing FBI-1 in preadipocytes resulted in reduced expression of the cell cycle regulator cyclin A, which may explain FBI-1 induced inhibition of proliferation. Interestingly, FBI-1 repressed cyclin A promoter activity through an indirect mechanisms that did not involve direct binding of FBI-1 to the promoter sequence, but rather FBI-1 inhibition of transcriptional activator Sp1 binding to a regulatory element at -452 to -443. We also show that FBI-1 promotes terminal preadipocyte differentiation through a mechanism involving decreased levels of expression of the PPARgamma inhibitor E2F-4. FBI-1 significantly reduced E2F-4 promoter activity. Contrary to cyclin A, we found FBI-1-induced repression of E2F-4 is mediated by a direct mechanism via a FBI-1 regulatory element at -11 to -5. As function of transcriptional repressors normally depends on the presence of regulatory co-factors we also performed expression profiling of potential FBI-1 co-repressors throughout adipogenesis. In these experiments Sin3A and histon deacetylase (HDAC)-1 showed a similar expression pattern compared to FBI-1. Strikingly, co-immunoprecipitation studies revealed that FBI-1 binds Sin3A and HDAC-1 to form a repressor complex. Furthermore, by mutational analysis the amino terminal Poxvirus (POZ) domain of FBI-1 was found to be important for Sin3A and HDAC-1 binding. Taken together, FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms.
Jacquier-Sarlin, M R; Polla, B S
The heat-shock (HS) response is a ubiquitous cellular response to stress, involving the transcriptional activation of HS genes. Reactive oxygen species (ROS) have been shown to regulate the activity of a number of transcription factors. We investigated the redox regulation of the stress response and report here that in the human pre-monocytic line U937 cells, H2O2 induced a concentration-dependent transactivation and DNA-binding activity of heat-shock factor-1 (HSF-1). DNA-binding activity was, however, lower with H2O2 than with HS. We thus hypothesized a dual regulation of HSF by oxidants. We found that oxidizing agents, such as H2O2 and diamide, as well as alkylating agents, such as iodoacetic acid, abolished, in vitro, the HSF-DNA-binding activity induced by HS in vivo. The effects of H2O2 in vitro were reversed by the sulphydryl reducing agent dithiothreitol and the endogenous reductor thioredoxin (TRX), while the effects of iodoacetic acid were irreversible. In addition, TRX also restored the DNA-binding activity of HSF oxidized in vivo, while it was found to be itself induced in vivo by both HS and H2O2. Thus, H2O2 exerts dual effects on the activation and the DNA-binding activity of HSF: on the one hand, H2O2 favours the nuclear translocation of HSF, while on the other, it alters HSF-DNA-binding activity, most likely by oxidizing critical cysteine residues within the DNA-binding domain. HSF thus belongs to the group of ROS-modulated transcription factors. We propose that the time required for TRX induction, which may restore the DNA-binding activity of oxidized HSF, provides an explanation for the delay in heat-shock protein synthesis upon exposure of cells to ROS. PMID:8761470
Zhang, Huijuan; Hong, Yongbo; Huang, Lei; Li, Dayong; Song, Fengming
ERF transcription factors play critical roles in plant immune responses. Here, we report the function of AtERF014, a nucleus-localized transcriptional activator, in Arabidopsis immunity. Expression of AtERF014 was induced by Pseudomonas syringae pv. tomato (Pst) and Botrytis cinerea (Bc). AtERF014-overexpressing (OE) plants displayed increased Pst resistance but decreased Bc resistance, whereas AtERF014-RNAi plants exhibited decreased Pst resistance but increased Bc resistance. After Pst infection, expression of salicylic acid (SA)-responsive genes AtPR1 and AtPR5 in AtERF014-OE plants and of a jasmonic acid/ethylene-responsive gene AtPDF1.2 in AtERF014-RNAi plants was intensified but expression of AtPDF1.2 in AtERF014-OE plants and of AtPR1 and AtPR5 in AtERF014-RNAi plants was weakened. After Bc infection, expression of AtPR1 and AtPR5 in AtERF014-OE plants was attenuated but expression of AtPR1, AtPR5 and AtPDF1.2 in AtERF014-RNAi plants was strengthened. Pathogen- and flg22-induced ROS burst, expression of PTI genes and SA-induced defense were partially suppressed in AtERF014-RNAi plants, whereas pathogen-induced ROS and flg22-induced immune response were strengthened in AtER014-OE plants. Altered expression of AtERR014 affected expression of pectin biosynthetic genes and pectin content in AtERF014-RNAi plants was decreased. These data demonstrate that AtERF014 acts as a dual regulator that differentially modulates immunity against Pst and Bc in Arabidopsis. PMID:27445230
Natsubori, Akiyo; Honma, Ken-ichi; Honma, Sato
Behavioral rhythms induced by methamphetamine (MAP) treatment in rats are independent of the circadian pacemaker in the suprachiasmatic nucleus (SCN). To know the site and mechanism of an underlying oscillation (MAP-induced oscillator; MAO), extra-SCN circadian rhythms in the discrete brain areas were examined in rats with and without the SCN. To fix the phase of MAO, MAP was supplied in drinking water at a restricted time of day for 14 days (R-MAP) and subsequently given ad libitum (ad-MAP). Plain water was given to the controls at the same restricted time (R-Water). Clock gene Per2 expression was measured by a bioluminescence reporter in cultured brain tissues. In SCN-intact rats, MAO was induced by R-MAP and behavioral rhythms were phase-delayed from the restricted time under ad-MAP with relative coordination. Circadian Per2 rhythms in R-MAP rats were not affected in the SCN but were slightly phase-advanced in the olfactory bulb (OB), caudate-putamen (CPU) and substantia nigra (SN) as compared with R-Water rats. Following SCN lesion, R-MAP-induced MAO phase-shifted more slowly and did not show a sign of relative coordination. In these rats, circadian Per2 rhythms were significantly phase-shifted in the OB and SN as compared with SCN-intact rats. These findings indicate that MAO was induced by MAP given at a restricted time of day in association with phase-shifts of the extra-SCN circadian oscillators in the brain dopaminergic areas. The findings also suggest that these extra-SCN oscillators are the components of MAO and receive dual regulation by MAO and the SCN circadian pacemaker.
Zhang, Huijuan; Hong, Yongbo; Huang, Lei; Li, Dayong; Song, Fengming
ERF transcription factors play critical roles in plant immune responses. Here, we report the function of AtERF014, a nucleus-localized transcriptional activator, in Arabidopsis immunity. Expression of AtERF014 was induced by Pseudomonas syringae pv. tomato (Pst) and Botrytis cinerea (Bc). AtERF014-overexpressing (OE) plants displayed increased Pst resistance but decreased Bc resistance, whereas AtERF014-RNAi plants exhibited decreased Pst resistance but increased Bc resistance. After Pst infection, expression of salicylic acid (SA)-responsive genes AtPR1 and AtPR5 in AtERF014-OE plants and of a jasmonic acid/ethylene-responsive gene AtPDF1.2 in AtERF014-RNAi plants was intensified but expression of AtPDF1.2 in AtERF014-OE plants and of AtPR1 and AtPR5 in AtERF014-RNAi plants was weakened. After Bc infection, expression of AtPR1 and AtPR5 in AtERF014-OE plants was attenuated but expression of AtPR1, AtPR5 and AtPDF1.2 in AtERF014-RNAi plants was strengthened. Pathogen- and flg22-induced ROS burst, expression of PTI genes and SA-induced defense were partially suppressed in AtERF014-RNAi plants, whereas pathogen-induced ROS and flg22-induced immune response were strengthened in AtER014-OE plants. Altered expression of AtERR014 affected expression of pectin biosynthetic genes and pectin content in AtERF014-RNAi plants was decreased. These data demonstrate that AtERF014 acts as a dual regulator that differentially modulates immunity against Pst and Bc in Arabidopsis.
Fan, Qing; Kopp, Sarah; Connolly, Sarah A.; Muller, William J.; Longnecker, Richard
Glycoprotein D (gD) of herpes simplex virus type 1 (HSV-1) is one of four glycoproteins essential for HSV entry and cell fusion. The purpose of this study was to determine the plasticity of gD to tolerate insertion or deletion mutations and to construct an oncolytic HSV-1 that utilizes the disialoganglioside GD2 as a HSV-1 entry receptor. We found that the N-terminus of gD tolerates long insertions, whereas residues adjacent to the gD Ig-like V-type core tolerated shorter insertions (up to 15 amino acids), but not greater than 60 amino acids. Recombinant HSV-1 containing the ch14.18 single chain variable fragment (scFv) at the N-terminus of gD failed to mediate entry, even though the ch14.18 scFv-gD chimera Fc bound to neuroblastoma cells expressing GD2. Finally, we found that hyperfusogenic gB mutants enhanced fusion to a greater degree with the gB receptor the paired immunoglobulin-like type 2 receptor alpha (PILRα) than with gD receptors HVEM and nectin-1. Hyperfusogenic gB could restore the fusion function with PILRα when a gD constructed contained only the “profusion domain” (PFD), suggesting the hyperfusogenic form of gB may regulate fusion of PILRα via a novel mechanism through gH/gL and the gD PFD. PMID:28255168
Arulanandam, Rozanne; Batenchuk, Cory; Varette, Oliver; Zakaria, Chadi; Garcia, Vanessa; Forbes, Nicole E; Davis, Colin; Krishnan, Ramya; Karmacharya, Raunak; Cox, Julie; Sinha, Anisha; Babawy, Andrew; Waite, Katherine; Weinstein, Erica; Falls, Theresa; Chen, Andrew; Hamill, Jeff; De Silva, Naomi; Conrad, David P; Atkins, Harold; Garson, Kenneth; Ilkow, Carolina; Kærn, Mads; Vanderhyden, Barbara; Sonenberg, Nahum; Alain, Tommy; Le Boeuf, Fabrice; Bell, John C; Diallo, Jean-Simon
In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.
Carceller, Fernando; Aleu, Aitziber; Casasco, Alfredo; Guimaraens, Leopoldo; López-Pino, Migel A; Madero, Luís; Ramírez, Manuel
New therapies are needed to improve current results in diffuse intrinsic pontine glioma. We present here the initial experience of administering Celyvir, autologous mesenchymal stem cells infected with ICOVIR-5, an oncolytic adenovirus that selectively replicates in cancer cells, by means of superselective intra-arterial delivery, in a patient diagnosed of diffuse intrinsic pontine glioma. Feasibility, safety, and morbidity rates of the superselective catheterization technique are comparable with those of diagnostic angiography. The intra-arterial approach warrants a greater contact of the mesenchymal stem cells with the tumor mass, and minimizes hemorrhages or vascular disruption. The tolerance to the 2 administrations was excellent, with no acute or delayed adverse effect, underscoring the feasibility of this technique for the delivery of virotherapies and/or cellular therapies in this location.
Fan Junkai; Xiao Tian; Gu Jinfa; Wei Na; He Lingfeng; Ding Miao; Liu Xinyuan
Angiogenesis plays a key role in the development of a wide variety of malignant tumors. The approach of targeting antiangiogenesis has become an important field of cancer gene therapy. In this study, the antiangiogenesis protein K5 (the kringle 5 of human plasminogen) has been mutated by changing leucine71 to arginine to form mK5. Then the ZD55-mK5, which is an oncolytic adenovirus expressing mK5, was constructed. It showed stronger inhibition on proliferation of human umbilical vein endothelial cell. Moreover, in tube formation and embryonic chorioallantoic membrane assay, ZD55-mK5 exhibited more effective antiangiogenesis than ZD55-K5. In addition, ZD55-mK5 generated obvious suppression on the growth of colorectal tumor xenografts and prolonged the life span of nude mice. These results indicate that ZD55-mK5 is a potent agent for inhibiting the tumor angiogenesis and tumor growth.
Forbes, Nicole E.; Krishnan, Ramya; Diallo, Jean-Simon
Oncolytic viruses (OVs) not only kill cancer cells by direct lysis but also generate a significant anti-tumor immune response that allows for prolonged cancer control and in some cases cures. How to best stimulate this effect is a subject of intense investigation in the OV field. While pharmacological manipulation of the cellular innate anti-viral immune response has been shown by several groups to improve viral oncolysis and spread, it is increasingly clear that pharmacological agents can also impact the anti-tumor immune response generated by OVs and related tumor vaccination strategies. This review covers recent progress in using pharmacological agents to improve the activity of OVs and their ability to generate robust anti-tumor immune responses. PMID:25101247
Gomez-Gutierrez, Jorge G.; Nitz, Jonathan; Sharma, Rajesh; Wechman, Stephen L.; Riedinger, Eric; Martinez-Jaramillo, Elvis; Zhou, Heshan Sam; McMasters, Kelly M.
Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial. PMID:26561948
Laborda, Eduardo; Puig-Saus, Cristina; Cascalló, Manel; Chillón, Miguel
Abstract The contamination of adenovirus (Ad) stocks with adeno-associated viruses (AAV) is usually unnoticed, and it has been associated with lower Ad yields upon large-scale production. During Ad propagation, AAV contamination needs to be detected routinely by polymerase chain reaction without symptomatic suspicion. In this study, we describe that the coinfection of either Ad wild type 5 or oncolytic Ad with AAV results in a large-plaque phenotype associated with an accelerated release of Ad from coinfected cells. This accelerated release was accompanied with the expected decrease in Ad yields in two out of three cell lines tested. Despite this lower Ad yield, coinfection with AAV accelerated cell death and enhanced the cytotoxicity mediated by Ad propagation. Intratumoral coinjection of Ad and AAV in two xenograft tumor models improved antitumor activity and mouse survival. Therefore, we conclude that accidental or intentional AAV coinfection has important implications for Ad-mediated virotherapy. PMID:24020980
Greenwood, R; Bhalla, A; Gordon, A; Roberts, J
Bizarre behaviour disturbances in four patients occurring during incomplete recovery from herpes simplex encephalitis are described. Some aspects of their behaviour were similar to that originally described by Klüver and Bucy in monkeys following bilateral temporal lobectomy. Previous reports of behavioural disturbances in man after herpes simplex encephalitis are reviewed and attention drawn to the aggressive and disruptive behaviour that is often seen. With the reduced mortality in herpes simplex encephalitis in recent years it is possible that behaviour disturbances such as those described here will be seen more frequently. Images PMID:6619889
Tomkins, Andrew; White, Catherine; Higgins, Stephen Peter
We report the case of an 18-year-old woman presenting with ulceration of the cervix caused by primary type 2 herpes simplex infection in the absence of skin lesions. The differential diagnosis included cervical cancer and we referred the patient for urgent colposcopy. However, laboratory tests proved the viral aetiology of the cervical ulceration and the cervix had healed completely 3 weeks later. The case highlights the need to consider herpes simplex infection in the differential diagnosis of ulceration of the cervix even when there are no cutaneous signs of herpes.
