Abstract 6708: MAIT engagers: Bispecific antibody-mediated redirection of mucosal associated invariant T cells to treat solid tumors

Abstract

Abstract Background. Using bispecific antibodies (BiXAb) to redirect T cells to engage and kill cancer cells is an efficacious modality in the treatment of haematological cancers but has had limited success in the treatment of solid tumors. Mucosal-Associated Invariant T cells (MAITs) are an abundant subset of non-conventional T-cells with potent cytotoxic capacity (up to 20% of circulating T-cells) that are naturally resident in many tissues and solid tumors. MAIT cells utilize a semi-invariant TCR and recognize bacterial metabolites presented in the context of the MR1 protein. Biomunex has generated bispecific antibodies that bind the MAIT semi-invariant TCR (iTCR) and the HER2 receptor tyrosine kinase expressed on tumor cells. At difference to classical T-cell engagers that activate all T-cell subsets, MAIT engagers only modulate the activity of the cytotoxic MAIT cells leading to efficient tumor control and greater safety profile. Methods. Using the Biomunex proprietary BiXAb platform, bispecific, tetravalent antibodies were generated that target the MAIT iTCR and the HER2. MAIT-cell activation, proliferation and degranulation were followed by gating on MAIT cells within a purified CD8 cell population. Tumor cell lines (varying in [HER2] expression) 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. Cytotoxicity of tumor-resident MAITs, from fresh patient samples, was determined by impedence measurements and in patient-derived 3D organoids by The Hub organoids (imaging). For in vivo analysis, sub-cutaneous tumor growth was measured with callipers. 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 TCE (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. Ex vivo cytotoxicity of tumor-resident MAIT cells using dissociated ovarian cancer samples at “real E:T ratios”, MAIT engager-mediated cytotoxicity of patient-derived organoids (CRC) and in vivo evaluation of tumor control will be shown. Conclusions. MAIT cell redirection is a promising approach for the treatment of solid tumors that has 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 Rousseau, Gaetano Sodaro, Lise Fenou, Maxime Audin, Alexandre Ivagnes, Han-Heinrich Oberg, Pierre Emmanuel Gerard, Isabelle Navarro-Teulon, Daniela Wesch, Matthias Peipp, Julie Prigent. MAIT engagers: Bispecific antibody-mediated redirection of mucosal associated invariant T cells to treat solid tumors [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 6708.