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Oncolytic HSV and T cells

David F Bauer, Larisa Pereboeva, G Yancey Gillespie, Gretchen A Cloud, Osama Elzafarany, Catherine Langford, James M Markert, Lawrence S Lamb
We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor...
2016: Journal of Immunology Research
Hiroshi Fukuhara, Yasushi Ino, Tomoki Todo
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...
August 3, 2016: Cancer Science
Ji Young Yoo, Alena C Jaime-Ramirez, Chelsea Bolyard, Hongsheng Dai, Tejaswini Nallanagulagari, Jeffrey Wojton, Brian Hurwitz, Theresa Relation, Jun-Ge Yu, Tae Jin Lee, Michael T Lotze, Jianying Zhang, Carlo M Croce, Jianhua Yu, Michael A Caligiuri, Matthew Old, Balveen Kaur
BACKGROUND: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV) expressing GMCSF are currently FDA-approved. While proteasome blockade can increase oHSV replication, immunological consequences and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to Natural Killier (NK) cell immunotherapy. EXPERIMENTAL DESIGN: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death...
July 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Aldo Pourchet, Steven R Fuhrmann, Karsten A Pilones, Sandra Demaria, Alan B Frey, Matthew Mulvey, Ian Mohr
Although counteracting innate defenses allows oncolytic viruses (OVs) to better replicate and spread within tumors, CD8(+) T-cells restrict their capacity to trigger systemic anti-tumor immune responses. Herpes simplex virus-1 (HSV-1) evades CD8(+) T-cells by producing ICP47, which limits immune recognition of infected cells by inhibiting the transporter associated with antigen processing (TAP). Surprisingly, removing ICP47 was assumed to benefit OV immuno-therapy, but the impact of inhibiting TAP remains unknown because human HSV-1 ICP47 is not effective in rodents...
March 2016: EBioMedicine
A Takasu, A Masui, M Hamada, T Imai, S Iwai, Y Yura
Molecules essential for the induction of immunogenic cell death (ICD) are called damage-associated molecular patterns (DAMPs). The effects of oncolytic herpes simplex virus type 1 (HSV-1) on the production of DAMPs were examined in squamous cell carcinoma (SCC) cells. The cytopathic effects of HSV-1 RH2 were observed in mouse SCCVII cells infected at a high multiplicity of infection (MOI), and the amounts of viable cells were decreased. After being infected with RH2, ATP and high mobility group box 1 (HMGB1) were released extracellulary, while calreticulin (CRT) translocated to the cell membrane...
April 2016: Cancer Gene Therapy
Ismael Samudio, Katayoun Rezvani, Hila Shaim, Elyse Hofs, Mor Ngom, Luke Bu, Guoyu Liu, Jason T C Lee, Suzan Imren, Vivian Lam, Grace F T Poon, Maryam Ghaedi, Fumio Takei, Keith Humphries, William Jia, Gerald Krystal
Herein we demonstrate that oncolytic herpes simplex virus-1 (HSV-1) potently activates human peripheral blood mononuclear cells (PBMCs) to lyse leukemic cell lines and primary acute myeloid leukemia samples, but not healthy allogeneic lymphocytes. Intriguingly, we found that UV light-inactivated HSV-1 (UV-HSV-1) is equally effective in promoting PBMC cytolysis of leukemic cells and is 1000- to 10 000-fold more potent at stimulating innate antileukemic responses than UV-inactivated cytomegalovirus, vesicular stomatitis virus, reovirus, or adenovirus...
May 26, 2016: Blood
T Shibata, H Uchida, T Shiroyama, Y Okubo, T Suzuki, H Ikeda, M Yamaguchi, Y Miyagawa, T Fukuhara, J B Cohen, J C Glorioso, T Watabe, H Hamada, H Tahara
Oncolytic herpes simplex virus (HSV) vectors have attracted increasing attention as novel anti-cancer agents. HSV entry is triggered by the binding of glycoprotein D (gD) to its receptors, such as herpesvirus entry mediator or nectin-1. We have recently reported the construction of a fully retargeted HSV platform that incorporates single-chain antibodies (scFv) into gD to mediate entry exclusively via tumor-associated antigens. In this study, we created an scFv directed against epithelial cell adhesion molecule (EpCAM), a recognized carcinoma-associated antigen, and inserted it into the retargeted HSV platform that is ablated for gD recognition of its canonical receptors and contains the entry-enhancing mutations in gB we previously identified...
June 2016: Gene Therapy
Shaun Xiaoliu Zhang
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...
November 2015: Discovery Medicine
Dominique Bollino, Aric Colunga, Baiquan Li, Laure Aurelian
Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus ΔPK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether ΔPK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism...
February 2016: Journal of General Virology
P-Y Wang, H M Swain, A L Kunkler, C-Y Chen, B J Hutzen, M A Arnold, K A Streby, M H Collins, B Dipasquale, J R Stanek, J Conner, T H van Kuppevelt, J C Glorioso, P Grandi, T P Cripe
Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors...
