Abstract 4572: mONCR-177 oncolytic virotherapy stimulates anti-tumor and anti-viral immunogenicity
Authors: Hayes Melissa , Denslow Agnieszka , Hewett Jacqueline , Wambua Daniel , Kong Lingxin , Spinale Jacob , Grzesik Peter , Lee Jennifer , Farkaly Terry , Kennedy Edward M. , Lerner Lorena , Queva Christophe , Haines Brian , Feau Sonia 
Published: September 2020

Abstract
Oncolytic viruses represent a promising 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 potent oncolysis and stimulation of antitumor immunity. ONCR-177 is replication competent in tumor cells, but its replication and neuropathic activities are attenuated in healthy cells using microRNA-dependent degradation of viral transcripts and by mutations in UL37 that prevent retrograde transport in neurons. In addition, ONCR-177 encodes five immune-stimulatory transgenes: IL-12, CCL4, FLT3LG, a PD-1 humanized antagonist VHH nanobody, and a CTLA4 blocking monoclonal antibody. Transgenes were chosen to efficiently recruit effector T (CD8 and CD4 Th1), NK, and classical dendritic cells to the tumor, and to counter upregulation of immune checkpoints. The individual and collective mechanisms of action of the transgenes are designed to augment local and distant innate and adaptive anti-tumor immune responses.
Tumor-specific response was evaluated using mONCR-177, 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 and a MC38 colon adenocarcinoma model, immune responses elicited by intratumoral injection of mONCR-177 and ONCR-159 were compared. Intratumoral T cell responses were evaluated for a tumor-associated antigen (TAA) and an HSV specific antigen in the MC38 model.
In the CT26 tumor model, treatment with mONCR-177 resulted in greater immune infiltration with a higher activation status and an improved CD8:Treg ratio. Treatment with mONCR-177 elicited significantly more tumor antigen specific IFNγ and TNFα producing, intratumoral CD8T cells. The increase in anti-tumor response with mONCR-177 treatment was further evidenced by the increase in polyfunctional CD8 T cells producing IFNγ, TNFα, and/or IL-2 in response to TAA stimulation.
In the MC38 tumor model, treatment with mONCR-177 resulted in greater immune infiltration in both the injected and non-injected tumor. The CD8:Treg ratio was improved and PD-1 expression was decreased. Tumor antigen specific cytokine production was higher with mONCR-177 treatment. Additionally, a significant increase in HSV-specific polyfunctional CD8+ T cells was observed.
mONCR-177 effectively stimulates an intratumoral immune response to both tumor and viral antigens. Treatment results in increased infiltrating immune cells, activation, and polyfunctional CD8+ T cells. These results highlight the dual modality mechanism of action of mONCR-177 treatment through direct tumor cell killing and immune stimulation through the antiviral response, and their enhancement by the immune stimulatory transgenes.
Citation Format: Melissa Hayes, Agnieszka Denslow, Jacqueline Hewett, Daniel Wambua, Lingxin Kong, Jacob Spinale, Peter Grzesik, Jennifer Lee, Terry Farkaly, Edward M. Kennedy, Lorena Lerner, Christophe Queva, Brian Haines, Sonia Feau. mONCR-177 oncolytic virotherapy stimulates anti-tumor and anti-viral immunogenicity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4572.