Abstract 593: Anti-tumor immunity and efficacy of combination treatment of M6223 and bintrafusp alfa versus the combination of M6223 and anti-PD-L1 in preclinical tumor models
Authors: Xu Chunxiao , Yalavarthi Sireesha , Bourin Clotilde , Kelton Christie , Halle Joern-Peter , Moisan Jacques 
Published: June 2022

Abstract
Background: T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor expressed on lymphocytes and has recently emerged as a target in cancer immunotherapy. M6223 is a fully human antagonistic anti-TIGIT antibody in immunoglobulin (Ig) G1 format with Fc-mediated effector function. Preclinical studies demonstrated that M6223 could induce an anti-tumor immune response by complementary mechanisms including but not limited to direct blockade of the TIGIT pathway, stimulation of CD226 dimerization/activation, and depletion of TIGIT+ immune subsets by Fc-mediated effector function. M6223 showed dose-dependent anti-tumor efficacy in multiple preclinical tumor models. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β "trap") fused via a flexible linker to the C-terminus of each heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti-PD-L1), was designed to target two key immunosuppressive pathways in the tumor microenvironment.
Methods: To attenuate the tumor immunosuppressive microenvironment, the anti-tumor immunity and efficacy of combining M6223 with bintrafusp alfa was investigated in syngeneic models in humanized mice with huTIGIT knock-in sequences.
Results: M6223 combined with bintrafusp alfa significantly enhanced anti-tumor efficacy and extended survival compared with either monotherapies or the combination of M6223 with anti-PD-L1. M6223 combined with bintrafusp alfa stimulated higher CD8+ T cells and natural killer cells infiltration, proliferation and cytotoxicity in tumor microenvironment in comparison to the combination of M6223 with anti-PD-L1. The ratio of CD8+ T cells to regulatory T cells and the ratio of CD226 to TIGIT were significantly increased, indicating the conversion of the tumor microenvironment from an immuno-suppressive phenotype to a more immune-permissive phenotype. With the combination therapy, bintrafusp alfa was the main driver promoting CD8+ T cell proliferation, infiltration, and cytotoxicity. Alternatively, adding M6223 to bintrafusp alfa may decrease the risk of immune resistance caused by elevated TIGIT expression triggered by bintrafusp alfa treatment.
Conclusion: These complementary mechanisms of M6223 and bintrafusp alfa orchestrate antitumor activity in preclinical tumor models. Currently, M6223 and bintrafusp alfa combination is being investigated in a Phase I clinical trial (NCT04457778) in patients with metastatic or locally advanced solid unresectable tumors.
Citation Format: Chunxiao Xu, Sireesha Yalavarthi, Clotilde Bourin, Christie Kelton, Joern-Peter Halle, Jacques Moisan. Anti-tumor immunity and efficacy of combination treatment of M6223 and bintrafusp alfa versus the combination of M6223 and anti-PD-L1 in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 593.