Choi, Joung-Woo; Jung, Soo-Jung; Kasala, Dayananda; Hwang, June Kyu; Hu, Jun; Bae, You Han; Yun, Chae-Ok
Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH 6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH 6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH 7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX. PMID:25575865
Meseck, M.; Derecho, I.; Lopez, P.; Knoblauch, C.; McMahon, R.; Anderson, J.; Dunphy, N.; Quezada, V.; Khan, R.; Huang, P.; Dang, W.; Luo, M.; Hsu, D.; Woo, S.L.C.; Couture, L.
Abstract Vesicular stomatitis virus (VSV) is an oncolytic virus currently being investigated as a promising tool to treat cancer because of its ability to selectively replicate in cancer cells. To enhance the oncolytic property of the nonpathologic laboratory strain of VSV, we generated a recombinant vector [rVSV(MΔ51)-M3] expressing murine gammaherpesvirus M3, a secreted viral chemokine-binding protein that binds to a broad range of mammalian chemokines with high affinity. As previously reported, when rVSV(MΔ51)-M3 was used in an orthotopic model of hepatocellular carcinoma (HCC) in rats, it suppressed inflammatory cell migration to the virus-infected tumor site, which allowed for enhanced intratumoral virus replication leading to increased tumor necrosis and substantially prolonged survival. These encouraging results led to the development of this vector for clinical translation in patients with HCC. However, a scalable current Good Manufacturing Practice (cGMP)-compliant manufacturing process has not been described for this vector. To produce the quantities of high-titer virus required for clinical trials, a process that is amenable to GMP manufacturing and scale-up was developed. We describe here a large-scale (50-liter) vector production process capable of achieving crude titers on the order of 109 plaque-forming units (PFU)/ml under cGMP. This process was used to generate a master virus seed stock and a clinical lot of the clinical trial agent under cGMP with an infectious viral titer of approximately 2 × 1010 PFU/ml (total yield, 1 × 1013 PFU). The lot has passed all U.S. Food and Drug Administration-mandated release testing and will be used in a phase 1 clinical translational trial in patients with advanced HCC. PMID:21083425
Choi, Joung-Woo; Jung, Soo-Jung; Kasala, Dayananda; Hwang, June Kyu; Hu, Jun; Bae, You Han; Yun, Chae-Ok
Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX.
Wares, Joanna R; Crivelli, Joseph J; Yun, Chae-Ok; Choi, Il-Kyu; Gevertz, Jana L; Kim, Peter S
Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.
Ausubel, L J; Meseck, M; Derecho, I; Lopez, P; Knoblauch, C; McMahon, R; Anderson, J; Dunphy, N; Quezada, V; Khan, R; Huang, P; Dang, W; Luo, M; Hsu, D; Woo, S L C; Couture, L
Vesicular stomatitis virus (VSV) is an oncolytic virus currently being investigated as a promising tool to treat cancer because of its ability to selectively replicate in cancer cells. To enhance the oncolytic property of the nonpathologic laboratory strain of VSV, we generated a recombinant vector [rVSV(MΔ51)-M3] expressing murine gammaherpesvirus M3, a secreted viral chemokine-binding protein that binds to a broad range of mammalian chemokines with high affinity. As previously reported, when rVSV(MΔ51)-M3 was used in an orthotopic model of hepatocellular carcinoma (HCC) in rats, it suppressed inflammatory cell migration to the virus-infected tumor site, which allowed for enhanced intratumoral virus replication leading to increased tumor necrosis and substantially prolonged survival. These encouraging results led to the development of this vector for clinical translation in patients with HCC. However, a scalable current Good Manufacturing Practice (cGMP)-compliant manufacturing process has not been described for this vector. To produce the quantities of high-titer virus required for clinical trials, a process that is amenable to GMP manufacturing and scale-up was developed. We describe here a large-scale (50-liter) vector production process capable of achieving crude titers on the order of 10(9) plaque-forming units (PFU)/ml under cGMP. This process was used to generate a master virus seed stock and a clinical lot of the clinical trial agent under cGMP with an infectious viral titer of approximately 2 × 10(10) PFU/ml (total yield, 1 × 10(13) PFU). The lot has passed all U.S. Food and Drug Administration-mandated release testing and will be used in a phase 1 clinical translational trial in patients with advanced HCC.
Choi, Joung-Woo; Kim, Hyun Ah; Nam, Kihoon; Na, Youjin; Yun, Chae-Ok; Kim, SungWan
Despite adenovirus (Ad) vector's numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma.
Anderson, Bambi D; Nakamura, Takafumi; Russell, Stephen J; Peng, Kah-Whye
Live attenuated Edmonston B strain of measles virus (MV-Edm) is a potent and specific oncolytic agent, but the mechanism underlying its tumor selectivity is unknown. The virus causes cytopathic effects (CPEs) of extensive syncytial formation in tumor cells but minimal damage or cell killing in normal cells. The CPE is dependent on expression of viral proteins and the presence of CD46, the major cellular receptor of MV-Edm. Using a virally encoded soluble marker peptide to provide a quantitative readout of the level of viral gene expression, we determined that tumor cells and normal cells expressed comparable levels of viral proteins. CD46 mediates virus attachment, entry, and virus-induced cell-to-cell fusion. Using engineered cells expressing a range of CD46 densities, we determined that whereas virus entry increased progressively with CD46 density, cell fusion was minimal at low receptor densities but increased dramatically above a threshold density of CD46 receptors. It is well established that tumor cells express abundant CD46 receptors on their surfaces compared with their normal counterparts. Thus, at low CD46 densities typical of normal cells, infection occurs, but intercellular fusion is negligible. At higher densities typical of tumor cells, infection leads to extensive cell fusion. Intercellular fusion also results in enhancement of viral gene expression through recruitment of neighboring uninfected cells into the syncytium, further amplifying the CPE. Discrimination between high and low CD46 receptor density provides a compelling basis for the oncolytic specificity of MV-Edm and establishes MV-Edm as a promising CD46-targeted cancer therapeutic agent.
Haug, Bengt Erik; Camilio, Ketil André; Eliassen, Liv Tone; Stensen, Wenche; Svendsen, John Sigurd; Berg, Kristel; Mortensen, Bjarte; Serin, Guillaume; Mirjolet, Jean-Francois; Bichat, Francis; Rekdal, Øystein
Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate. This peptide showed relative high plasma protein binding abilities and a human plasma half-life of 160 min, resulting in formation of nontoxic metabolites. In addition, the lead candidate demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study.
Ganova, L A; Kovtoniuk, G V; Korshun, L N; Kiseleva, E K; Tereshchenko, M I; Vudmaska, M I; Moĭsa, L N; Shevchuk, V A; Spivak, N Ia
The lysate and recombinant antigens of various production included informula of ELISA-test-systems were analyzed. The ELISA-test-systems are used for detection of IgG to Herpes simplex virus type I and II. For testing the panel of serums PTH 201 (BBI Inc.) were used. The samples of this panel contain antibodies to Herpes simplex virus type I and II in mixed titers. The 69 serums of donors were used too (17 samples had IgG to Herpes simplex virus type I, 23 samples to Herpes simplex virus type II and 29 samples had no antibodies to Herpes simplex virus). The diagnostic capacity of mixture of recombinant antigens gG1 Herpes simplex virus type I and gG2 Herpes simplex virus type II (The research-and-production complex "DiaprofMed") was comparable with mixture of lysate antigen Herpes simplex virus type I and II (Membrane) EIE Antigen ("Virion Ltd."). In the test-systems for differentiation of IgG to Herpes simplex virus type I the recombinant antigen gG1 Herpes simplex virus type I proved to be comparable with commercial analogue Herpes simplex virus-1 gG1M ("Viral Therapeutics Inc."'). At the same time, capacity to detect IgG to Herpes simplex virus type II in recombinant protein gG2 Herpes simplex virus type II is significantly higher than in its analogue Herpes simplex virus-2 gG2c ("Viral Therapeutics Inc.").
Zhang, Haipeng; Lin, Yuan; Li, Kai; Liang, Jiankai; Xiao, Xiao; Cai, Jing; Tan, Yaqian; Xing, Fan; Mai, Jialuo; Li, Yuan; Chen, Wenli; Sheng, Longxiang; Gu, Jiayu; Zhu, Wenbo; Yin, Wei; Qiu, Pengxin; Su, Xingwen; Lu, Bingzheng; Tian, Xuyan; Liu, Jinhui; Lu, Wanjun; Dou, Yunling; Huang, Yijun; Hu, Bing; Kang, Zhuang; Gao, Guangping; Mao, Zixu; Cheng, Shi-Yuan; Lu, Ling; Bai, Xue-Tao; Gong, Shoufang; Yan, Guangmei; Hu, Jun
Cancers figure among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next 2 decades. Development of novel therapeutic agents is urgently needed for clinical cancer therapy. Alphavirus M1 is a Getah-like virus isolated from China with a genome of positive single-strand RNA. We have previously identified that alphavirus M1 is a naturally existing oncolytic virus with significant anticancer activity against different kinds of cancer (e.g., liver cancer, bladder cancer, and colon cancer). To support the incoming clinical trial of intravenous administration of alphavirus M1 to cancer patients, we assessed the safety of M1 in adult nonhuman primates. We previously presented the genome sequencing data of the cynomolgus macaques (Macaca fascicularis), which was demonstrated as an ideal animal species for virus infection study. Therefore, we chose cynomolgus macaques of either sex for the present safety study of oncolytic virus M1. In the first round of administration, five experimental macaques were intravenously injected with six times of oncolytic virus M1 (1 × 10(9) pfu/dose) in 1 week, compared with five vehicle-injected control animals. The last two rounds of injections were further completed in the following months in the same way as the first round. Body weight, temperature, complete blood count, clinical biochemistries, cytokine profiles, lymphocytes subsets, neutralizing antibody, and clinical symptoms were closely monitored at different time points. Magnetic resonance imaging was also performed to assess the possibility of encephalitis or arthritis. As a result, no clinical, biochemical, immunological, or medical imaging or other pathological evidence of toxicity was found during the whole process of the study. Our results in cynomolgus macaques suggested the safety of intravenous administration of oncolytic virus M1 in cancer patients in the future.
Liu, Hui; Li, Lu; Meng, Haitao; Qian, Qijun
An attractive strategy among adenovirus-based oncolytic systems is to design adenoviral vectors to express pro-apoptotic genes, in which this gene-virotherapy approach significantly enhances tumor cell death by activating apoptotic pathways. However, the existence of cancer cells with apoptotic defects is one of the major obstacles in gene-virotherapy. Here, we investigated whether a strategy that combines the oncolytic effects of an adenoviral vector with simultaneous expression of Beclin-1, an autophagy gene, offers a therapeutic advantage for leukemia. A Beclin-1 cDNA was cloned in an oncolytic adenovirus with chimeric Ad5/11 fiber (SG511-BECN). SG511-BECN treatment induced significant autophagic cell death, and resulted in enhanced cell killing in a variety of leukemic cell lines and primary leukemic blasts. SG511-BECN effects were seen in chronic myeloid leukemia and acute myeloid leukemia with resistance to imatinib or chemotherapy, but exhibited much less cytotoxicity on normal cells. The SG511-BECN-induced autophagic cell death could be partially reversed by RNA interference knockdown of UVRAG, ATG5, and ATG7. We also showed that SG511-BECN strongly inhibited the growth of leukemic progenitors in vitro. In murine leukemia models, SG511-BECN prolonged the survival and decreased the xenograft tumor size by inducing autophagic cell death. Our results suggest that infection of leukemia cells with an oncolytic adenovirus overexpressing Beclin-1 can induce significant autophagic cell death and provide a new strategy for the elimination of leukemic cells via a unique mechanism of action distinct from apoptosis. PMID:23765161
Cremer, Kenneth J.; Mackett, Michael; Wohlenberg, Charles; Notkins, Abner Louis; Moss, Bernard
In humans, herpes simplex virus causes a primary infection and then often a latent ganglionic infection that persists for life. Because these latent infections can recur periodically, vaccines are needed that can protect against both primary and latent herpes simplex infections. Infectious vaccinia virus recombinants that contain the herpes simplex virus type 1 (HSV-1) glycoprotein D gene under control of defined early or late vaccinia virus promoters were constructed. Tissue culture cells infected with these recombinant viruses synthesized a glycosylated protein that had the same mass (60,000 daltons) as the glycoprotein D produced by HSV-1. Immunization of mice with one of these recombinant viruses by intradermal, subcutaneous, or intraperitoneal routes resulted in the production of antibodies that neutralized HSV-1 and protected the mice against subsequent lethal challenge with HSV-1 or HSV-2. Immunization with the recombinant virus also protected the majority of the mice against the development of a latent HSV-1 infection of the trigeminal ganglia. This is the first demonstration that a genetically engineered vaccine can prevent the development of latency.
... between a common type of herpes virus and aggressive brain cancers, according to a new study that ... researchers analyzed tumor tissue from 125 patients with aggressive brain cancers called gliomas. Ninety-nine of the ...
Nair, Preeti; Gharote, Harshkant; Singh, Pooja; Jain-Choudhary, Palak
Herpes zoster is a localised disease caused by reactivation of the varicella zoster virus that enters the cutaneous nerve endings during an earlier episode of chicken pox, travels to the dorsal root ganglia, and remains in latent form. The condition is characterised by occurrence of multiple, painful, unilateral vesicles and ulceration, and shows a typical single dermatome innervated by single dorsal root or cranial sensory ganglion. Involvement of three or more dermatomes is known as disseminated zoster and seen in immunocompromised individuals. Complications of herpes zoster include ocular sequelae, bacterial superinfection of the lesions, meningoencephalitis and postherpetic neuralgia. The incidence of herpes zoster increases with age and immunosuppression, therefore prompt management is necessary to avoid morbidity and mortality in these individuals. We present two case reports of herpes zoster, one involving the maxillary and mandibular branches of the trigeminal nerve while the other involves all branches of the trigeminal nerve. PMID:25331144
... during any type of sex (oral, vaginal, or anal). Girls should have their partners use a dental_ ... BC Date reviewed: January 2015 For Teens For Kids For Parents MORE ON THIS TOPIC Genital Herpes ...
