OncoVEX(mGM-CSF)expands tumor antigen-specific CD8+ T-cell response in preclinical models.

Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) have demonstrated clinical efficacy in advanced melanoma, but only a subset of patients with inflamed tumors are responsive. Talimogene laherparepvec (T-VEC), a modified herpes simplex virus type 1 (HSV-1) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), is a first-in-class oncolytic immunotherapy approved for the treatment of melanoma and has been shown to inflame the tumor microenvironment. To evaluate the potential and mechanisms of T-VEC to elicit systemic antitumor immunity and overcome resistance to checkpoint inhibitors in murine tumor models, OncoVEXmGM-CSF was developed similarly to T-VEC, except the human GM-CSF transgene was replaced with murine GM-CSF. Previous work had demonstrated that OncoVEXmGM-CSF generated systemic antitumor immunity dependent on CD8+ T cells in an immune checkpoint-sensitive tumor cell model. A novel B16F10 syngeneic tumor model with both HSV-1-permissive subcutaneous tumors and HSV-1-refractory experimental lung metastasis was used to study the local and systemic effects of OncoVEXmGM-CSF treatment alone or in combination with checkpoint inhibitors. Intratumoral injection of OncoVEXmGM-CSF in combination with an anti-CTLA-4 or anti-PD-1 blocking antibody led to increased tumor growth inhibition, a reduction in the number of lung metastases, and prolonged animal survival. OncoVEXmGM-CSF induced both neoantigen-specific and tumor antigen-specific T-cell responses. Furthermore, cured mice from the combination treatment of OncoVEXmGM-CSF and anti-CTLA-4 antibody rejected tumor rechallenges. These data support the concept that T-VEC and checkpoint inhibition may be an effective combination to treat patients with advanced melanoma.

Estrada J ，Zhan J ，Mitchell P ，Werner J ，Beltran PJ ，DeVoss J ，Qing J ，Cooke KS ... -  《Journal for ImmunoTherapy of Cancer》

Local Delivery of OncoVEX(mGM-CSF) Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade.

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy.Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190-202. ©2017 AACR.

Moesta AK ，Cooke K ，Piasecki J ，Mitchell P ，Rottman JB ，Fitzgerald K ，Zhan J ，Yang B ，Le T ，Belmontes B ，Ikotun OF ，Merriam K ，Glaus C ，Ganley K ，Cordover DH ，Boden AM ，Ponce R ，Beers C ，Beltran PJ ... -  《-》

Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1.

Thomas S ，Kuncheria L ，Roulstone V ，Kyula JN ，Mansfield D ，Bommareddy PK ，Smith H ，Kaufman HL ，Harrington KJ ，Coffin RS ... -  《Journal for ImmunoTherapy of Cancer》

Combination immunotherapy including OncoVEX(mGMCSF) creates a favorable tumor immune micro-environment in transgenic BRAF murine melanoma.

Talimogene Laherparepvec (OncoVEXmGMCSF), an oncolytic virus, immune checkpoint inhibitor anti-programmed cell death protein 1 (anti-PD1), and BRAF inhibition (BRAFi), are all clinically approved for treatment of melanoma patients and are effective through diverse mechanisms of action. Individually, these therapies also have an effect on the tumor immune microenvironment (TIME). Evaluating the combination effect of these three therapies on the TIME can help determine when combination therapy is most appropriate for further study. In this study, we use a transgenic murine melanoma model (Tyr::CreER; BRAFCA/+; PTENflox/flox), to evaluate the TIME in response to combinations of BRAFi, anti-PD1, and OncoVEXmGMCSF. We find that mice treated with the triple combination BRAFi + anti-PD1 + OncoVEXmGMCSF have decreased tumor growth compared to BRAFi alone and prolonged survival compared to control. Flow cytometry shows an increase in percent CD8 + /CD3 + cytotoxic T Lymphocytes (CTLs) and a decrease in percent FOXP3 + /CD4 + T regulatory cells (Tregs) in tumors treated with OncoVEXmGMCSF compared to mice not treated with OncoVEXmGMCSF. Immunogenomic analysis at 30d post-treatment shows an increase in Th1 and interferon-related genes in mice receiving OncoVEXmGMCSF + BRAFi. In summary, treatment with combination BRAFi + anti-PD1 + OncoVEXmGMCSF is more effective than any single treatment in controlling tumor growth, and groups receiving OncoVEXmGMCSF had more tumoral infiltration of CTLs and less intratumoral Tregs in the TIME. This study provides rational basis to combine targeted agents, oncolytic viral therapy, and checkpoint inhibitors in the treatment of melanoma.

Gartrell RD ，Blake Z ，Rizk EM ，Perez-Lorenzo R ，Weisberg SP ，Simoes I ，Esancy C ，Fu Y ，Davari DR ，Barker L ，Finkel G ，Mondal M ，Minns HE ，Wang SW ，Fullerton BT ，Lozano F ，Chiuzan C ，Horst B ，Saenger YM ... -  《-》

Oncolytic viral therapy with a combination of HF10, a herpes simplex virus type 1 variant and granulocyte-macrophage colony-stimulating factor for murine ovarian cancer.

Ovarian cancer is the most frequent cause of gynecological cancer-related mortality as a majority of patients are diagnosed at an advanced stage with intraperitoneal dissemination because of the absence of initial symptoms. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the maturation of specialized antigen-presenting cells. In this study, we utilized a herpes simplex virus (HSV) amplicon expressing murine GM-CSF combined with HF10 (mGM-CSF amplicon), a highly attenuated HSV type 1 strain functioning as a helper virus to strengthen anti-tumor immune response, for the treatment of ovarian cancer with intraperitoneal dissemination. A mouse ovarian cancer cell line, OV2944-HM-1 (HM-1), was intraperitoneally injected, following which HF10 only or the mGM-CSF amplicon was injected intraperitoneally three times. HF10 injection prolonged survival and decreased intraperitoneal dissemination, but to a lesser extent than the mGM-CSF amplicon. Although HF10 replication was not observed in HM-1 cells, expression of VP5, a late gene coding the major capsid protein of HSV, was detected. Moreover, mGM-CSF production was detected in transfected HM-1 cells. Immunohistochemical staining revealed the infiltration of CD4- and CD8-positive cells into the peritoneal tumor(s). A significantly increased CD4+ T cell concentration was observed in the spleen. Murine splenic cells after each treatment were stimulated with HM-1 cells, and the strongest immune response was observed in the mice that received mGM-CSF amplicon injections. These results suggested that the mGM-CSF amplicon is a promising agent for the treatment of advanced ovarian cancer with intraperitoneal dissemination.

Goshima F ，Esaki S ，Luo C ，Kamakura M ，Kimura H ，Nishiyama Y ... -  《-》