February 2016: Gene Therapy
S T Workenhe, T Ketela, J Moffat, B P Cuddington, K L Mossman
Oncolytic human herpes simplex virus type 1 (HSV-1) shows promising treatment efficacy in late-stage clinical trials. The anticancer activity of oncolytic viruses relies on deregulated pathways in cancer cells, which make them permissive to oncolysis. To identify pathways that restrict HSV-1 KM100-mediated oncolysis, this study used a pooled genome-wide short hairpin RNA library and found that depletion of the splicing factor arginine-rich splicing factor 2 (SRSF2) leads to enhanced cytotoxicity of breast cancer cells by KM100...
May 12, 2016: Oncogene
Christian T Farrar, Jason S Buhrman, Guanshu Liu, Anne Kleijn, Martine L M Lamfers, Michael T McMahon, Assaf A Gilad, Giulia Fulci
PURPOSE: To (a) evaluate whether the lysine-rich protein (LRP) magnetic resonance (MR) imaging reporter gene can be engineered into G47Δ, a herpes simplex-derived oncolytic virus that is currently being tested in clinical trials, without disrupting its therapeutic effectiveness and (b) establish the ability of chemical exchange saturation transfer (CEST) MR imaging to demonstrate G47Δ-LRP. MATERIALS AND METHODS: The institutional subcommittee for research animal care approved all in vivo procedures...
June 2015: Radiology
S Okunaga, A Takasu, N Meshii, T Imai, M Hamada, S Iwai, Y Yura
Low-intensity ultrasound is a useful method to enhance the delivery of drugs to target cells via a range of mechanisms including the transient formation of micropores in the cell membrane, a process known as sonoporation. The effect of ultrasound on oncolytic herpes simplex virus type-1 (HSV-1) infection in oral squamous cell carcinoma (SCC) was examined. Human SCC cell line SAS and oncolytic HSV-1 RH2, which was deficient in the neurovirulent γ134.5 gene and exhibited cell fusion actions, were used. Cells grown in multi-well plates were infected with HSV-1 and exposed to ultrasound in the presence or absence of microbubbles after an adsorption period...
April 2015: Cancer Gene Therapy
Xinping Fu, Armando Rivera, Lihua Tao, Xiaoliu Zhang
Adoptive T-cell therapy has shown promises for cancer treatment. However, for treating solid tumors, there is a need for improving the ability of the adoptively transferred T cells to home to tumor sites. We explored the possibility of using an oncolytic virus derived from HSV-2, which can actively pull T effector cells to the site of infection, as a local attractant for migration of adoptively transferred T cells. Our data show that intratumoral administration of this virus can indeed attract active migration of the adoptively transferred T cells to the treated tumor...
January 20, 2015: Oncotarget
Jiani Wang, Lihua Xu, Weigen Zeng, Pan Hu, Musheng Zeng, Samuel D Rabkin, Renbin Liu
BACKGROUND: Oncolytic herpes simplex virus (HSV) can replicate in and kill cancer cells while sparing the adjacent normal tissue. Hepatocellular carcinoma (HCC) is amongst the most common and lethal cancers, especially in Third World countries. In this study, the cytotoxicity of a third-generation oncolytic HSV, G47Δ, was investigated in different human HCC cell lines and in an immortalized human hepatic cell line. Additionally, subcutaneous models of HCC were established to evaluate the in vivo anti-tumor efficacy of G47Δ...
2014: Cancer Cell International
Mikiya Ishihara, Naohiro Seo, Jun Mitsui, Daisuke Muraoka, Maki Tanaka, Junichi Mineno, Hiroaki Ikeda, Hiroshi Shiku
Oncolytic virotherapy combined with immunomodulators is a novel noninvasive strategy for cancer treatment. In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor. Two murine tumor models were used to evaluate the therapeutic efficacies of HF10 virotherapy combined with DTA-1. The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry...
2014: PloS One
Howard L Kaufman, Carl E Ruby, Tasha Hughes, Craig L Slingluff
In 2012, it was estimated that 9180 people in the United States would die from melanoma and that more than 76,000 new cases would be diagnosed. Surgical resection is effective for early-stage melanoma, but outcomes are poor for patients with advanced disease. Expression of tumor-associated antigens by melanoma cells makes the disease a promising candidate for immunotherapy. The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) has a variety of effects on the immune system including activation of T cells and maturation of dendritic cells, as well as an ability to promote humoral and cell-mediated responses...
2014: Journal for Immunotherapy of Cancer
Tyrel T Smith, Justin C Roth, Gregory K Friedman, G Yancey Gillespie
Cancer stem cells (CSCs) are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy. To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics...
February 2014: Oncolytic Virotherapy
Samuel T Workenhe, Jonathan G Pol, Brian D Lichty, Derek T Cummings, Karen L Mossman
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...
November 2013: Cancer Immunology Research
William F Goins, Shaohua Huang, Justus B Cohen, Joseph C Glorioso
Virus vectors have been employed as gene transfer vehicles for various preclinical and clinical gene therapy applications, and with the approval of Glybera (alipogene tiparvovec) as the first gene therapy product as a standard medical treatment (Yla-Herttuala, Mol Ther 20: 1831-1832, 2013), gene therapy has reached the status of being a part of standard patient care. Replication-competent herpes simplex virus (HSV) vectors that replicate specifically in actively dividing tumor cells have been used in Phase I-III human trials in patients with glioblastoma multiforme, a fatal form of brain cancer, and in malignant melanoma...
2014: Methods in Molecular Biology
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