Durzyńska, Julia; Pacholska-Bogalska, Joanna; Kaczmarek, Maria; Hanć, Tomasz; Durda, Magdalena; Skrzypczak, Magdalena; Goździcka-Józefiak, Anna
The aim of the study was to develop a multiplex PCR (mPCR) for a rapid and simultaneous detection of herpes simplex 1 (HSV-1), herpes simplex 2 (HSV-2), and human cytomegalovirus (HCMV) DNA in squamous oral cells obtained from adolescents. Accuracy of the method was tested in a group of 513 adolescents, almost 11% of subjects were positive for infection with herpes viruses. Correlations with gender, age, and place of residence were sought. A similar incidence of HSV-2 and HCMV was found (4.3% and 5.4%, respectively) and the incidence of HSV-1 was the lowest (1%) in the study group. Conversely to HSV-2, HCMV was detected mostly in the youngest individuals. The same occurrence of all viruses was observed in boys and girls. The mPCR method described is suggested as a useful tool for epidemiologic studies of active herpes infections.
Nørgård, Bente; Nørgaard, Mette; Czeizel, Andrew E; Puhó, Erzsébet; Sørensen, Henrik T
According to previous case reports, some congenital abnormalities (CAs) of the brain, such as microcephaly, are a result of intrauterine herpes simplex virus infection. A population-based case-control study was conducted to determine the risk of neural tube defects (NTDs) after maternal herpes labialis infection during pregnancy. Data were taken from the Hungarian Case-Control Surveillance of Congenital Abnormalities from 1980 to 1996, which included 1202 children with NTDs and 21641 comparison children with CAs other than NTDs. The adjusted relative risks (odds ratio [OR]) for NTDs associated with maternal herpes labialis in the first trimester of pregnancy was OR 1.19 (95% confidence interval [CI] 0.68-2.06), and in the entire pregnancy was OR 0.94 (95% CI 0.61-1.44). Self-reported maternal herpes labialis during pregnancy was not associated with a substantially increased risk of NTDs in infants.
Nair, Preeti; Gharote, Harshkant; Singh, Pooja; Jain-Choudhary, Palak
Herpes zoster is a localised disease caused by reactivation of the varicella zoster virus that enters the cutaneous nerve endings during an earlier episode of chicken pox, travels to the dorsal root ganglia, and remains in latent form. The condition is characterised by occurrence of multiple, painful, unilateral vesicles and ulceration, and shows a typical single dermatome innervated by single dorsal root or cranial sensory ganglion. Involvement of three or more dermatomes is known as disseminated zoster and seen in immunocompromised individuals. Complications of herpes zoster include ocular sequelae, bacterial superinfection of the lesions, meningoencephalitis and postherpetic neuralgia. The incidence of herpes zoster increases with age and immunosuppression, therefore prompt management is necessary to avoid morbidity and mortality in these individuals. We present two case reports of herpes zoster, one involving the maxillary and mandibular branches of the trigeminal nerve while the other involves all branches of the trigeminal nerve.
Few schools have policies to deal specifically with herpes and Acquired Immune Deficiency Syndrome (AIDS). Discusses some schools and states that have developed such policies and includes a source list for more information. (MD)
Field, Scott S
Type 1 herpes simplex virus (HSV-1) is very prevalent yet in rare circumstances can lead to fatal neonatal disease. Genital acquisition of type 2 HSV is the usual mode for neonatal herpes, but HSV-1 transmission by genital or extragenital means may result in greater mortality rates. A very rare scenario is presented in which the mode of transmission was likely through breast lesions. The lesions were seen by nurses as well as the lactation consultant and obstetrician in the hospital after delivery of the affected baby but not recognized as possibly being caused by herpes. The baby died 9 days after birth with hepatic failure and disseminated intravascular coagulation. Peripartum health care workers need to be aware of potential nongenital (including from the breast[s]) neonatal herpes acquisition, which can be lethal.
Sims, John R; Massoll, Nicole A; Suen, James Y
Herpes simplex virus infection of the larynx is an exceedingly rare clinical entity, most frequently reported in the pediatric population or in immunocompromised adults. We present a 62-year-old woman presented with neck pain, hoarseness, crepitus over the larynx, and what appeared to be a necrotic mass of the right true vocal cord on laryngoscopy. Due to near-complete destruction of the cartilaginous framework of the larynx, a total laryngectomy was performed. The final pathology report showed squamous mucosal changes consistent with herpes simplex infection, confirmed by immunohistochemical staining. Though herpes simplex laryngitis is uncommon, this case shows the potential for herpes simplex to cause extensive damage and compromise airway patency when left untreated.
Buijs, P R A; van Amerongen, G; van Nieuwkoop, S; Bestebroer, T M; van Run, P R W A; Kuiken, T; Fouchier, R A M; van Eijck, C H J; van den Hoogen, B G
Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic potential. Detailed preclinical information regarding the safety of oncolytic NDV is scarce. In this study, we evaluated the toxicity, biodistribution and shedding of intravenously injected oncolytic NDVs in non-human primates (Macaca fascicularis). Two animals were injected with escalating doses of a non-recombinant vaccine strain, a recombinant lentogenic strain or a recombinant mesogenic strain. To study transmission, naive animals were co-housed with the injected animals. Injection with NDV did not lead to severe illness in the animals or abnormalities in hematologic or biochemistry measurements. Injected animals shed low amounts of virus, but this did not lead to seroconversion of the contact animals. Postmortem evaluation demonstrated no pathological changes or evidence of virus replication. This study demonstrates that NDV generated in embryonated chicken eggs is safe for intravenous administration to non-human primates. In addition, our study confirmed results from a previous report that naïve primate and human sera are able to neutralize egg-generated NDV. We discuss the implications of these results for our study and the use of NDV for virotherapy.
Qiao, Jian; Dey, Mahua; Chang, Alan L; Kim, Julius W; Miska, Jason; Ling, Alex; M Nettlebeck, Dirk; Han, Yu; Zhang, Lingjiao; Lesniak, Maciej S
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is associated with poor survival. Virotherapy is a promising candidate for the development of effective, novel treatments for GBM. Recent studies have underscored the potential of virotherapy in enhancing antitumor immunity despite the fact that its mechanisms remain largely unknown. Here, using a syngeneic GBM mouse model, we report that intratumoral virotherapy significantly modulates the tumor microenvironment. We found that intratumoral administration of an oncolytic adenovirus, AdCMVdelta24, decreased tumor-infiltrating CD4+ Foxp3+ regulatory T cells (Tregs) and increased IFNγ-producing CD8+ T cells in treated tumors, even in late stage disease in which a highly immunosuppressive tumor microenvironment is considered to be a significant barrier to immunotherapy. Importantly, intratumoral AdCMVdelta24 treatment augmented systemically transferred tumor-antigen-specific T cell therapy. Furthermore, mechanistic studies showed (1) downregulation of Foxp3 in Tregs that were incubated with media conditioned by virus-infected tumor cells, (2) downregulation of indoleamine 2,3 dioxygenase 1 (IDO) in glioma cells upon infection by AdCMVdelta24, and (3) reprograming of Tregs from an immunosuppressive to a stimulatory state. Taken together, our findings demonstrate the potency of intratumoral oncolytic adenoviral treatment in enhancing antitumor immunity through the regulation of multiple aspects of immune suppression in the context of glioma, supporting further clinical development of oncolytic adenovirus-based immune therapies for malignant brain cancer. PMID:26405578
Spurrell, Emma; Gangeswaran, Rathi; Wang, Pengju; Cao, Fengyu; Gao, Dongling; Feng, Baisui; Wold, William; Tollefson, Ann
Oncolytic viruses based on adenovirus type 5 (Ad5) have been developed as a new class of therapeutic agents for cancers that are resistant to conventional therapies. Clinical experience shows that these agents are safe, but virotherapy alone has not achieved long-term cure in cancer patients. The vast majority of oncolytic adenoviruses used in clinical trials to date have deletion of the E3B genes. It has been demonstrated that the antitumor potency of the E3B-deleted mutant (dl309) is inferior to adenovirus with E3B genes intact. Tumors treated with dl309 show markedly greater macrophage infiltration than E3B-intact adenovirus. However, the functional mechanisms for this were not previously known. Here, we demonstrate that deletion of E3B genes increases production of chemokines by monocytes after adenovirus infection and increases monocyte migration. The E3B 14,700-Da protein (E3B-14.7K) inhibits STAT1 function by preventing its phosphorylation and nuclear translocation. The STAT1 inhibitor, fludarabine, rescues the effect of E3B-14.7K deletion by downregulating target chemokine expression in human and murine monocytes and results in an enhanced antitumor efficacy with dl309 in vivo. These findings have important implications for clinical use of E3B-deleted oncolytic adenovirus and other E3B-deleted adenovirus vector-based therapy. PMID:24335311
Eike, Liv-Marie; Yang, Nannan; Rekdal, Øystein; Sveinbjørnsson, Baldur
Host defense peptides (HDPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line defense against intruding pathogens, and several HDPs have been shown to possess anticancer activity. Structure-activity relationship studies on the HDP bovine lactoferricin revealed a de novo design of a nonamer peptide LTX-315, with oncolytic properties. In the present study, we investigated the oncolytic activity of LTX-315 in human melanoma cells (A375). LTX-315 induced a rapid plasma membrane disruption and cell death within 2 hours. At a low concentration, fluorescence-labeled LTX-315 was internalized and accumulated in cytoplasmic vacuoles in close proximity to the mitochondria. The mitochondrial membrane potential was shown to depolarize as a consequence of LTX-315 treatment and at ultrastructural level, the mitochondria morphology was significantly altered. Release of danger signals (DAMPs) such as ATP, Cytochrome C and HMGB1 into the cell supernatant of cultured cells was evident minutes after peptide treatment. The oncolytic effect of LTX-315 involving perturbation of both the cell membrane and the mitochondria with subsequent release of DAMPs may highlight the ability of LTX-315 to induce complete regression and long-term protective immune responses as previously reported in experimental animal models. PMID:26472184
Wang, Weiguo; Ji, Weidan; Hu, Huanzhang; Ma, Juming; Li, Xiaoya; Mei, Weiqun; Xu, Yang; Hu, Huizhen; Yan, Yan; Song, Qizhe; Li, Zhigang; Su, Changqing
Gene therapy is a promising adjuvant therapeutic strategy for cancer treatment. To overcome the limitations of current gene therapy, such as poor transfection efficiency of vectors, low levels of transgene expression and lack of tumor targeting, the Survivin promoter was used to regulate the selective replication of oncolytic adenovirus in tumor cells, and the heat shock protein 70 (Hsp70) gene was loaded as the anticancer transgene to generate an AdSurp-Hsp70 viral therapy system. The efficacy of this targeted immunotherapy was examined in gastric cancer. The experiments showed that the oncolytic adenovirus can selectively replicate in and lyse the Survivin-positive gastric cancer cells, without significant toxicity to normal cells. AdSurp-Hsp70 reduced viability of cancer cells and inhibited tumor growth of gastric cancer xenografts in immuno-deficient and immuno-reconstruction mouse models. AdSurp-Hsp70 produced dual antitumor effects due to viral replication and high Hsp70 expression. This therapeutic system used the Survivin promoter-regulated oncolytic adenovirus vector to mediate targeted expression of the Hsp70 gene and ensure safety and efficacy for subsequent gene therapy programs against a variety of cancers.
Liu, Zuqiang; Ravindranathan, Roshni; Kalinski, Pawel; Guo, Z. Sheng; Bartlett, David L.
Both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. Here we hypothesized that an oncolytic poxvirus would attract T cells into the tumour, and induce PD-L1 expression in cancer and immune cells, leading to more susceptible targets for anti-PD-L1 immunotherapy. Our results demonstrate in colon and ovarian cancer models that an oncolytic vaccinia virus attracts effector T cells and induces PD-L1 expression on both cancer and immune cells in the tumour. The dual therapy reduces PD-L1+ cells and facilitates non-redundant tumour infiltration of effector CD8+, CD4+ T cells, with increased IFN-γ, ICOS, granzyme B and perforin expression. Furthermore, the treatment reduces the virus-induced PD-L1+ DC, MDSC, TAM and Treg, as well as co-inhibitory molecules-double-positive, severely exhausted PD-1+CD8+ T cells, leading to reduced tumour burden and improved survival. This combinatorial therapy may be applicable to a much wider population of cancer patients. PMID:28345650
van Erp, Elisabeth A; Kaliberova, Lyudmila N; Kaliberov, Sergey A; Curiel, David T
Conditionally replicative adenoviruses are promising agents for oncolytic virotherapy. Various approaches have been attempted to retarget adenoviruses to tumor-specific antigens to circumvent deficiency of receptor for adenoviral binding and to provide an additional level of tumor specificity. Functional incorporation of highly specific targeting molecules into the viral capsid can potentially retarget adenoviral infection. However, conventional antibodies are not compatible with the cytoplasmic adenovirus capsid synthesis. The goal of this study was to evaluate the utility of single variable domains derived from heavy chain camelid antibodies for retargeting of adenovirus infection. We have combined transcriptional targeting using a tumor-specific promoter with transductional targeting through viral capsid incorporation of antihuman carcinoembryonic antigen single variable domains. Obtained data demonstrated that employment of a single variable domain genetically incorporated into an adenovirus fiber increased specificity of infection and efficacy of replication of single variable domain-targeted oncolytic adenovirus. The double targeting, both transcriptional through the C-X-C chemokine receptor type 4 promoter and transductional using the single variable domain, is a promising means to improve the therapeutic index for these advanced generation conditionally replicative adenoviruses. A successful strategy to transductional retargeting of oncolytic adenovirus infection has not been shown before and therefore we believe this is the first employment of transductional targeting using single variable domains derived from heavy chain camelid antibodies to enhance specificity of conditionally replicative adenoviruses.
