Abstract 4026: The combination of DLL4/VEGF-a blockade and immunomodulation can eliminate MHC class I negative tumors in mice

Abstract

Abstract CTX-009 is a bispecific antibody targeting VEGF-A and DLL4 which is undergoing clinical investigation in patients with multiple tumor types, including biliary tract and colon cancers. In biliary tract cancers, checkpoint inhibitor therapy has been shown to improve outcomes when combined with chemotherapy. In an effort to increase the breadth and duration of response of CTX-009, we set out to investigate the combined anti-tumor efficacy of this bispecific antibody and immunotherapy in preclinical models. Here we report the evaluation of the combination of the mouse surrogates of CTX-009 and CTX-471, an agonistic anti-mouse CD137 antibody, or monoclonal antibodies that disrupt the PD-1/PD-L1 signaling axis. Coupling VEGF-A/DLL4 targeting with either CD137 agonism or PD-1/PD-L1 blockade markedly increased the anti-tumor efficacy of the individual treatments alone in multiple syngeneic mouse tumor models. Tumor growth inhibition was accompanied by pharmacodynamic evidence consistent with enhancement of anti-tumor immunity. Notably, the combination of CTX-009 and CTX-471 retained potent anti-tumor activity even in a tumor line (MC38) which was made MHC I deficient through the deletion of the beta 2 microglobulin gene. This system may model the clinically relevant unmet need characterized by tumor escape through the loss of antigen presentation machinery such as HLA LOH. Interestingly, the model cell lines CT26 and MC38 failed to thrive in the B2M-deficient setting and depletion of NK cells markedly increased their ability to grow. This implies that NK cells might be involved in controlling tumor growth in this setting, and that the combined action of CTX-471 and CTX-009 in the tumor stroma enhances NK cell activity. The findings presented here suggest that CTX-009 may provide enhanced clinical benefit when combined with immunomodulatory agents, such as agonistic anti-CD137 antibodies or PD-1/PD-L1 blockers in tumors where immune checkpoint inhibitors have failed. Citation Format: Diana I. Albu, Rachael Duffy, Amy Daniel Ulumben, Jason Kong, Jessica Zolotarevsky, Melissa Brundin, Mei Su, Ruturaj Jadhav, Kris F. Sachsenmeier, Bing Gong, Thomas J. Schuetz, Alberto Visintin. The combination of DLL4/VEGF-a blockade and immunomodulation can eliminate MHC class I negative tumors in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4026.