Anti-CEA chimeric antigen receptor T cells in combination with suppressor cell targeting for the treatment of colorectal cancer peritoneal metastases (VAC7P.1043)

Abstract Colorectal peritoneal metastases (PM) is a grave condition in which tumor cells disseminate throughout the abdomen. Chimeric antigen receptor T cell (CAR-T) immunotherapy is a promising therapy for PM. We developed a novel regional delivery approach to maximize CAR-T efficacy against PM while limiting systemic toxicity. Murine tumor cells expressing CEA and luciferase were injected intraperitoneally (IP) in mice to induce PM (day 0). We injected murine anti-CEA CAR-T IP on days 3 and 6, alone or in combination with antibodies against Ly6G/Ly6C, PDL1 or GITR to target myeloid suppressor cells (MSC) or regulatory T cells (Treg), which we have shown to be present in PM. Tumor burden was measured by bioluminescence. In comparison to unmodified T cells, CAR-T alone mediated a 22-fold reduction of tumor burden (p=0.028). The combination of CAR-T with anti-PDL1, anti-GITR or anti-Ly6G/Ly6C treated groups showed 25-fold, 104-fold and 153-fold reductions, respectively. The CAR-T + anti-GITR and CAR-T + anti-Ly6G/Ly6C groups had a significantly better treatment response than CAR-T alone (p=0.005 and p=0.017). On days 8 and 10, CAR-T + anti-Ly6G/Ly6C tumor burdens dropped below detectable levels. Upon gross inspection, CAR-T treated mice did not have detectable tumor. Our findings demonstrate that targeting MSC and Treg in addition to regional IP CAR-T delivery represents a viable immunotherapeutic strategy that resulted in complete responses in mice with established PM.