Choi, Joung-Woo; Park, Ji Won; Na, Youjin; Jung, Soo-Jung; Hwang, June Kyu; Choi, Dongho; Lee, Kyeong Geun; Yun, Chae-Ok
Adenovirus (Ad) is a widely used vector for cancer gene therapy but its therapeutic efficacy is limited by low coxsackievirus and adenovirus receptor (CAR) expression in tumors and non-specifically targeted infection. Ad infectivity and specificity can be markedly improved by creating Ad-magnetic nanoparticles cluster complexes and directing their migration with an external magnetic field (MGF). We electrostatically complexed GFP-expressing, replication-incompetent Ad (dAd) with PEGylated and cross-linked iron oxide nanoparticles (PCION), generating dAd-PCION complexes. The dAd-PCION showed increased transduction efficiency, independent of CAR expression, in the absence or presence of an MGF. Cancer cell killing and intracellular oncolytic Ad (HmT)-PCION replication significantly increased with MGF exposure. Site-directed, magnetically-targeted delivery of the HmT-PCION elicited significantly greater therapeutic efficacy versus treatment with naked HmT or HmT-PCION without MGF in CAR-negative MCF7 tumors. Immunohistochemical tumor analysis showed increased oncolytic Ad replication in tumors following infection by HmT-PCION using an MGF. Whole-body bioluminescence imaging of tumor-bearing mice showed a 450-fold increased tumor-to-liver ratio for HmT-PCION with, versus without, MGF. These results demonstrate the feasibility and potential of external MGF-responsive PCION-coated oncolytic Ads as smart hybrid vectors for cancer gene therapy.
Colson, Fany; Arrese, Jorge E.; Nikkels, Arjen F.
A 52-year-old White man presented with a dozen small, well-restricted, punctiform, asymptomatic, blue-gray macules on the left shoulder. A few months earlier, he had been treated with oral acyclovir for herpes zoster (HZ) affecting the left C7–C8 dermatomes. All the blue macules appeared over a short period of time and then remained stable. The patient had not experienced any previous trauma or had tattooing in this anatomical region. The clinical diagnosis suggested blue nevi. Dermatoscopy revealed small, well-limited, dark-blue, compact, homogeneous areas evoking dermal blue nevi. An excisional biopsy was performed and the histological examination confirmed a blue nevus. As far as we are aware of, this is the first report of eruptive blue nevi following HZ, and it should be included in the differential diagnosis of zosteriform dermatoses responding to an isotopic pathway. In addition, a brief review concerning eruptive nevi is presented. PMID:27462219
Pain associated with herpes zoster arise from the virul neuritis of the suffered trigeminal or spinal dorsal ganglion. Prolonged neuritis makes an irreversible nerve injury and continuous pain impulse develops a central sensitization. A post-herpetic neuralgia is thought to be a neuropathic pain due to the irreversible nerve injury and sensitization. It is important to treat herpetic pain completely before the development of the post-herpetic neuralgia, because there are few effective therapies to cure post-herpetic neuralgia. A sympathetic nerve block increases the nerve blood flow supply, and may improve the nerve injury. It is also known that some sympathetic mechanisms relate to the development of the sensitization. A sensory nerve block reduces pain impulse to the dorsal horn, and may interfere the sensitization. A cortico-steroid administrated with a nerve block can reduce the neuritis, and may improve the nerve injury.
Choi, Hwan Jun; Kim, Jun Hyuk; Lee, Young Man
Herpes zoster is a common dermatologic disease characterized by unilateral pain and vesicular lesions over the unilateral sensory dermatomes being caused by the reactivation of varicella zoster virus, and its incidence seems to be increasing recently. In case of involving the ganglion of the fifth cranial nerve (trigeminal nerve), it can descend down the affected nerve into the skin, then producing an eruption in the dermatome. Among the patients with this disease, about 40% to 50% had associated conditions such as diabetes mellitus, hypertension, pulmonary tuberculosis, liver diseases, peptic ulcer, hypothyroidism, or pharyngitis but rarely facial trauma. Generally, herpes zoster was commonly associated with systemic disorders, and the treatment duration was prolonged in associated diseases. However, herpes zoster occurring specifically at the site of previously traumatized facial bone has not yet been reported. Retrospective study of 1 case of herpes zoster with blow-out fracture, which had been treated with acyclovir and steroid, was done. Follow-up length was about 3 months. After treatment, the patient became stable, and there was no complication. We treated herpes zoster developing within a recent operative subciliary scar, and the case is presented with the review of literature. Finally, facial trauma or reconstruction of the orbital floor with alloplastic implant might be a risk factor for herpes zoster in traumatized patient.
Wilkinson, Michelle J; Smith, Henry G; Pencavel, Timothy D; Mansfield, David C; Kyula-Currie, Joan; Khan, Aadil A; McEntee, Gráinne; Roulstone, Victoria; Hayes, Andrew J; Harrington, Kevin J
The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP-delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV-1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology.
Buntinx, F; Bartholomeeusen, S; Belmans, A; Mathei, C; Opdenakker, G; Sweldens, K; Truyers, C; Van Ranst, M
The association between herpes zoster and subsequent cancer risk is still unclear. Consequently, doubts remain regarding the need for investigation of herpes patients for co-existing or subsequent malignancy. This is a retrospective cohort study comparing cancer risk in patients after herpes zoster and age-/sex-matched non-herpes zoster patients, in a primary care-based continuous morbidity database. We tested for interaction by gender, age, diabetes, HRT use or antiviral therapy. Analyses were repeated for patients with and without herpes simplex. The hazard ratio (HR) comparing cancer risk in herpes zoster vs. control patients was significant in all women, women aged > 65 years and subgroups of breast and colorectal cancer (HRs 1·60, 1·82, 2·14, 2·19, respectively). For men, a significant association was found for haematological cancers (HR 2·92). No associations were found with herpes simplex. No interaction was identified with antiviral therapy, diabetes or HRT treatment. We concluded that there was a moderate significant association between herpes zoster and subsequent cancer risk in women aged > 65 years, without any influence of antiviral therapy. No association was found with herpes simplex. There is insufficient reason for extensively testing older patients with herpes zoster or herpes simplex for the presence of occult cancer.
... Herpes Simplex Virus Types 1 and 2 Serological Assays; Confirmation of Effective Date AGENCY: Food and... corrects the regulation classifying herpes simplex virus (HSV) serological assays by removing the...
... Data & Statistics Sexually Transmitted Diseases Figure 48. Genital Herpes — Initial Visits to Physicians’ Offices, United States, 1966 – ... page . NOTE : The relative standard errors for genital herpes estimates of more than 100,000 range from ...
Sanders, Jennifer E; Garcia, Sylvia E
Herpes simplex virus is a common virus that causes a variety of clinical presentations ranging from mild to life-threatening. Orolabial and genital herpes are common disorders that can often be managed in an outpatient setting; however, some patients do present to the emergency department with those conditions, and emergency clinicians should be aware of possible complications in the pediatric population. Neonatal herpes is a rare disorder, but prompt recognition and initiation of antiviral therapy is imperative, as the morbidity and mortality of the disease is high. Herpes encephalitis is an emergency that also requires a high index of suspicion to diagnose. Herpes simplex virus is also responsible for a variety of other clinical presentations, including herpes gladiatorum, herpetic whitlow, eczema herpeticum, and ocular herpes. This issue reviews the common clinical presentations of the herpes simplex virus, the life-threatening infections that require expedient identification and management, and recommended treatment regimens.
Wodarz, Dominik; Hofacre, Andrew; Lau, John W; Sun, Zhiying; Fan, Hung; Komarova, Natalia L
Oncolytic viruses replicate selectively in tumor cells and can serve as targeted treatment agents. While promising results have been observed in clinical trials, consistent success of therapy remains elusive. The dynamics of virus spread through tumor cell populations has been studied both experimentally and computationally. However, a basic understanding of the principles underlying virus spread in spatially structured target cell populations has yet to be obtained. This paper studies such dynamics, using a newly constructed recombinant adenovirus type-5 (Ad5) that expresses enhanced jellyfish green fluorescent protein (EGFP), AdEGFPuci, and grows on human 293 embryonic kidney epithelial cells, allowing us to track cell numbers and spatial patterns over time. The cells are arranged in a two-dimensional setting and allow virus spread to occur only to target cells within the local neighborhood. Despite the simplicity of the setup, complex dynamics are observed. Experiments gave rise to three spatial patterns that we call "hollow ring structure", "filled ring structure", and "disperse pattern". An agent-based, stochastic computational model is used to simulate and interpret the experiments. The model can reproduce the experimentally observed patterns, and identifies key parameters that determine which pattern of virus growth arises. The model is further used to study the long-term outcome of the dynamics for the different growth patterns, and to investigate conditions under which the virus population eliminates the target cells. We find that both the filled ring structure and disperse pattern of initial expansion are indicative of treatment failure, where target cells persist in the long run. The hollow ring structure is associated with either target cell extinction or low-level persistence, both of which can be viewed as treatment success. Interestingly, it is found that equilibrium properties of ordinary differential equations describing the dynamics in local
Nikkels, Arjen F; Pièrard, Gérald E
Infections by herpes simplex virus (HSV) types I and II are diverse and quite frequent. After primary infection, the virus establishes a life-long latency in the sensory ganglia and recrudescences may occur at an unpredictable rate. Recurrent labial and genital herpes infections represent the majority of clinical manifestations of HSV infections. Their management is currently well established using evidence-based medicine data. Primary labial herpes is generally not treated with antivirals in otherwise healthy children, although intravenous aciclovir may be offered in severe primary infections, particularly in the immunocompromised patient. The decision whether or not to treat recurrent labial herpes should be evaluated individually and depends on the frequency and severity of relapses, the impairment of the quality of life, and the cost of therapy. Patients with mild disease may benefit from topical therapy, and those with severe and frequent recurrences may be considered for intermittent or long-term oral antiviral therapy. Primary genital herpes is treated with oral or intravenous antivirals, depending on the severity of the infection and associated symptoms. Recurrent genital herpes can be managed with episodic short courses of oral antivirals in patients whose recurrences are moderate to severe and rare, and have a clear prodrome. Patients with >5 episodes/year, severe recurrences or unrecognisable prodromes may be best managed with long-term suppressive antiviral prophylaxis. HSV is also responsible for a variety of other clinical manifestations, including herpetic whitlow, neonatal infection, disseminated and atypical cutaneous infections, traumatic herpes, eczema herpeticum, and HSV-associated erythema multiforme. HSV infection may also represent a complication following cosmetic procedures of the oro-facial region, surgical and dental interventions, sun exposure and burns. Precise treatment guidelines for these HSV infections are not firmly established.
Bauchat, Jeanette R
Neuraxial morphine administration is a common strategy for providing postcesarean delivery analgesia. Morphine delivered via this route increases the risk of herpes labialis (oral herpes) reactivation, a disease common in women of childbearing age. A primary concern is risk of transmission to the neonate from maternal reactivation. The benefits to the mother of this form of analgesia outweigh the risk of neonatal herpes acquired postpartum from maternal recurrence because serious neonatal morbidity from recurrent herpes has not been described.
AD_________________ Award Number: W81XWH-11-1-0498 TITLE: Engineered Herpes Simplex Viruses for the...August 2012 4. TITLE AND SUBTITLE Engineered Herpes Simplex Viruses for the Treatment of Malignant Peripheral Nerve Sheath Tumors 5a. CONTRACT NUMBER...for each blot. Glyco-protein D is produced at extraordinarily high levels by our herpes simplex virus, and thus, it is quite common in herpes simplex
Mehta, Satish K.; Pierson, Duane L.
Space flight has many adverse effects on human physiology. Changes in multiple systems, including the cardiovascular, musculoskeletal, neurovestibular, endocrine, and immune systems have occurred (12, 32, 38, 39). Alterations in drug pharmacokinetics and pharmacodynamics (12), nutritional needs (31), renal stone formation (40), and microbial flora (2) have also been reported. Evidence suggests that the magnitude of some changes may increase with time in space. A variety of changes in immunity have been reported during both short (.16 days) and long (>30 days) space missions. However, it is difficult to determine the medical significance of these immunological changes in astronauts. Astronauts are in excellent health and in superb physical condition. Illnesses in astronauts during space flight are not common, are generally mild, and rarely affect mission objectives. In an attempt to clarify this issue, we identified the latent herpes viruses as medically important indicators of the effects of space flight on immunity. This chapter demonstrates that space flight leads to asymptomatic reactivation of latent herpes viruses, and proposes that this results from marked changes in neuroendocrine function and immunity caused by the inherent stressfullness of human space flight. Astronauts experience uniquely stressful environments during space flight. Potential stressors include confinement in an unfamiliar, crowded environment, isolation, separation from family, anxiety, fear, sleep deprivation, psychosocial issues, physical exertion, noise, variable acceleration forces, increased radiation, and others. Many of these are intermittent and variable in duration and intensity, but variable gravity forces (including transitions from launch acceleration to microgravity and from microgravity to planetary gravity) and variable radiation levels are part of each mission and contribute to a stressful environment that cannot be duplicated on Earth. Radiation outside the Earth
Normal facial movement is required for chewing, swallowing, speaking, and protecting the eye. Bell's palsy causes most cases of acute, unilateral facial palsy; infection with herpes simplex virus (HSV) type 1 may be its major cause. Varicella zoster virus (VZV) reactivation (Ramsay Hunt syndrome) is less common, but may appear without skin lesions in a form indistinguishable from Bell's palsy. Symptoms improve in nearly all patients with Bell's palsy, and most patients with Ramsay Hunt syndrome, but many are left with functional and cosmetic deficits. Steroids are frequently used to optimize outcomes in Bell's palsy, but proof of their effectiveness is marginal. Oral prednisone has been studied extensively, although some reports have suggested a higher recovery rate with intravenous steroids. Given the existing data, we support the use of oral prednisone in those patients with complete facial palsy, and no contraindications to their use (Fig. 1). In this author's opinion, the greatly increased cost and inconvenience of intravenous steroids cannot be justified by the data available. Antiviral agents may also be effective in treatment of Bell's palsy; HSV is susceptible to acyclovir and related agents. There have been few investigations of acyclovir treatment in Bell's palsy, but one controlled study showed added benefit when the drug was used with prednisone. The risk and cost of acyclovir is low enough that we support its use, with oral steroids, in those patients with complete facial paralysis. Several small studies have implied that oral acyclovir improves the outcome of facial palsy for patients with Ramsay Hunt syndrome. Although these studies do not prove efficacy, evidence for the benefits of antiviral agents in other forms of zoster is strong enough to recommend their use when the facial nerve is involved. VZV is less sensitive to acyclovir than HSV, so higher doses are recommended to treat Ramsay Hunt syndrome. Because some Ramsay Hunt syndrome patients
Olin, Laura; Wald, Anna
A 42-year-old bisexual man with a history of recurrent oral herpes and no history of genital herpes was noted to have antibody to herpes simplex virus type 2 (HSV-2) only. During a symptomatic oral recurrence, HSV-2 was found in a perioral lesion as well as in the genital area.
...; Reclassification of the Herpes Simplex Virus Serological Assay Device AGENCY: Food and Drug Administration, HHS... the herpes simplex virus (HSV) serological assay device type, which is classified as class II (special... tests to identify antibodies to herpes simplex virus in serum, and the devices that consist of...
