Abstract 6361: A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody

Abstract Immune checkpoint inhibitors, including monoclonal antibodies targeting the PD-1/PD-L1 axis, induce robust antitumor immunity in a subset of patients with various cancers. Despite continued success of these therapies, some patients experience limited efficacy owing to clinically complex and unresolved mechanisms of primary and acquired immunotherapy resistance. To begin to understand the mechanisms of acquired resistance to anti-PD-1 blockade, we developed a syngeneic murine CT26 colorectal tumor model that is resistant to anti-PD-1 therapy. To achieve this, CT26 tumors were subjected to successive rounds of increasing levels of anti-PD-1 therapy. When tumors grew out, they were cultured in vitro and then re-implanted and re-treated for three rounds until PD-1 resistance was achieved. To characterize the underlying drivers of acquired resistance across the generation of the model, wild type and anti-PD-1 resistant tumors and cultured cell lines were evaluated by flow cytometric immunophenotyping and RNA-sequencing analysis. To assess how observed changes in the tumor microenvironment impact response to various therapeutics, the resistant tumors were treated with anti-PD-1 therapy or SEA-TGT, a nonfucosylated anti-TIGIT mAb with enhanced Fc-function that drives activity through multiple modes of action. As expected, treatment with anti-PD-1 monotherapy was ineffective, however, treatment with SEA-TGT demonstrated potent anti-tumor activity. These data are consistent with responsiveness to anti-TIGIT agents in other in vivo models of PD-1 resistance and/or PD-1 refractory response, indicating that the factors driving resistance to anti-PD-1 therapy can be different than those driving response to other known checkpoint molecules such as TIGIT. Thus, investigational agents such as SEA-TGT may have the potential to be efficacious in tumors that are primary or secondarily resistant to anti-PD-1 therapy. We have initiated a phase 1 study (NCT04254107) evaluating the safety, tolerability, and activity of SEA-TGT monotherapy and in combination with anti-PD-1 therapy in patients with advanced malignancies. Citation Format: David R. Gruber, Weiping Zeng, Bob Thurman, Brian P. O'Connor, Shyra J. Gardai, Alyson J. Smith. A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6361.