Treatment with M51R Vesicular Stomatitis Virus Induces Clonal Antitumor CD8+ T Cell Expansion in Colon Cancer

Abstract Developing new and effective treatments for patients with metastatic colorectal cancer is crucial, as this condition is the fourth leading cause of cancer-related deaths. The potential of the M51R vesicular stomatitis virus (M51R VSV) as an oncolytic virus for various malignancies, including colorectal cancer, is being explored by our group and others. However, the immune response to this treatment is poorly understood. To address this knowledge gap, we conducted a study using a syngeneic murine model of colorectal cancer by administering M51R VSV at two doses and analyzing the resulting immune response. We found that both doses of M51R VSV induced a robust immune response, with overexpression of genes associated with NK cell function, antigen processing and presentation, and CD8 + T cell phenotype and function. CyTOF analysis showed an increased CD8 + T cell frequency and decreased G-MDSCs and FoxP3 + CD25 - Treg cells. TCR sequence analysis revealed clonal expansion of a-CT26 CD8 + T cells targeted against tumor-associated antigens, making combination therapy with CAR T cells a promising approach. Our work also suggests that combination therapy with M51R VSV and immune checkpoint inhibitors may be beneficial. These findings provide a strong foundation for advancing M51R VSV-based therapies for metastatic colorectal cancer in a population of patients with limited immunotherapeutic options.