...; Reclassification of the Herpes Simplex Virus Serological Assay Device AGENCY: Food and Drug Administration, HHS... controls for the herpes simplex virus (HSV) serological assay device type, which is classified as class II... serological tests to identify antibodies to herpes simplex virus in serum, and the devices that consist...
Benabdellah, A; Souhil, Touati; Farouk, Zaoui Omar
Motor complications after herpes zoster are not uncommon. There have been reports of muscular paralysis following herpes zoster. The association between diaphragmatic paralysis and zoster was first reported in 1949 by Halpern. The case presented below showed diaphragmatic involvement following herpes zoster in a HIV-tuberculosis coinfected patient.
Harney, B A; Easty, D L; Skinner, G R
A rabbit and a mouse model of herpes simplex eye disease have been used to evaluate a sub-unit herpes simplex vaccine. Various immunization schedules were investigated. The vaccine was found to stimulate humoral and cellular immune responses and to offer protection against corneal infection with liver herpes simplex virus.
Chakrabarty, Arun; Pang, Katie R; Wu, Jashin J; Narvaez, Julio; Rauser, Michael; Huang, David B; Beutner, Karl R; Tyring, Stephen K
There are eight members of the herpesviridae family: herpes simplex virus-1 (HSV-1), HSV-2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human herpes virus-6, human herpes virus-7 and human herpes virus-8. The diseases caused by viruses of the herpesviridae family are treated with and managed by systemic and topical antiviral therapies and immunomodulating drugs. Because these viruses establish a latent state in hosts, antiherpetic agents, such as nucleoside analogues, only control symptoms of disease or prevent outbreaks, and cannot cure the infections. There is a need for treatments that require less frequent dosing, can be taken even when lesions are more advanced than the first signs or symptoms, and can treat resistant strains of the viruses without the toxicities of existing therapies. Immunomodulating agents, such as resiquimod, can act on the viruses indirectly by inducing host production of cytokines, and can thereby reduce recurrences of herpes. The new helicase primase inhibitors, which are the first non-nucleoside antiviral compounds, are being investigated for treatment of HSV disease, including infections resistant to existing therapy.
Cecil, Alexander; Gentschev, Ivaylo; Adelfinger, Marion; Nolte, Ingo; Dandekar, Thomas; Szalay, Aladar A
Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a novel approach for cancer therapy. In this study we describe for the first time the use of dynamic boolean modeling for tumor growth prediction of vaccinia virus GLV-1h68-injected canine tumors including canine mammary adenoma (ZMTH3), canine mammary carcinoma (MTH52c), canine prostate carcinoma (CT1258), and canine soft tissue sarcoma (STSA-1). Additionally, the STSA-1 xenografted mice were injected with either LIVP 1.1.1 or LIVP 5.1.1 vaccinia virus strains. Antigen profiling data of the four different vaccinia virus-injected canine tumors were obtained, analyzed and used to calculate differences in the tumor growth signaling network by type and tumor type. Our model combines networks for apoptosis, MAPK, p53, WNT, Hedgehog, TK cell, Interferon, and Interleukin signaling networks. The in silico findings conform with in vivo findings of tumor growth. Boolean modeling describes tumor growth and remission semi-quantitatively with a good fit to the data obtained for all cancer type variants. At the same time it monitors all signaling activities as a basis for treatment planning according to antigen levels. Mitigation and elimination of VACV- susceptible tumor types as well as effects on the non-susceptible type CT1258 are predicted correctly. Thus the combination of Antigen profiling and semi-quantitative modeling optimizes the therapy already before its start.
Hastie, Eric; Grdzelishvili, Valery Z
Oncolytic virus (OV) therapy is an emerging anti-cancer approach that utilizes viruses to preferentially infect and kill cancer cells, while not harming healthy cells. Vesicular stomatitis virus (VSV) is a prototypic non-segmented, negative-strand RNA virus with inherent OV qualities. Antiviral responses induced by type I interferon pathways are believed to be impaired in most cancer cells, making them more susceptible to VSV than normal cells. Several other factors make VSV a promising OV candidate for clinical use, including its well-studied biology, a small, easily manipulated genome, relative independence of a receptor or cell cycle, cytoplasmic replication without risk of host-cell transformation, and lack of pre-existing immunity in humans. Moreover, various VSV-based recombinant viruses have been engineered via reverse genetics to improve oncoselectivity, safety, oncotoxicity and stimulation of tumour-specific immunity. Alternative delivery methods are also being studied to minimize premature immune clearance of VSV. OV treatment as a monotherapy is being explored, although many studies have employed VSV in combination with radiotherapy, chemotherapy or other OVs. Preclinical studies with various cancers have demonstrated that VSV is a promising OV; as a result, a human clinical trial using VSV is currently in progress.
Fujiwara, Toshiyoshi; Kagawa, Shunsuke; Tazawa, Hiroshi
Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials; data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer.
Atsumi, Satoru; Matsumine, Akihiko; Toyoda, Hidemi; Niimi, Rui; Iino, Takahiro; Nakamura, Tomoki; Matsubara, Takao; Asanuma, Kunihiro; Komada, Yoshihiro; Uchida, Atsumasa; Sudo, Akihiro
The poliovirus receptor CD155, is essential for poliovirus to infect and induce death in neural cells. Recently, CD155 has been shown to be selectively expressed on certain types of tumor cells originating from the neural crest, including malignant glioma and neuroblastoma. However, the expression pattern of CD155 in soft tissue sarcoma has not been examined. Therefore, we first examined CD155 expression in sarcoma cell lines, and found the expression of both CD155 mRNA and protein in 12 soft and bone tissue sarcoma cell lines. Furthermore, we examined the effect of live attenuated poliovirus (LAPV) on 6 bone and soft tissue sarcoma cell lines in vitro, and found that LAPV induced apoptosis by activating caspases 7 and 3 in all of these cell lines. Furthermore, in BALB/c nu/nu mice xenotransplanted with HT1080 fibrosarcoma cells, administration of live attenuated poliovirus caused growth suppression of the tumors. These results suggest that oncolytic therapy using a LAPV may represent a new option for the treatment of bone and soft tissue sarcomas.
Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C
Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery.
Downs-Canner, Stephanie; Guo, Zong Sheng; Ravindranathan, Roshni; Breitbach, Caroline J; O'Malley, Mark E; Jones, Heather L; Moon, Anne; McCart, Judith Andrea; Shuai, Yongli; Zeh, Herbert J; Bartlett, David L
We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15–30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted. PMID:27203445
Kim, Youra; Clements, Derek R.; Sterea, Andra M.; Jang, Hyun Woo; Gujar, Shashi A.; Lee, Patrick W. K.
Dendritic cells (DCs) are specialized antigen-presenting cells that have a notable role in the initiation and regulation of innate and adaptive immune responses. In the context of cancer, appropriately activated DCs can induce anti-tumor immunity by activating innate immune cells and tumor-specific lymphocytes that target cancer cells. However, the tumor microenvironment (TME) imposes different mechanisms that facilitate the impairment of DC functions, such as inefficient antigen presentation or polarization into immunosuppressive DCs. These tumor-associated DCs thus fail to initiate tumor-specific immunity, and indirectly support tumor progression. Hence, there is increasing interest in identifying interventions that can overturn DC impairment within the TME. Many reports thus far have studied oncolytic viruses (OVs), viruses that preferentially target and kill cancer cells, for their capacity to enhance DC-mediated anti-tumor effects. Herein, we describe the general characteristics of DCs, focusing on their role in innate and adaptive immunity in the context of the TME. We also examine how DC-OV interaction affects DC recruitment, OV delivery, and anti-tumor immunity activation. Understanding these roles of DCs in the TME and OV infection is critical in devising strategies to further harness the anti-tumor effects of both DCs and OVs, ultimately enhancing the efficacy of OV-based oncotherapy. PMID:26690204
Leveille, S; Samuel, S; Goulet, M-L; Hiscott, J
Oncolytic viruses (OVs) are promising therapeutic agents for cancer treatment, with recent studies emphasizing the combined use of chemotherapeutic compounds and prodrug suicide gene strategies to improve OV efficacy. In the present study, the synergistic activity of recombinant vesicular stomatitis virus (VSV)-MΔ51 virus expressing the cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) suicide gene and 5-fluorocytosine (5FC) prodrug was investigated in triggering tumor cell oncolysis. In a panel of VSV-sensitive and -resistant cells-prostate PC3, breast MCF7 and TSA, B-lymphoma Karpas and melanoma B16-F10-the combination treatment increased killing of non-infected bystander cells in vitro via the release of 5FC toxic derivatives. In addition, we showed a synergistic effect on cancer cell killing with VSV-MΔ51 and the active form of the drug 5-fluorouracil. Furthermore, by monitoring VSV replication at the tumor site and maximizing 5FC bioavailability, we optimized the treatment regimen and improved survival of animals bearing TSA mammary adenocarcinoma. Altogether, this study emphasizes the potency of the VSV-CD::UPRT and 5FC combination, and demonstrates the necessity of optimizing each step of a multicomponent therapy to design efficient treatment.
Kim, Pyung-Hwan; Kim, Jaesung; Kim, Tae-il; Nam, Hye Yeong; Yockman, James W; Kim, Minjung; Kim, Sung Wan; Yun, Chae-Ok
Systemic administration of adenovirus (Ad) vectors is complicated by host immune responses and viral accumulation in the liver, resulting in a short circulatory virus half-life, low efficacy, and host side effects. Ad surface modification is thus required to enhance safety and therapeutic efficacy. An arginine-grafted bioreducible polymer (ABP) was chemically conjugated to the Ad surface, generating Ad-ΔE1/GFP-ABP. A hepatocellular carcinoma [HCC]-selective oncolytic Ad complex, YKL-1001-ABP, was also generated. Transduction efficiency of Ad-ΔE1/GFP-ABP was enhanced compared to naked Ad-ΔE1/GFP. YKL-1001-ABP elicited an enhanced and specific killing effect in liver cancer cells (Huh7 and HepG2) expressing α-fetoprotein (AFP). Compared with naked Ad, systemic administration of ABP-conjugated Ad resulted in reduced liver toxicity and interleukin (IL)-6 production in vitro and in vivo. Ad-ΔE1/GFP-ABP was more resistant to the neutralizing effects of human serum compared to naked Ad-ΔE1/GFP. ABP conjugation extended blood circulation time 45-fold and reduced anti-Ad Ab neutralization. Moreover, systemic administration of YKL-1001-ABP markedly suppressed growth of Huh7 hepatocellular carcinoma. These results demonstrate that chemical conjugation of ABP to the Ad surface improves safety and efficacy, indicating that ABP-conjugated Ad is a potentially useful cancer therapeutic agent to target cancer via systemic administration.
Guo, Zong Sheng; Liu, Zuqiang; Bartlett, David L.
Oncolytic viruses (OVs) are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD), including immunogenic apoptosis, necrosis/necroptosis, pyroptosis, and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high-mobility group box 1, uric acid, and other damage-associated molecular patterns as well as pathogen-associated molecular patterns as danger signals, along with tumor-associated antigens, to activate dendritic cells and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis, or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells toward certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity, and thus the overall therapeutic efficacy. PMID:24782985
Brown, Michael C.; Gromeier, Matthias
Achieving tumor-specific, robust, and durable effector cytotoxic immune responses is key to successful immunotherapy. This has been accomplished with adoptive cell transfer of ex vivo-expanded autologous tumor-infiltrating or engineered T cells, or with immune checkpoint inhibitors, enhancing inherent T cell reactivity. A natural ability to recruit effector responses makes tumor-targeting (‘oncolytic’) viruses attractive as immunotherapy vehicles. However, most viruses actively block inflammatory and immunogenic events; or, host innate immune responses may prevent immune initiating events in the first place. Moreover, the mechanisms of how virus infection can produce effector responses against host (tumor) neo-antigens are unclear. We are pioneering oncolytic immunotherapy based on poliovirus, which has no specific mechanism to interfere with host immune activation, exhibits lytic cytotoxicity in the presence of an antiviral interferon response and pre-existing immunity, and engages a powerful innate immune sensor implicated in recruiting cytotoxic T cell responses. Central to this approach is a unique confluence of factors that drive tumor-specific viral translation and cytotoxicity. PMID:26105699
Johnson, Richard T.
The pathogenesis of herpes simplex virus encephalitis and myelitis was studied in suckling mice using routine titration procedures and fluorescent antibody staining for the identification of infected cells. After intracerebral inoculation virus was shown to disperse rapidly in the cerebrospinal fluid (CSF), multiply in meninges and ependyma, and then invade the underlying parenchyma infecting both neurons and glia. Following extraneural inoculation virus gained access to the central nervous system (CNS) by both hematogenous and neural pathways. After intraperitoneal and intranasal inoculation virus was found to multiply in viscera and produce viremia; foci of CNS infection then developed around small cerebral vessels. After subcutaneous and intranasal inoculation neural spread of virus was demonstrated along corresponding peripheral and cranial nerves. This spread resulted from the centripetal infection of endoneural cells (Schwann cells and fibroblasts). Antigen was not found in axons even after infection of the corresponding ganglion cell perikaryon. Subsequent spread within the CNS was unrelated to neural tracts, and there was no evidence of axonal spread of virus in the host-virus system studied. These findings are discussed in relation to previous and current theories of the viral "blood-brain barrier" and neural pathways of infection. PMID:14164487
Wolfsen, H C; Bolen, J W; Bowen, J L; Fenster, L F
Fulminant hepatitis due to herpes simplex virus (HSV) in adults is a rare and deadly disease. We describe a 23-year-old woman with a 20-year history of Crohn's disease (CD) who was hospitalized with an acute febrile illness and diarrhea. A computed tomography (CT) scan of the abdomen demonstrated an intramural sigmoid colon abscess and multiple abscesses in the liver. Despite high-dose parenteral corticosteroids and broad-spectrum antibiotics, the patient remained acutely ill, with high fever and markedly elevated serum transaminase levels, but no jaundice. Sigmoid resection and wedge liver biopsy were performed at laparotomy. Histologic examination documented HSV-type intranuclear inclusions and inflammation with necrosis in both the sigmoid colon and liver specimens. The patient subsequently died despite parenteral acyclovir treatment. Although rare, fulminant hepatitis due to HSV simplex virus should be considered in the differential diagnosis of all patients with severe hepatitis. Of special note, the necrotizing liver lesions may be mistaken for pyogenic abscesses on CT scan.
