Local Delivery of OncoVEXmGM-CSF Generates Systemic Anti-Tumor 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 anti-tumor immune responses driving efficacy in murine syngeneic models.<br /><br />Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEX^mGM-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. <br /><br />Results: Treatment with OncoVEX^mGM-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 OncoVEX^mGM-CSF-cured mice significantly protected from tumor challenge. Lastly, combination of OncoVEX^mGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8⁺ anti-AH1 T cells and systemic efficacy. <br /><br />Conclusions: The data support a dual MOA for OncoVEX^mGM-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.

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