Inhibiting IL-23 Signaling Overcomes Immunotherapy Resistance in Colorectal Cancer Pre-Clinical Models

INTRODUCTION: Immunotherapy offers hope for patients with cancer who fail conventional chemotherapy. However, it remains ineffective in colorectal cancer (CRC). Strategies to overcome this limitation are not well studied in CRC. METHODS: Colorectal cancer cells (MC-38) were implanted subcutaneously into C57/B6 mice and divided into the following groups (i) isotype control (ii) immunotherapy (anti PD-L1) (iii) anti-IL-23 antibody and (iv) combination of anti-PDL1 and anti-Il-23 antibodies. Survival was measured after start of treatment (14 days) as measure of therapeutic efficacy using Kaplan-Meier Survival curve. At endpoint, tumor infiltrating immune cells were analyzed by flowcytometry. RESULTS: Mice that were treated with combination of anti-Il-23 and anti-PDL1 antibody (median survival: 38 days) showed greater median survival compared with mice that were treated with either agent alone (median survival: 21-24 days), suggesting IL-23 inhibition overcomes immunotherapy resistance. Treatment with just immunotherapy or just anti-IL23 had no significant prolongation in survival compared with isotype control (Figure). No gross toxicities were identified on combination treatment. Flowcytometric analyses of immune infiltrate to study the change in immune tumor microenvironment will be presented. CONCLUSION: Inhibition of IL-23 concurrently with immune checkpoint inhibitor holds promise in reversing resistance of immunotherapy in CRC and may hold promise in treatment of patients with advanced CRC.Figure