Mullooly, J. P.; Riedlinger, K.; Chun, C.; Weinmann, S.; Houston, H.
We estimated age-specific herpes zoster (HZ) incidence rates in the Kaiser Permanente Northwest Health Plan (KPNW) during 1997-2002 and tested for secular trends and differences between residents of two states with different varicella vaccine coverage rates. The cumulative proportions of 2-year-olds vaccinated increased from 35% in 1997 to 85% in 2002 in Oregon, and from 25% in 1997 to 82% in 2002 in Washington. Age-specific HZ incidence rates in KPNW during 1997-2002 were compared with published rates in the Harvard Community Health Plan (HCHP) during 1990-1992. The overall HZ incidence rate in KPNW during 1997-2002 (369/100,000 person-years) was slightly higher than HCHP's 1990-1992 rate when adjusted for age differences. For children 6-14 years old, KPNW's rates (182 for females, 123 for males) were more than three times HCHP's rates (54 for females, 39 for males). This increase appears to be associated with increased exposure of children to oral corticosteroids. The percentage of KPNW children exposed to oral corticosteroids increased from 2.2% in 1991 to 3.6% in 2002. Oregon residents had slightly higher steroid exposure rates during 1997-2002 than Washington residents. There were significant increases in HZ incidence rates in Oregon and Washington during 1997-2002 among children aged 10-17 years, associated with increased exposure to oral steroids. PMID:15816149
Koelle, David M
Infections with herpes simplex virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) can have serious medical consequences. Although antiviral medications can suppress symptomatic disease, asymptomatic shedding and transmission, they neither cure nor alter the natural history of HSV infections. Manipulation of the immune response is one potential method to decrease disease burden. Current research on prophylactic and therapeutic vaccination approaches is discussed in this review, with a focus on compounds that have entered clinical trials or that display novel compositions or proposed mechanisms of action. One such vaccine is an alum and monophosphoryl lipid A-adjuvanted subunit glycoprotein D2 vaccine that has demonstrated activity in the prevention of HSV-2 infection and disease in HSV-uninfected women in a phase III clinical trial. Further confirmatory clinical trials of this vaccine are currently underway. Other vaccine formats also in development include attenuated live or replication-incompetent HSV-2 strains and technologies that target virus-specific CD8 T-cell responses.
Galdiero, Stefania; Falanga, Annarita; Tarallo, Rossella; Russo, Luigi; Galdiero, Emilia; Cantisani, Marco; Morelli, Giancarlo; Galdiero, Massimiliano
Herpes simplex virus (HSV) is a significant human pathogen causing mucocutaneous lesions primarily in the oral or genital mucosa. Although acyclovir (ACV) and related nucleoside analogs provide successful treatment, HSV remains highly prevalent worldwide and is a major cofactor for the spread of human immunodeficiency virus. Encephalitis, meningitis, and blinding keratitis are among the most severe diseases caused by HSV. ACV resistance poses an important problem for immunocompromised patients and highlights the need for new safe and effective agents; therefore, the development of novel strategies to eradicate HSV is a global public health priority. Despite the continued global epidemic of HSV and extensive research, there have been few major breakthroughs in the treatment or prevention of the virus since the introduction of ACV in the 1980s. A therapeutic strategy at the moment not fully addressed is the use of small peptide molecules. These can be either modeled on viral proteins or derived from antimicrobial peptides. Any peptide that interrupts protein-protein or viral protein-host cell membrane interactions is potentially a novel antiviral drug and may be a useful tool for elucidating the mechanisms of viral entry. This review summarizes current knowledge and strategies in the development of synthetic and natural peptides to inhibit HSV infectivity.
Wagner, E K; Bloom, D C
The clinical manifestations of herpes simplex virus infection generally involve a mild and localized primary infection followed by asymptomatic (latent) infection interrupted sporadically by periods of recrudescence (reactivation) where virus replication and associated cytopathologic findings are manifest at the site of initial infection. During the latent phase of infection, viral genomes, but not infectious virus itself, can be detected in sensory and autonomic neurons. The process of latent infection and reactivation has been subject to continuing investigation in animal models and, more recently, in cultured cells. The initiation and maintenance of latent infection in neurons are apparently passive phenomena in that no virus gene products need be expressed or are required. Despite this, a single latency-associated transcript (LAT) encoded by DNA encompassing about 6% of the viral genome is expressed during latent infection in a minority of neurons containing viral DNA. This transcript is spliced, and the intron derived from this splicing is stably maintained in the nucleus of neurons expressing it. Reactivation, which can be induced by stress and assayed in several animal models, is facilitated by the expression of LAT. Although the mechanism of action of LAT-mediated facilitation of reactivation is not clear, all available evidence argues against its involving the expression of a protein. Rather, the most consistent models of action involve LAT expression playing a cis-acting role in a very early stage of the reactivation process. PMID:9227860
Doronin, Konstantin; Shashkova, Elena V.; May, Shannon M.; Hofherr, Sean E.
Abstract Oncolytic adenoviruses are anticancer agents that replicate within tumors and spread to uninfected tumor cells, amplifying the anticancer effect of initial transduction. We tested whether coating the viral particle with polyethylene glycol (PEG) could reduce transduction of hepatocytes and hepatotoxicity after systemic (intravenous) administration of oncolytic adenovirus serotype 5 (Ad5). Conjugating Ad5 with high molecular weight 20-kDa PEG but not with 5-kDa PEG reduced hepatocyte transduction and hepatotoxicity after intravenous injection. PEGylation with 20-kDa PEG was as efficient at detargeting adenovirus from Kupffer cells and hepatocytes as virus predosing and warfarin. Bioluminescence imaging of virus distribution in two xenograft tumor models in nude mice demonstrated that PEGylation with 20-kDa PEG reduced liver infection 19- to 90-fold. Tumor transduction levels were similar for vectors PEGylated with 20-kDa PEG and unPEGylated vectors. Anticancer efficacy after a single intravenous injection was retained at the level of unmodified vector in large established prostate carcinoma xenografts, resulting in complete elimination of tumors in all animals and long-term tumor-free survival. Anticancer efficacy after a single intravenous injection was increased in large established hepatocellular carcinoma xenografts, resulting in significant prolongation of survival as compared with unmodified vector. The increase in efficacy was comparable to that obtained with predosing and warfarin pretreatment, significantly extending the median of survival. Shielding adenovirus with 20-kDa PEG may be a useful approach to improve the therapeutic window of oncolytic adenovirus after systemic delivery to primary and metastatic tumor sites. PMID:19469693
Son, Jee Hee; Chung, Bo Young; Kim, Hye One; Cho, Hee Jin
Cases involving dermatomal herpes zoster in two or more locations are rare, especially in immunocompetent patients. When two noncontiguous dermatomes are involved, if affected unilaterally, it is called herpes zoster duplex unilateralis; if bilaterally, bilateralis. Here, we report two cases of herpes zoster duplex unilateralis. A 66-year-old man presented with painful erythematous grouped vesicles on his left scalp, forehead, trunk, and back (left [Lt.] V1, Lt. T8). Histologic findings were consistent with herpetic infection. A 33-year-old woman presented with painful erythematous grouped vesicles and crust on her left forehead and neck (Lt. V1, Lt. C5). Both patients were treated with oral administration of famcyclovir 750 mg/day for seven days. PMID:27904277
Gilbert, Lisa K; Omisore, Folashade
Patients diagnosed with genital herpes typically undergo a period of psychological adjustment. Although healthcare providers can play a key role in this adjustment, in several patient surveys patients have expressed dissatisfaction with the information and counselling offered by professionals. To address this gap, providers must first identify the common questions and myths that are not addressed, or are addressed inadequately. This article is that first step. Through a content analysis of herpes chat-room transcripts captured on their website from autumn 2001 to spring 2006, researchers from the American Social Health Association identified common herpes questions and myths. The 1968 chat passages were coded into 12 themes and 50 sub-themes. Frequently, visitors' questions concerned transmission, symptoms and diagnosis followed by natural history, psychosocial issues and treatment options. The results of this analysis will aid in the creation of tailored messages to address common factual questions and provide psychosocial support.
A case of acute herpes zoster neuralgia (shingles) in a 78-year-old patient is described. The value and importance of immunizing against herpes zoster to decrease the incidence and severity of both acute herpes zoster neuralgia and postherpetic neuralgia are described. --This report is adapted from paineurope 2015: Issue 1, ©Haymarket Medical Publications Ltd., and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, Ltd., and is distributed free of charge to health care professionals in Europe. Archival issues can be viewed via the Web site: www.paineurope.com , at which health professionals can find links to the original articles and request copies of the quarterly publication and access additional pain education and pain management resources.
Narovlyansky, A N; Ivanova, A M; Shevlyagina, N V; Didenko, L V; Borovaya, T G; Izmest'eva, A V; Sanin, A V; Pronin, A V; Ershov, F I
An experimental model of the primary genital herpes (herpes simplex type 2, HSV-2) in the female guinea pigs was suggested to study the infectious process activity of polyprenyl phosphates (PPP) and PPP+acyclovir (AC) complex treatment. The morphofunctional features of the guinea pig ovaries were studied in the control and experimental groups (the latter were inoculated with PPP and/or AC as a primary infection treatment) at the stage of the recurrent genital herpes aggravation. It was shown that in the case of combined PPP +AC use significant changes in the disease symptoms were observed, as well as a decrease in the infectious process activity and duration, and positive remote effect on the ovarian morphophysiology.
Dropulic, Lesia K; Cohen, Jeffrey I
HSV infections are prevalent worldwide. A vaccine to prevent genital herpes would have a significant impact on this disease. Several vaccines have shown promise in animal models; however, so far these have not been successful in human clinical studies. Prophylactic HSV vaccines to prevent HSV infection or disease have focused primarily on eliciting antibody responses. Potent antibody responses are needed to result in sufficiently high levels of virus-specific antibody in the genital tract. Therapeutic vaccines that reduce recurrences need to induce potent T-cell responses at the site of infection. With the increasing incidence of HSV-1 genital herpes, an effective herpes vaccine should protect against both HSV-1 and HSV-2. Novel HSV vaccines, such as replication-defective or attenuated viruses, have elicited humoral and cellular immune responses in preclinical studies. These vaccines and others hold promise in future clinical studies. PMID:23252387
Cases, Margaret; Leduc, Charles; Farmer, Patricia L; Richardson, Susan E; Zoutman, Dick E
Herpes simplex virus has protean manifestations and is an important cause of morbidity in the immunocompromised host. We report a case of recurrent lymphadenopathy and rash in a patient with chronic lymphocytic leukemia. The elusive clinical diagnosis eventually required core biopsy of a lymph node with immunohistochemistry and confirmation by polymerase chain reaction. This case illustrates the challenging clinical and laboratory diagnosis of herpes simplex virus lymphadenitis and the need to maintain a high index of suspicion for infection when treating an immunocompromised patient with unusual and/or persistent symptoms.
Among the human herpes viruses, three are neurotropic and capable of producing severe neurological abnormalities: herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV). Both the acute, primary infection and the reactivation from the site of latent infection, the dorsal sensory ganglia, are associated with severe human morbidity and mortality. The peripheral nervous system is one of the major loci affected by these viruses. The present review details the virology and molecular biology underlying the human infection. This is followed by detailed description of the symtomatology, clinical presentation, diagnosis, course, therapy, and prognosis of disorders of the peripheral nervous system caused by these viruses.
Harada, Yukinori; Hara, Yuuta
Herpes simplex encephalitis (HSE) can be complicated by adverse events in the acute phase. We herein present the case of a 71-year-old woman with HSE complicated by cerebral hemorrhage. She presented with acute deterioration of consciousness and fever and was diagnosed with HSE based on the detection of herpes simplex virus-1 in the cerebrospinal fluid by a polymerase chain reaction. The cerebral hemorrhage developed during acyclovir therapy; however, its diagnosis was delayed for 2 days. After the conservative treatment of the cerebral hemorrhage, the patient made a near-complete recovery. Cerebral hemorrhage should be considered as an acute-phase complication of HSE. PMID:28090058
Veraldi, S; Vaira, F; Nazzaro, G
Clopidogrel is an adenosine diphosphate receptor antagonist used for the prevention of vascular events in patients with atherothrombotic diseases manifested by recent myocardial infarction, ischemic stroke or peripheral arterial disease. Diarrhoea, rash and pruritus are rather common side effects of clopidogrel. Other side effects include epistaxis, nausea, abdominal pain, vomiting, gastritis, gastric and duodenal ulcer. Thrombocytopenia is the most common laboratory abnormality. Leucopenia and neutropenia are rare. We report three cases of purpuric herpes zoster in patients in therapy with clopidogrel. To our knowledge, only one case of haemorrhagic herpes zoster has been published in a patient in therapy with this drug.
Myers, Jaime L; Buhi, Eric R; Marhefka, Stephanie; Daley, Ellen; Dedrick, Robert
Disclosure is often a challenge for individuals living with genital herpes. This study explores determinants of genital herpes disclosure with one's most recent sexual partner using an online questionnaire (n = 93). The majority of participants reported (80.4%) disclosure. Among non-disclosers, fear of negative partner reactions was the primary reason for non-disclosure. Age, relationship commitment, time in relationship, and expectations of partner's reaction were statistically significant predictors at the bivariate level. Reaction expectations and relationship commitment remained significant in the multivariate logistic regression model. Findings indicate that future disclosure research should focus on relationship context and managing negative expectations to increase disclosure.
Marques, Silvio Alencar; Hortense, Juliana
Herpes zoster-associated urinary retention is an uncommon event related to virus infection of the S2-S4 dermatome. The possible major reasons are ipsilateral hemicystitis, neuritis-induced or myelitis-associated virus infection. We report a case of a 65-year-old immunocompetent female patient who presented an acute urinary retention after four days under treatment with valacyclovir for gluteal herpes zoster. The patient had to use a vesical catheter, was treated with antibiotics and corticosteroids and fully recovered after eight weeks. PMID:25387508
Kukhanova, M K; Korovina, A N; Kochetkov, S N
WHO reports that 90% of human population is infected by different types of herpesviruses, which develop latency or cause oral and genital herpes, conjunctivitis, eczema herpeticum, and other diseases. Herpesvirus almost always accompanies HIV-infection and complicates AIDS treatment. Herpes simplex virus type 1 is one of the most wide spread viruses from the Herpesviridae family. HSV virion, genome structure, replication mechanisms, antiherpes drug development strategies, including design of prodrugs, and mutations causing ACV-resistance in clinical HSV isolates are discussed in this review.
