POTENTIATION OF ANTI-TUMOR IMMUNITY BY ONCOLYTIC VIRUS IN SITU VACCINATION

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PROJECT SUMMARY/ABSTRACT Oncolytic viruses (OV) are an emerging class of therapeutics capitalizing on their preferential ability to replicate in cancer cells and modify the tumor microenvironment. Using Newcastle Disease Virus (NDV) as an OV model, we were one of the first groups to identify OV ability to induce tumor-infiltrating lymphocytes and synergize with immune checkpoint blockade. Based on this rationale, we have conducted a clinical trial of intraperitoneal (IP) ONCOS-102 (oncolytic adenovirus) in combination with anti-PD-L1 antibody durvalumab in patients with advanced ovarian and colorectal cancer (NCT02963831). Despite these studies, major gaps exist in our understanding of how OVs interact with the immune system. While an increase in TILs or “making tumors hot” is commonly used as a readout of response to OV, such readouts are highly nonspecific: (1) It is largely unknown whether the increase in TILs represents primarily tumor-reactive or OV-reactive T cells; (2) It is unknown whether the OV-reactive T cells positively or negatively impact anti-tumor immunity; (3) It is unknown how the balance between the tumor-reactive or OV-reactive T cells is influenced by biologically distinct OVs. In our preliminary studies, we find that intratumoral NDV markedly expands the number of T cell clones that are shared between the different tumor sites and that dominant T cell clones in the treated and distant tumors are associated with distinct T cell phenotypes, thus possibly identifying tumor- vs. OV-reactive T cells. Using immunologic and genetic tools such as T cell receptor (TCR) sequencing and single cell RNA-sequencing and our team’s expertise in computational biology, immunology and virology, the key objectives of our study are to define the balance between the OV-reactive and tumor-reactive T cells generated in response to OV therapy and to determine the impact of OV-reactive T cells on T cell-mediated anti-tumor immunity. In Aim 1, we will identify the distinct TCR sequences and phenotypes associated with OV-reactive and tumor-reactive T cells and will quantify their balance in the treated and distant tumors. We will determine how prior anti-OV immunity and OV-specific CD4 or CD8 T cells impact the anti-tumor T cell response and therapeutic efficacy. To ensure broad applicability of our findings, we will test our hypothesis in two distinct mouse models: flank B16 melanoma and peritoneal model of ovarian carcinoma MPB1 and will employ NDV (RNA virus) and vaccinia (DNA virus) as two biologically distinct virus models. In Aim 2, we will leverage the tumor microenvironment data as well as TCR data from pre- and on-treatment tumors and blood from our clinical trial of oncolytic adenovirus ONCOS-102 in combination with durvalumab to determine how putative OV- and tumor-reactive T cells evolve in tumors and in peripheral blood and whether these parameters are predictive of clinical benefit. This study will determine how different OVs activate anti-viral and anti-tumor adaptive immune response and will enable us to understand the nature of OV-induced T cell responses beyond “hot vs. cold” within the context of mouse and human studies. These findings will be key to understand the nature of immune responses to OVs in trials and to enable future development of strategies aiming to enhance anti-tumor rather than anti-OV immunity.