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Although oncolytic viruses have shown clinical efficacy for local treatment of cancerous tumors, the ability to induce immune-mediated regression to visceral lesions is not robust. Immune checkpoint modulation has been efficacious in a fraction of cancers associated with an inflamed microenvironment but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies has the exciting potential to be an effective cancer therapy. Oncolytic virus can be genetically modified to decrease pathogenicity to normal cells and to increase their lytic potential and ability to stimulate antitumor immunity, thus improving the risk-benefit ratio for cancer patients. Oncorus oHSV (ONCR) are novel oncolytic herpes simplex virus type-1 vectors developed for the treatment of solid tumors. ONCR utilizes a unique conditional-lethal strategy in which tissue-specific miRs binding sites are inserted into early genes essential for viral replication and in the neurovirulence gene ICP34.5. This strategy curtails viral replication in normal cells, including neurons, and limits the expression of g34.5 to tumor cells, thus promoting potent viral replication in presence of type I interferon. Fifteen immunostimulatory transgenes and combination thereof were systematically evaluated in dual flank syngeneic mouse tumor models to test both for oncolysis and abscopal efficacy on the contralateral noninjected tumor. Among the selected transgenes, IL-12 was found to elicit the most potent efficacy on the ipsilateral and contralateral tumors. We demonstrated that the replication of ONCR and the expression of IL-12 was limited to the injected tumors. By contrast, induction of systemic immunity as assessed by IFNg production in contralateral tumors and in plasma was observed. ONCR expressing IL-12 elicited efficacy in multiple subcutaneous and metastatic models. Additional payloads designed to stimulate antigen presentation, recruitment of immune cells and inhibition of tumor immune suppression were identified as further enhancing IL-12 activity. Data supporting the selection of a suite of payloads cloned into a single ONCR vector will be presented. ONCR represents a new class of oncolytic virus that promote antitumor responses through a multiprong mechanism of action dependent on selective tumor cell killing, the induction of systemic antitumor immunity and reversion of immune suppression. Citation Format: Lorena Lerner, Edward M. Kennedy, Terry Farkaly, Allison Colthart, Caity Montagna, Prajna Behera, Judith Jacques, Peter Grzesik, Jennifer Lee, Agnieszka Denslow, Jacqueline Gursha, Brian Haines, Michael Ball, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Michael Paglia, Laura Viggiano Salta, Lorenz Ponce, Caroline Webb, Mitchell Finer, Christophe Quéva. microRNA attenuated oHSV-1 armed with multiple immunomodulatory payloads mediates robust and selective antitumor immune response in preclinical tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B23.

Oncolytic viruses represent a new class of therapeutic agents for the treatment of cancers that poorly respond to immune checkpoint inhibitors. Oncorus is developing ONCR-177, an oncolytic herpes simplex virus engineered for enhanced oncolysis and antitumor immunity. ONCR-177 is replication competent in tumor cells, but its replication and neuropathic activities are attenuated in healthy cells using miRNA-dependent degradation of viral transcripts and by mutations in UL37 that prevent retrograde transport in neurons. Efficacy is enhanced by a gain of function in the fusogenic glycoprotein B to enhance viral entry and inactivation of US12 to restore antigen processing. ONCR-177 is armed with five immunostimulatory transgenes: IL-12, CCL4, FLT3LG, a PD-1 humanized antagonist VHH nanobody, and the CTLA4 blocking monoclonal antibody ipilimumab. The antitumor effect of ONCR-177 utilizes two distinct modalities of immune stimulation. First, ONCR-177 is specific for tumor cells where infection and replication result in direct tumor cell killing. Second, lysis of tumor cells and expression of ONCR-177 immune payloads stimulate the immune environment through multiple mechanisms: innate signaling through production of PAMP/DAMP signals, immune cell recruitment, exposure of tumor-specific antigens, and activation of the adaptive immune response. Tumor-specific immunogenicity was evaluated using mONCR-171, a mouse functional surrogate for ONCR-177, that is built on the same base vector ONCR-159 but expresses the immune transgenes suitable for murine studies. In a CT26 bilateral colon carcinoma tumor model, immune responses elicited by intratumoral injection of mONCR-171 and ONCR-159 were compared. Intratumoral T cells were evaluated for effector phenotype and function in response to a tumor-associated antigen. We observed a shift toward enhanced activation in the mONCR-171 treatment group. Treatment with mONCR-171 resulted in more tumor-associated CD8+ T cells, higher activation, and more effector cells. This group also had lower PD-1 expression, fewer Treg cells, and a favorable CD8:Treg ratio. The tumor-specific response was assessed using the CT26 tumor-associated antigen AH1, a peptide derived from envelope glycoprotein 70 (gp70) of endogenous murine leukemia virus (MuLV). Treatment with mONCR-171 elicited significantly more IFNγ and TNFα producing, intratumoral CD8+ T cells, producing significantly higher levels of IFNγ. The increase in antitumor immunogenicity with mONCR-171 treatment was further evidenced by the increase in polyfunctional CD8+ T cells, producing IFNγ, TNFα, and/or IL-2 in response to antigen stimulation. These results highlight the dual modality mechanism of action of mONCR-171 treatment though the direct tumor cell killing and immune stimulation through the antiviral response and their enhancement by the immune stimulatory transgenes. Citation Format: Melissa Hayes, Agnieska Denslow, Jacqueline Gurshaw, Daniel Wambua, Shreeya Khatiwada, Lingxin Kong, Jacob Spinale, Prajna Behera, Peter Grzesik, Jennifer Lee, Terry Farkaly, Edward Kennedy, Lorena Lerner, Christophe Quéva, Brian Haines, Sonia Feau. Dual mechanism of ONCR-177 enhances antitumor immunogenicity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B74.