Harada, Yukinori; Hara, Yuuta
Herpes simplex encephalitis (HSE) can be complicated by adverse events in the acute phase. We herein present the case of a 71-year-old woman with HSE complicated by cerebral hemorrhage. She presented with acute deterioration of consciousness and fever and was diagnosed with HSE based on the detection of herpes simplex virus-1 in the cerebrospinal fluid by a polymerase chain reaction. The cerebral hemorrhage developed during acyclovir therapy; however, its diagnosis was delayed for 2 days. After the conservative treatment of the cerebral hemorrhage, the patient made a near-complete recovery. Cerebral hemorrhage should be considered as an acute-phase complication of HSE.
James, Scott H; Kimberlin, David W
Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) are highly prevalent viruses capable of establishing lifelong infection. Genital herpes in women of childbearing age represents a major risk for mother-to-child transmission (MTCT) of HSV infection, with primary and first-episode genital HSV infections posing the highest risk. The advent of antiviral therapy with parenteral acyclovir has led to significant improvement in neonatal HSV disease mortality. Further studies are needed to improve the clinician's ability to identify infants at increased risk for HSV infection and prevent MTCT, and to develop novel antiviral agents with increased efficacy in infants with HSV infection.
Pierson, D. L.; Mehta, S. K.; Stowe, R.
Latent viruses are ubiquitous and reactivate during stressful periods with and without symptoms. Latent herpes virus reactivation is used as a tool to predict changes in the immune status in astronauts and to evaluate associated health risks. Methods: Viral DNA was detected by real time polymerase chain reaction in saliva and urine from astronauts before, during and after short and long-duration space flights. Results and Discussion: EpsteinBarr virus (EBV), cytomegalovirus (CMV), and varicella zoster virus (VZV) reactivated, and viral DNA was shed in saliva (EBV and VZV) or urine (CMV). EBV levels in saliva during flight were 10fold higher than baseline levels. Elevations in EBV specific CD8+ T-cells, viral antibody titers, and specific cytokines were consistent with viral reactivation. Intracellular levels of cytokines were reduced in EBVspecific Tcells. CMV, rarely present in urine of healthy individuals, was shed in urine of 27% of astronauts during all phases of spaceflight. VZV, not found in saliva of asymptomatic individuals, was found in saliva of 50% of astronauts during spaceflight and 35 days after flight. VZV recovered from astronaut saliva was found to be live, infectious virus. DNA sequencing demonstrated that the VZV recovered from astronauts was from the common European strain of VZV. Elevation of stress hormones accompanied viral reactivation indicating involvement of the hypothalmic-pituitary-adrenal and sympathetic adrenal-medullary axes in the mechanism of viral reactivation in astronauts. A study of 53 shingles patients found that all shingles patients shed VZV DNA in their saliva and the VZV levels correlated with the severity of the disease. Lower VZV levels in shingles patients were similar to those observed in astronauts. We proposed a rapid, simple, and cost-effective assay to detect VZV in saliva of patients with suspected shingles. Early detection of VZV infection allows early medical intervention.
Schirm, J; Mulkens, P S
Bell's palsy, which is defined as idiopathic peripheral facial paralysis of sudden onset, accounts for > 50% of all cases of facial paralysis. Different theories on the etiology of Bell's palsy have been proposed and investigated. Various clinical studies have suggested an etiological link between Bell's palsy and herpes simplex virus (HSV). In addition, animal experiments have shown the ability of HSV to induce facial paralysis. In our opinion, the possible link between Bell's palsy and HSV can only be explored properly by studying the human facial nerve, and especially the geniculate ganglion itself. Different groups have tried to detect hypothetically reactivated and hypothetically latent HSV in the facial nerves of Bell's palsy patients and control patients, respectively. The isolation of infectious HSV from facial nerve tissue by conventional cell culture methods appeared to be very difficult, also when Bell's palsy patients were tested. Instead, modern molecular methods, such as in situ hybridization and the polymerase chain reaction (PCR) could easily detect HSV DNA in geniculate ganglia. The detection of HSV-specific latency-associated transcripts in the ganglia of control patients provided further evidence for the hypothetically latent state of HSV in the geniculate ganglia in these patients. Recent PCR experiments performed by a Japanese group strongly suggest that the area adjacent to the geniculate ganglia does not usually contain any HSV at all, except in patients with Bell's palsy. This well-controlled study provides conclusive evidence that reactivation of HSV genomes from the geniculate ganglia is the most important cause of Bell's palsy. Consequently, it has been suggested that "Bell's palsy" be renamed as "herpetic facial paralysis".
LeGoff, Jérôme; Mayaud, Philippe; Gresenguet, Gérard; Weiss, Helen A.; Nzambi, Khonde; Frost, Eric; Pepin, Jacques; Belec, Laurent
The performances of commercial enzyme-linked immunosorbent assays (ELISAs) in detecting herpes simplex virus type 2 (HSV-2) antibodies have been inconsistent for African and human immunodeficiency virus (HIV)-positive populations. We compared the performances of the HerpeSelect and Kalon glycoprotein G2 ELISAs for patients with genital ulcer disease in Ghana and the Central African Republic. Sera from 434 women were tested with the HerpeSelect assay, and a subsample (n = 199) was tested by the Kalon assay. Ulcer swabs and cervicovaginal lavage samples were tested for HSV-2 DNA by PCR. HSV-2-seronegative women with detectable genital HSV-2 DNA were retested for HSV-2 antibodies 14 and 28 days later by the two ELISAs. A total of 346 (80%) women were positive by HerpeSelect at baseline, and 225 (54%) had detectable genital (lesional or cervicovaginal) HSV-2 DNA. Sixty-six (19%) HerpeSelect-positive samples had low-positive index values (1.1 to 3.5), and 58% of these samples had detectable genital HSV-2 DNA. Global agreement between the two serological assays was 86%. Concordance was high (99%) for sera that were negative by HerpeSelect or had high index values (>3.5). Defining infection detected by HSV-2 DNA PCR and/or Kalon assay as true infection, 71% of sera with low-positive index values were associated with true HSV-2 infection. Twenty-five women were identified as having nonprimary first-episode genital HSV-2 infection. Rates of HSV-2 seroconversion at day 14 were 77% (10/13 patients) by HerpeSelect assay and 23% (3/13 patients) by Kalon assay, with four additional seroconversions detected by Kalon assay at day 28. HIV serostatus did not influence assay performance. Low index values obtained with the HerpeSelect assay may correspond to true HSV-2 infection, in particular to nonprimary first episodes of genital HSV-2 infection, and need to be interpreted in the context of clinical history. PMID:18385443
LeGoff, Jérôme; Mayaud, Philippe; Gresenguet, Gérard; Weiss, Helen A; Nzambi, Khonde; Frost, Eric; Pepin, Jacques; Belec, Laurent
The performances of commercial enzyme-linked immunosorbent assays (ELISAs) in detecting herpes simplex virus type 2 (HSV-2) antibodies have been inconsistent for African and human immunodeficiency virus (HIV)-positive populations. We compared the performances of the HerpeSelect and Kalon glycoprotein G2 ELISAs for patients with genital ulcer disease in Ghana and the Central African Republic. Sera from 434 women were tested with the HerpeSelect assay, and a subsample (n = 199) was tested by the Kalon assay. Ulcer swabs and cervicovaginal lavage samples were tested for HSV-2 DNA by PCR. HSV-2-seronegative women with detectable genital HSV-2 DNA were retested for HSV-2 antibodies 14 and 28 days later by the two ELISAs. A total of 346 (80%) women were positive by HerpeSelect at baseline, and 225 (54%) had detectable genital (lesional or cervicovaginal) HSV-2 DNA. Sixty-six (19%) HerpeSelect-positive samples had low-positive index values (1.1 to 3.5), and 58% of these samples had detectable genital HSV-2 DNA. Global agreement between the two serological assays was 86%. Concordance was high (99%) for sera that were negative by HerpeSelect or had high index values (>3.5). Defining infection detected by HSV-2 DNA PCR and/or Kalon assay as true infection, 71% of sera with low-positive index values were associated with true HSV-2 infection. Twenty-five women were identified as having nonprimary first-episode genital HSV-2 infection. Rates of HSV-2 seroconversion at day 14 were 77% (10/13 patients) by HerpeSelect assay and 23% (3/13 patients) by Kalon assay, with four additional seroconversions detected by Kalon assay at day 28. HIV serostatus did not influence assay performance. Low index values obtained with the HerpeSelect assay may correspond to true HSV-2 infection, in particular to nonprimary first episodes of genital HSV-2 infection, and need to be interpreted in the context of clinical history.
Steuerwald, Nury; Grdzelishvili, Valery Z.
Vesicular stomatitis virus (VSV) based recombinant viruses (such as VSV-ΔM51) are effective oncolytic viruses (OVs) against a majority of pancreatic ductal adenocarcinoma (PDAC) cell lines. However, some PDAC cell lines are highly resistant to VSV-ΔM51. We recently showed that treatment of VSV-resistant PDAC cells with ruxolitinib (JAK1/2 inhibitor) or TPCA-1 (IKK-β inhibitor) breaks their resistance to VSV-ΔM51. Here we compared the global effect of ruxolitinib or TPCA-1 treatment on cellular gene expression in PDAC cell lines highly resistant to VSV-ΔM51. Our study identified a distinct subset of 22 interferon-stimulated genes (ISGs) downregulated by both ruxolitinib and TPCA-1. Further RNA and protein analyses demonstrated that 4 of these genes (MX1, EPSTI1, XAF1, and GBP1) are constitutively co-expressed in VSV-resistant, but not in VSV-permissive PDACs, thus serving as potential biomarkers to predict OV therapy success. Moreover, shRNA-mediated knockdown of one of such ISG, MX1, showed a positive effect on VSV-ΔM51 replication in resistant PDAC cells, suggesting that at least some of the identified ISGs contribute to resistance of PDACs to VSV-ΔM51. As certain oncogene and tumor suppressor gene variants are often associated with increased tropism of OVs to cancer cells, we also analyzed genomic DNA in a set of PDAC cell lines for frequently occurring cancer associated mutations. While no clear correlation was found between such mutations and resistance of PDACs to VSV-ΔM51, the analysis generated valuable genotypic data for future studies. PMID:27533247
Mansfield, D C; Kyula, J N; Rosenfelder, N; Chao-Chu, J; Kramer-Marek, G; Khan, A A; Roulstone, V; McLaughlin, M; Melcher, A A; Vile, R G; Pandha, H S; Khoo, V; Harrington, K J
Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice. PMID:26814609
Kochneva, Galina; Sivolobova, Galina; Tkacheva, Anastasiya; Grazhdantseva, Antonina; Troitskaya, Olga; Nushtaeva, Anna; Tkachenko, Anastasiya; Kuligina, Elena; Richter, Vladimir; Koval, Olga
Vaccinia virus (VACV) oncolytic therapy has been successful in a number of tumor models. In this study our goal was to generate a double recombinant vaccinia virus (VV-GMCSF-Lact) with enhanced antitumor activity that expresses exogenous proteins: the antitumor protein lactaptin and human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lactaptin has previously been demonstrated to act as a tumor suppressor in mouse hepatoma as well as MDA-MB-231 human adenocarcinoma cells grafted into SCID mice. VV-GMCSF-Lact was engineered from Lister strain (L-IVP) vaccinia virus and has deletions of the viral thymidine kinase and vaccinia growth factor genes. Cell culture experiments revealed that engineered VV-GMCSF-Lact induced the death of cultured cancer cells more efficiently than recombinant VACV coding only GM-CSF (VV-GMCSF-dGF). Normal human MCF-10A cells were resistant to both recombinants up to 10 PFU/cell. The selectivity index for breast cancer cells measured in pair cultures MCF-7/MCF-10A was 200 for recombinant VV-GMCSF-Lact coding lactaptin and 100 for VV-GMCSF-dGF. Using flow cytometry we demonstrated that both recombinants induced apoptosis in treated cells but that the rate in the cells with active caspase −3 and −7 was higher after treatment with VV-GMCSF-Lact than with VV-GMCSF-dGF. Tumor growth inhibition and survival outcomes after VV-GMCSF-Lact treatment were estimated using immunodeficient and immunocompetent mice models. We observed that VV-GMCSF-Lact efficiently delays the growth of sensitive and chemoresistant tumors. These results demonstrate that recombinant VACVs coding an apoptosis-inducing protein have good therapeutic potential against chemoresistant tumors. Our data will also stimulate further investigation of coding lactaptin double recombinant VACV in clinical settings. PMID:27708236
Yang, Yuefeng; Xu, Weidong; Neill, Thomas; Hu, Zebin; Wang, Chi-Hsiung; Xiao, Xianghui; Stock, Stuart R; Guise, Theresa; Yun, Chae-Ok; Brendler, Charles B; Iozzo, Renato V; Seth, Prem
The development of novel therapies for breast cancer bone metastasis is a major unmet medical need. Toward that end, we have constructed an oncolytic adenovirus, Ad.dcn, and a nonreplicating adenovirus, Ad(E1-).dcn, both containing the human decorin gene. Our in vitro studies showed that Ad.dcn produced high levels of viral replication and the decorin protein in the breast tumor cells. Ad(E1-).dcn-mediated decorin expression in MDA-MB-231 cells downregulated the expression of Met, β-catenin, and vascular endothelial growth factor A, all of which are recognized decorin targets and play pivotal roles in the progression of breast tumor growth and metastasis. Adenoviral-mediated decorin expression inhibited cell migration and induced mitochondrial autophagy in MDA-MB-231 cells. Mice bearing MDA-MB-231-luc skeletal metastases were systemically administered with the viral vectors, and skeletal tumor growth was monitored over time. The results of bioluminescence imaging and X-ray radiography indicated that Ad.dcn and Ad(E1-).dcn significantly inhibited the progression of bone metastases. At the terminal time point, histomorphometric analysis, micro-computed tomography, and bone destruction biomarkers showed that Ad.dcn and Ad(E1-).dcn reduced tumor burden and inhibited bone destruction. A nonreplicating adenovirus Ad(E1-).luc expressing the luciferase 2 gene had no significant effect on inhibiting bone metastases, and in several assays, Ad.dcn and Ad(E1-).dcn were better than Ad.luc, a replicating virus expressing the luciferase 2 gene. Our data suggest that adenoviral replication coupled with decorin expression could produce effective antitumor responses in a MDA-MB-231 bone metastasis model of breast cancer. Thus, Ad.dcn could potentially be developed as a candidate gene therapy vector for treating breast cancer bone metastases.
