Abstract 7297: Enhanced efficacy of CTX-471, a CD137 agonist antibody, in models of immune checkpoint failure via simultaneous blockade of neo-angiogenesis

Abstract CTX-471 is a monoclonal agonistic anti-CD137 antibody currently under investigation in solid tumors. To increase the breadth and duration of response of CTX-471 we set out to investigate its anti-tumor efficacy in combination with anti-angiogenesis agents in murine models. CTX-009 is a bispecific antibody targeting VEGF-A and DLL4 which is undergoing clinical investigation in multiple cancer types, including biliary tract and colorectal cancers. Encouraged by early findings showing activity of the combination in a B2m negative mouse tumor model, engineered to mimic HLA loss in patients, we broadened the exploration of the combinatorial treatment in an additional B2m knockout model using a different murine genetic background (CT26B2m-/-, Balb/c). Furthermore, we developed two novel mouse models of immunotherapy resistance without the enhanced NK cell susceptibility bias conferred by complete MHC-I loss due to B2m deletion. CT26 cells with an engineered deletion of the B2m gene were passaged in CT26 tumor-experienced mice and a line of CT26B2m-/- cells that escaped immune rejection was established (CT26 B2m knockout escapers, CT26B2m-/-E). For the second model, the H-2k1 MHC-I locus was knocked out in the MC38 cells, resulting in targeted homozygous loss. Using this approach, the expression of the other MHC-I alleles, and therefore natural resistance to NK cells, are expected to be left intact. Results: Coupling VEGF-A/Dll4 targeting with CD137 agonism markedly increased the anti-tumor efficacy of the individual treatments alone in the MC38B2m-/-, MC38H-2k1-/-, CT26B2m-/- models as well as in the highly IO resistant CT26B2m-/-E model. Tumor growth inhibition was accompanied by pharmacodynamic evidence consistent with decrease of vascular bed density and enhancement of cellular cytotoxic immunity. CTX-471 monotherapy was still efficacious, albeit blunted, in these IO resistant models. The latter preclinical results mirrored data from a Ph1 clinical trial of CTX-471, where evidence of NK activation following CTX-471 treatment was seen in both blood and tissue samples of patients with known defects in the antigen presentation machinery. The findings presented here suggest that an agonistic anti-CD137 antibody may provide enhanced clinical benefit when employed alongside an anti-angiogenesis agent, such as CTX-009, in tumors where immune checkpoint inhibitors had previously failed. Citation Format: Amy Daniel Ulumben, Diana I. Albu, Rachael Duffy, Tristan Lubinski, Jason Kong, Jessica Zolotaresvsky, Melissa Brundin, Mei Su, Ruturaj Jadhav, Bing Gong, Thomas Schuetz, Kris Sachsenmeier, Alberto Visintin. Enhanced efficacy of CTX-471, a CD137 agonist antibody, in models of immune checkpoint failure via simultaneous blockade of neo-angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7297.