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1134 Dynamic analyses of tumor microenvironment modulation by CAN-2409 treatment using kaede photoconvertible transgenic mice

Background CAN-2409 is a replication-defective adenovirus that delivers the HSV-thymidine kinase gene. Intratumoral administration of CAN-2409 followed by prodrug results in the formation of a toxic metabolite able to induce immuno-genic cell death, exposure of tumor-associated antigens, and activation of local and systemic immune responses. Use of state-of-the-art preclinical tools for dynamic assessment of the lymphocyte response in vivo will enable assessment of the evolution of the anti-tumor immune response induced by CAN-2409 and provide the immunological rationale for potential therapeutic combinatory approaches. Methods We utilized a dynamic labeling model 1 where MC38 tumor cells were implanted subcutaneously into photoconvertible Kaede mice; violet light was used to simultaneously label the entire tumor microenvironment (TME), enabling the dis-crimination of cells retained within the tumor (Kaede Red+) versus newly entering cells (Kaede Green+) and the ability to assess real-time changes occurring in the immune compartment of the TME. CAN-2409 was administered intratumorally on day 10 after tumor inoculation followed by prodrug (ganciclo-vir, 50mg/kg IP QD on days 11 to 14). Photoconversion occurred on day 12, and analysis was performed 48h later. Dynamic of MC38-tumor specific T cell clones was evaluated by flow cytometry. We also explored the effect of CAN-2409 in combination with immune checkpoint inhibition (ICI). Results Administration of CAN-2409 led to control of tumor growth and a significantly increased effector CD8 T cell response. Photolabeling of the TME revealed that rather than enhancing recruitment of T cells to the tumor, CAN-2409