Abstract B74: Dual mechanism of ONCR-177 enhances antitumor immunogenicity
Authors: Hayes Melissa , Denslow Agnieska , Gurshaw Jacqueline , Wambua Daniel , Khatiwada Shreeya , Kong Lingxin , Spinale Jacob , Behera Prajna , Grzesik Peter , Lee Jennifer , Farkaly Terry , Kennedy Edward , Lerner Lorena , Quéva Christophe , Haines Brian , Feau Sonia 
Published: March 2020

Abstract
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.