Isshiki Y, Chen X, Teater M, Karagiannidis I, Nam H, Cai W, Meydan C, Xia M, Shen H, Gutierrez J, Easwar Kumar V, Carrasco SE, Ouseph MM, Yamshon S, Martin P, Griess O, Shema E, Porazzi P, Ruella M, Brentjens RJ, Inghirami G, Zappasodi R, Chadburn A, Melnick AM, and Béguelin W
T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients., Competing Interests: Declaration of interests W.B. consulted for Eisai. A.M.M. has or recently had research funding from Janssen, Epizyme, Treeline Biosciences, and Daiichi Sankyo and consulted for Treeline Biosciences and Ipsen. R.Z. is a member of the scientific advisory board for iTEOS Therapeutics; is a consultant for Daiichi Sankyo and IFLI; has research grants form BMS and Astrazeneca; and is inventor on patent applications related to work on GITR, PD-1, and CTLA-4 (US20180244793A1, US10323091B2, WO2018106864A1, and WO2019094352A1). C.M. consulted for Thorne HealthTech. P.M. consulted for Abbvie, AstraZeneca, Beigene, Daiichi Sankyo, Epizyme, Genentech, Janssen, Merck, and Pepromene. A.C. is a member of the scientific advisory board for Leica Biosystems and consulted for Boehringer Ingelheim Pharmaceuticals, Inc. M.R. holds patents related to CD19 CAR-T cells; served as a consultant for NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scaylite, Bayer, Lumicks, viTToria bio, GLG, Guidepoint, and AbClon; receives research funding from AbClon, Oxford NanoImaging, viTToria Biotherapeutics, CURIOX, and Beckman Coulter; and is the scientific founder of viTToria Biotherapeutics. R.J.B. has licensed intellectual property to and collects royalties from BMS, Caribou, and Sanofi; received research funding from BMS; is a consultant to BMS, Atara Biotherapeutics Inc., and Triumvira; and was a consultant for Cargo Tx, CoImmune, and Gracell Biotechnologies Inc.; is a member of the scientific advisory board for Triumvira; and was a member of the scientific advisory board for Cargo Tx and CoImmune., (Copyright © 2024 Elsevier Inc. All rights reserved.)