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. 2025 Jan 13;43(1):49-68.e9.
doi: 10.1016/j.ccell.2024.11.006. Epub 2024 Dec 5.

EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function

Yusuke Isshiki  1 , Xi Chen  1 , Matt Teater  2 , Ioannis Karagiannidis  1 , Henna Nam  1 , Winson Cai  3 , Cem Meydan  4 , Min Xia  1 , Hao Shen  1 , Johana Gutierrez  1 , Vigneshwari Easwar Kumar  1 , Sebastián E Carrasco  5 , Madhu M Ouseph  6 , Samuel Yamshon  1 , Peter Martin  1 , Ofir Griess  7 , Efrat Shema  7 , Patrizia Porazzi  8 , Marco Ruella  8 , Renier J Brentjens  9 , Giorgio Inghirami  6 , Roberta Zappasodi  1 , Amy Chadburn  6 , Ari M Melnick  1 , Wendy Béguelin  10
Affiliations

EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function

Yusuke Isshiki et al. Cancer Cell. .

Abstract

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.

Keywords: CAR-T; DLBCL; EZH2; T cell immunotherapy; bispecific antibodies; follicular lymphoma.

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Conflict of interest statement

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.

References

    1. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, et al. (2017). Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med 377, 2545–2554. 10.1056/NEJMoa1708566. - DOI - PMC - PubMed
    1. Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, et al. (2022). Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med 386, 640–654. 10.1056/NEJMoa2116133. - DOI - PubMed
    1. Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, et al. (2022). Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med 386, 629–639. 10.1056/NEJMoa2116596. - DOI - PubMed
    1. Abramson JS, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, et al. (2023). Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood 141, 1675–1684. 10.1182/blood.2022018730. - DOI - PMC - PubMed
    1. Jacobson CA, Chavez JC, Sehgal AR, William BM, Munoz J, Salles G, Munshi PN, Casulo C, Maloney DG, de Vos S, et al. (2022). Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol 23, 91–103. 10.1016/S1470-2045(21)00591-X. - DOI - PubMed

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