Abstract B041: Preclinical antitumor activity and immune modulation of a novel non-fucosylated (NF) CTLA-4 inhibitor in a mouse model of resectable non-small cell lung cancer

Abstract Introduction: Ipilimumab (Ipi) blocks the cytotoxic T lymphocyte antigen-4 (CTLA-4) immune checkpoint expressed on T cells, thereby enhancing T cell antitumor activity. Ipi has improved outcomes in several tumor types; however, unfortunately, not all cancer patients benefit from Ipi, and many experience severe immune-related adverse events due to its peripheral effects. Therefore, more effective, less toxic CTLA-4 inhibitors are highly desirable. We previously reported the mechanism of action of a novel anti-CTLA-4 antibody, utilizing a non-fucosylated (NF) Fc region (anti-CTLA-4 NF) thought to augment T-cell priming and modulate regulatory T cells (Tregs). Here, we report the antitumor activity, efficacy, and impact on tumor immune infiltration of the anti-CTLA-4 NF agent in a mouse model of resectable non-small cell lung cancer (NSCLC), as well as the T-cell receptor repertoire changes in a superantigen mouse model. Methods: We injected 129/Sv male mice with luciferase-transfected 344SQ Kras G12D ;p53 R172HΔG mutant NSCLC (344SQ-Luc+) cells. Mice with established flank tumors were randomized to the following perioperative (neoadjuvant and adjuvant) treatment groups: Isotype (control), anti-CTLA-4 Fc-inert, anti-CTLA-4 Ipi-like (classical Ipi), and anti-CTLA-4 NF. Surgical resection of tumors was performed after the last neoadjuvant treatment. Antitumor activity was analyzed by ANOVA test. Lung cancer-specific survival was estimated by Kaplan-Meier method and compared between groups using a log-rank test. Before tumor resection, mice were imaged for bioluminescence assessment of tumors. Resected tumors were immune-profiled using flow cytometry. Surviving mice with no palpable tumors were rechallenged with 344SQ-Luc+ cells, and tumor volumes were measured for 31 days. Using a staphylococcal enterotoxin B-stimulated (SEB) human CTLA-4 knock-in (KI) model, T-cell receptor sequencing was performed in mice treated with anti-CTLA-4 NF and Ipi at pre- and post-treatment timepoints. Results: Neoadjuvant anti-CTLA-4 NF inhibited tumor growth and reduced tumor volumes compared to Ipi-like, Fc-inert and control (P<0.0001). Perioperative anti-CTLA-4 NF also prolonged survival compared to Ipi-like, Fc-inert, and control (P<0.05). Resected tumors from mice treated with neoadjuvant anti-CTLA-4 NF were characterized by numerically increased CD4+ effector memory T cells and decreased Tregs and naïve CD4+ T cells. Surviving mice that were rechallenged with 344SQ-Luc+ cells had impaired tumor growth compared to treatment-naïve mice (P<0.0001). In the SEB CTLA-4 KI model, anti-CTLA-4 NF treatment resulted in an enhanced T-cell repertoire compared to Ipi. Conclusions: Our results suggest that the non-fucosylated Fc of CTLA-4 can enhance antitumor activity, prolong survival, enrich the T-cell repertoire, and potentially impart immunological memory compared to Ipi. Citation Format: Michael Wang, Amy Jhatakia, Xin Sun, Cheuk H Leung, John T Le, Neha Gupta, Jack Lohre, Lili Chen, Heather Y Lin, Wei Hu, Nicholas Wilson, Tina Cascone. Preclinical antitumor activity and immune modulation of a novel non-fucosylated (NF) CTLA-4 inhibitor in a mouse model of resectable non-small cell lung cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B041.