Abstract 2121: MAIT engagers: Providing a large therapeutic window for the treatment of solid tumors

Abstract Background: MAIT cells are an abundant subset of non-conventional T-cells with potent cytotoxic capacity that are resident in most tissues and solid tumors. MAIT cell engagers are bispecific antibodies that are able to simultaneously bind the MAIT cell TCR and a tumor associated antigen, creating an immunological synapse, resulting in efficient elimination of cancer cells. These MAIT engagers only bind and activate MAIT cells and, at difference to classical CD3 engagers, do not cause cytokine release or activate regulatory T cells offering the promise of better safety and efficacy than CD3 engagers. Methods: Using the Biomunex proprietary BiXAb platform, bispecific, tetravalent antibodies were generated that target the MAIT iTCR (invariant T cell receptor) and the HER2 tumor associated antigen. MAIT-cell activation, proliferation and degranulation were followed by gating on MAIT cells within a purified CD8 cell population. Tumor cell lines (varying [HER2]) were co-cultured with MAIT cells and the BiXAbs in several cytotoxic assays (evaluated by Chromium release). Cytokine release was assessed by Legend Plex assays or ELISA. Regulatory T cells were enriched from PBMCs. Cytotoxicity of tumor-resident MAITs, from fresh patient samples, was determined by impedance measurements and in patient derived 3D organoids by imaging (The Hub organoids). Cytokine levels in serum of Cynomolgus monkeys was measured by Legend plex. Results: MAIT engagers induce the rapid activation, proliferation and degranulation of MAIT cells leading to efficient killing of engaged HER2+ cancer cells with a potency similar to that of a classical HER2-directed CD3-T cell engager (in clinical development). The MAIT engager did not activate the regulatory T cells or other CD4/CD8 subsets. In addition, using PBMCs, total cytokine release was 1000 fold less with the MAIT engager compared to a classical TCE, opening up a large therapeutic window, which should permit effective treatment of solid tumors. Strong signs of cytokine release syndrome and high blood cytokine levels were observed in cynomolgus monkeys treated with a CD3 engager whilst no effect was observed with the MAIT engager. Ex vivo cytotoxicity of tumor-resident MAIT cells using dissociated Ovarian cancer samples at “real E:T ratios” and MAIT engager-mediated cytotoxicity of patient derived organoids (CRC) demonstrate the antitumor capability of MAIT engagers in solid tumors. Conclusions: MAIT cell engagers are a promising approach for the treatment of solid tumors that have the potency and efficacy of a classical TCE but with a significantly improved cytokine safety profile leading to a larger therapeutic window. Citation Format: Simon Edward Plyte, Marie Fraudeau, Dorothee Winterberg, Claire Germain, Camille Rouseau, Gaetano Sodaro, Maxime Audin, Alexandre Ivagnes, Hans-Heiner Oberg, Pierre-Emmanuel Gerard, Matthias Peipp, Daniela Wesch, Julie Prigent. MAIT engagers: Providing a large therapeutic window for the treatment of solid tumors [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 2121.