Thomas, Michael A.; Nyanhete, Tinashe; Tuero, Iskra; Venzon, David; Robert-Guroff, Marjorie
Type 5 human adenoviruses (Ad5) deleted of genes encoding the early region 1B 55-kDa (E1B55K) protein including Onyx-015 (dl1520) and H101 are best known for their oncolytic potential. As a vaccine vector the E1B55K deletion may allow for the insertion of a transgene nearly 1,000 base pairs larger than now possible. This has the potential of extending the application for which the vectors are clinically known. However, the immune priming ability of E1B55K-deleted vectors is unknown, undermining our ability to gauge their usefulness in vaccine applications. For this reason, we created an E1B55K-deleted Ad5 vector expressing full-length single chain HIVBaLgp120 attached to a flexible linker and the first two domains of rhesus CD4 (rhFLSC) in exchange for the E3 region. In cell-based experiments the E1B55K-deleted vector promoted higher levels of innate immune signals including chemokines, cytokines, and the NKG2D ligands MIC A/B compared to an E1B55K wild-type vector expressing the same immunogen. Based on these results we evaluated the immune priming ability of the E1B55K-deleted vector in mice. The E1B55K-deleted vector promoted similar levels of Ad5-, HIVgp120, and rhFLSC-specific cellular and humoral immune responses as the E1B55K wild-type vector. In pre-clinical HIV-vaccine studies the wild-type vector has been employed as part of a very effective prime-boost strategy. This study demonstrates that E1B55K-deleted adenoviruses may serve as effective vaccine delivery vectors. PMID:27391605
Mansfield, D C; Kyula, J N; Rosenfelder, N; Chao-Chu, J; Kramer-Marek, G; Khan, A A; Roulstone, V; McLaughlin, M; Melcher, A A; Vile, R G; Pandha, H S; Khoo, V; Harrington, K J
Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice.
Rodriguez-Brenes, Ignacio A.; Hofacre, Andrew; Fan, Hung; Wodarz, Dominik
While virus growth dynamics have been well-characterized in several infections, data are typically collected once the virus population becomes easily detectable. Earlier dynamics, however, remain less understood. We recently reported unusual early dynamics in an experimental system using adenovirus infection of human embryonic kidney (293) cells. Under identical experimental conditions, inoculation at low infection multiplicities resulted in either robust spread, or in limited spread that eventually stalled, with both outcomes occurring with approximately equal frequencies. The reasons underlying these observations have not been understood. Here, we present further experimental data showing that inhibition of interferon-induced antiviral states in cells results in a significant increase in the percentage of robust infections that are observed, implicating a race between virus replication and the spread of the anti-viral state as a central mechanism. Analysis of a variety of computational models, however, reveals that this alone cannot explain the simultaneous occurrence of both viral growth outcomes under identical conditions, and that additional biological mechanisms have to be invoked to explain the data. One such mechanism is the ability of the virus to overcome the antiviral state through multiple infection of cells. If this is included in the model, two outcomes of viral spread are found to be simultaneously stable, depending on initial conditions. In stochastic versions of such models, the system can go by chance to either state from identical initial conditions, with the relative frequency of the outcomes depending on the strength of the interferon-based anti-viral response, consistent with the experiments. This demonstrates considerable complexity during the early phase of the infection that can influence the ability of a virus to become successfully established. Implications for the initial dynamics of oncolytic virus spread through tumors are discussed
Jing, Yuqi; Zaias, Julia; Duncan, Robert; Russell, Stephen J.; Merchan, Jaime R.
The urokinase receptor (uPAR) is a clinically relevant target for novel biological therapies. We have previously rescued oncolytic measles viruses fully retargeted against human (MV-h-uPA) or murine (MV-m-uPA) uPAR. Here, we investigated the in vivo effects of systemic administration of MV-m-uPA in immunocompetent cancer models. MV-m-uPA induced in vitro cytotoxicity and replicated in a receptor dependent manner in murine mammary (4T1), and colon (MC-38 and CT-26) cancer cells. Intravenous administration of MV-m-uPA to 4T1 tumor bearing mice was not associated with significant clinical or laboratory toxicity. Higher MV-N RNA copy numbers were detected in primary tumors, and viable viral particles were recovered from tumor bearing tissues only. Non-tumor bearing organs did not show histological signs of viral induced toxicity. Serum anti-MV antibodies were detected at day 14 of treatment. Immunohistochemistry and immunofluorescence studies confirmed successful tumor targeting and demonstrated enhanced MV-m-uPA induced tumor cell apoptosis in treated, compared to control mice. Significant antitumor effects and prolonged survival were observed after systemic administration of MV-m-uPA in colon (CT-26) and mammary (4T1) cancer models. The above results demonstrate safety and feasibility of uPAR targeting by an oncolytic virus, and confirm significant antitumor effects in highly aggressive syngeneic immunocompetent cancer models. PMID:24430235
Yoo, So Young; Bang, Seo Young; Jeong, Su-Nam; Kang, Dae Hwan; Heo, Jeong
Stem cell-like colon cancer cells (SCCs) pose a major challenge in colon cancer treatment because of their resistance to chemotherapy and radiotherapy. Oncolytic virus-based therapy has shown promising results in uncured cancer patients; however, its effects on SCCs are not well studied yet. Here, we engineered a cancer-favoring oncolytic vaccinia virus (CVV) as a potent biotherapeutic and investigated its therapeutic efficacy in terms of killing SCCs. CVV is an evolved Wyeth strain vaccinia virus (EVV) lacking the viral thymidine kinase. SCC models were established using human or mouse colon cancer spheres, which continuously expressed stemness markers. The cancer-favoring characteristics and different cytotoxic pathways for killing cancer cells successfully overrode general drug resistance, thereby killing colon cancer cells regardless of the presence of SCCs. Subcutaneously injected HT29 spheres showed lower growth in CVV-treated models than in 5-Fu-treated models. Intraperitoneally injected CT26 spheres induced tumor masses in the abdominal region. CVV-treated groups showed higher survival rates and smaller tumor mass formation, compared to 5-Fu-treated groups. Interestingly, the combined treatment of CVV with 5-Fu showed improved survival rates and complete suppression of tumor mass. The CVV developed in this study, thus, effectively suppresses SCCs, which can be synergistically enhanced by simultaneous treatment with the anticancer drug 5-Fu. Our novel CVV is highly advantageous as a next-generation therapeutic for treating colon cancer. PMID:26918725
Weibel, Stephanie; Langbein-Laugwitz, Johanna; Härtl, Barbara; Escobar, Hugo Murua; Nolte, Ingo; Chen, Nanhai G.; Aguilar, Richard J.; Yu, Yong A.; Zhang, Qian; Frentzen, Alexa; Szalay, Aladar A.
Virotherapy on the basis of oncolytic vaccinia virus (VACV) infection is a promising approach for cancer therapy. In this study we describe the establishment of a new preclinical model of feline mammary carcinoma (FMC) using a recently established cancer cell line, DT09/06. In addition, we evaluated a recombinant vaccinia virus strain, GLV-5b451, expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as an oncolytic agent against FMC. Cell culture data demonstrate that GLV-5b451 virus efficiently infected, replicated in and destroyed DT09/06 cancer cells. In the selected xenografts of FMC, a single systemic administration of GLV-5b451 led to significant inhibition of tumor growth in comparison to untreated tumor-bearing mice. Furthermore, tumor-specific virus infection led to overproduction of functional scAb GLAF-2, which caused drastic reduction of intratumoral VEGF levels and inhibition of angiogenesis. In summary, here we have shown, for the first time, that the vaccinia virus strains and especially GLV-5b451 have great potential for effective treatment of FMC in animal model. PMID:25093734
Yang, Y; Xu, H; Shen, J; Yang, Y; Wu, S; Xiao, J; Xu, Y; Liu, X-Y; Chu, L
Cancer-initiating cell (CIC) is critical in cancer development, maintenance and recurrence. The reverse expression pattern of coxsackie and adenovirus receptor (CAR) and αν integrin in bladder cancer decreases the infection efficiency of adenovirus. We constructed Arg-Gly-Asp (RGD)-modified oncolytic adenovirus, carrying EGFP or TNF-related apoptosis-inducing ligand (TRAIL) gene (Onco(Ad).RGD-hTERT-EGFP/TRAIL), and applied them to CAR-negative bladder cancer T24 cells and cancer-initiating T24 sphere cells. Onco(Ad).RGD-hTERT-EGFP had enhanced infection ability and cytotoxic effect on T24 cells and T24 sphere cells, but little cytoxicity on normal urothelial SV-HUC-1 cells compared with the unmodified virus Onco(Ad).hTERT-EGFP. Notably, Onco(Ad).RGD-hTERT-TRAIL induced apoptosis in T24 cells and T24 sphere cells. Furthermore, it completely inhibited xenograft initiation established by the oncolytic adenovirus-pretreated T24 sphere cells, and significantly suppressed tumor growth by intratumoral injection. These results provided a promising therapeutic strategy for CAR-negative bladder cancer through targeting CICs.
Achard, Carole; Boisgerault, Nicolas; Delaunay, Tiphaine; Roulois, David; Nedellec, Steven; Royer, Pierre-Joseph; Pain, Mallory; Combredet, Chantal; Mesel-Lemoine, Mariana; Cellerin, Laurent; Magnan, Antoine; Tangy, Frédéric; Grégoire, Marc; Fonteneau, Jean-François
Attenuated measles virus (MV) is currently being evaluated as an oncolytic virus in clinical trials and could represent a new therapeutic approach for malignant pleural mesothelioma (MPM). Herein, we screened the sensitivity to MV infection and replication of twenty-two human MPM cell lines and some healthy primary cells. We show that MV replicates in fifteen of the twenty-two MPM cell lines. Despite overexpression of CD46 by a majority of MPM cell lines compared to healthy cells, we found that the sensitivity to MV replication did not correlate with this overexpression. We then evaluated the antiviral type I interferon (IFN) responses of MPM cell lines and healthy cells. We found that healthy cells and the seven insensitive MPM cell lines developed a type I IFN response in presence of the virus, thereby inhibiting replication. In contrast, eleven of the fifteen sensitive MPM cell lines were unable to develop a complete type I IFN response in presence of MV. Finally, we show that addition of type I IFN onto MV sensitive tumor cell lines inhibits replication. These results demonstrate that defects in type I IFN response are frequent in MPM and that MV takes advantage of these defects to exert oncolytic activity. PMID:26539644
Wennier, Sonia Tusell; Liu, Jia; Li, Shoudong; Rahman, Masmudur M; Mona, Mahmoud; McFadden, Grant
Myxoma virus (MYXV) is a novel oncolytic virus that has been shown to replicate in pancreatic cancer cells, but its efficacy in animal models of pancreatic cancer has not been determined. The efficacy of MYXV as monotherapy or in combination with gemcitabine was evaluated in intraperitoneal dissemination (IPD) models of pancreatic cancer. The effects of an intact immune system on the efficacy of MYXV therapy was tested by comparing immunodeficient versus immunocompetent murine models and combination therapy with gemcitabine was also evaluated. In cell culture, MYXV replication was robust in a broad range of pancreatic cancer cells and also showed increased oncolysis in combination with gemcitabine. In animal models, MYXV treatment conferred survival benefits over control or gemcitabine-treated cohorts regardless of the cell line or animal model used. MYXV monotherapy was most effective in an immunocompetent IPD model, and resulted in 60% long-term survivors. In Pan02 engrafted immunocompetent IPD models, sequential treatment in which MYXV was administered first, followed by gemcitabine, was the most effective and resulted in 100% long-term survivors. MYXV is an effective oncolytic virus for pancreatic cancer and can be combined with gemcitabine to enhance survival, particularly in the presence of an intact host immune system.
Puig-Saus, C; Rojas, L A; Laborda, E; Figueras, A; Alba, R; Fillat, C; Alemany, R
Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.
Zamarin, Dmitriy; Holmgaard, Rikke B.; Ricca, Jacob; Plitt, Tamar; Palese, Peter; Sharma, Padmanee; Merghoub, Taha; Wolchok, Jedd D.; Allison, James P.
Emerging data suggest that locoregional cancer therapeutic approaches with oncolytic viruses can lead to systemic anti-tumour immunity, although the appropriate targets for intratumoral immunomodulation using this strategy are not known. Here we find that intratumoral therapy with Newcastle disease virus (NDV), in addition to the activation of innate immunity, upregulates the expression of T-cell co-stimulatory receptors, with the inducible co-stimulator (ICOS) being most notable. To explore ICOS as a direct target in the tumour, we engineered a recombinant NDV-expressing ICOS ligand (NDV-ICOSL). In the bilateral flank tumour models, intratumoral administration of NDV-ICOSL results in enhanced infiltration with activated T cells in both virus-injected and distant tumours, and leads to effective rejection of both tumours when used in combination with systemic CTLA-4 blockade. These findings highlight that intratumoral immunomodulation with an oncolytic virus expressing a rationally selected ligand can be an effective strategy to drive systemic efficacy of immune checkpoint blockade. PMID:28194010
Schenk, Ellen; Essand, Magnus; Kraaij, Robert; Adamson, Rachel; Maitland, Norman J; Bangma, Chris H
Prostate cancer is the most common malignancy in the Western world. Patients can be cured only when the tumor has not metastasized outside the prostate. However, treatment with curative intent fails in a significant number of men, often resulting in untreatable progressive disease with a fatal outcome. Oncolytic adenovirus therapy may be a promising adjuvant treatment to reduce local failure or the outgrowth of micrometastatic disease. Within the European gene therapy consortium GIANT, we have developed a novel prostate-specific oncolytic adenovirus: Ad[I/PPT-E1A]. This adenovirus specifically kills prostate cells via prostate-specific replication. This article describes the clinical development of Ad[I/PPT-E1A] with particular reference to the preclinical safety assessment of this novel virus. The preclinical safety assessment involved an efficacy study in a human orthotopic xenograft mouse model, a specificity study in human primary cells, and a toxicity study in normal mice. These studies confirmed that Ad[I/PPT-E1A] efficiently kills prostate tumor cells in vivo, is not harmful to other organs, and is well tolerated in mice after systemic delivery. The safety, as well as the immunological effects of Ad[I/PPT-E1A] as a local adjuvant therapy, will now be studied in a phase I dose-escalating trial in patients with localized prostate cancer who are scheduled for curative radical prostatectomy and can be used as an updated paradigm for similar therapeutic viruses.
Kim, Manbok; Rahman, Masmudur M.; Cogle, Christopher R.
Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.
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