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. 2025 Mar 10;43(3):537-551.e7.
doi: 10.1016/j.ccell.2025.01.013. Epub 2025 Feb 20.

EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models

Patrizia Porazzi  1 , Siena Nason  1 , Ziqi Yang  1 , Alberto Carturan  1 , Guido Ghilardi  1 , Puneeth Guruprasad  1 , Ruchi P Patel  1 , Melody Tan  2 , Anushka Anant Padmanabhan  1 , Jean Lemoine  1 , Eugenio Fardella  3 , Yunlin Zhang  1 , Raymone Pajarillo  1 , Linhui Chen  1 , Ositadimma Ugwuanyi  1 , Kelly Markowitz  4 , Devora Delman  4 , Mathew G Angelos  1 , Olga Shestova  5 , Yusuke Isshiki  6 , Tatiana Blanchard  7 , Wendy Béguelin  6 , Ari M Melnick  6 , Gerald P Linette  8 , Gregory L Beatty  9 , Beatriz M Carreno  8 , Ivan J Cohen  1 , Luca Paruzzo  1 , Stephen J Schuster  1 , Marco Ruella  10
Affiliations

EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models

Patrizia Porazzi et al. Cancer Cell. .

Abstract

Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers' methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.

Keywords: B cell lymphoma; CAR-T; EZH1; EZH2; T cell receptor; adoptive T cell therapy; chimeric antigen receptor T cells; epigenetics; multiple myeloma; solid cancers; tazemetostat; valemetostat.

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Conflict of interest statement

Declaration of interests M.R. holds multiple patents related to CAR-T immunotherapy that are managed by the University of Pennsylvania. M.R. has served as a consultant for nanoString, BMS, GSK, Bayer, GLG, Guidepoint, Lumicks, and AbClon. M.R. receives research funding from AbClon, Beckman Coulter, Lumicks, and Oxford Nano Imaging. M.R. is the scientific founder of viTToria Biotherapeutics. A.M.M. has or recently had research funding from Janssen, Epizyme, Treeline Biosciences, and Daiichi Sankyo and consulted for Treeline Biosciences and Ipsen. B.M.C. and G.P.L. are inventors on a patent (63/516,178) related to the targeting of LOXHD1 for immunotherapy. G.L.B. reports active roles as consultant/advisory board member for Seattle Genetics (now Seagen), Adicet Bio, Aduro Biotech, AstraZeneca, BiolineRx, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Cantargia, Cour Pharmaceuticals, Boehinger Ingelheim, Genmab, Hibercell, HotSpot Therapeutics, Incyte Corporation, Janssen, Merck, Molecular Partners, NanoGhost, Pancreatic Cancer Action Network, Shattuck Labs, and Verastem; reports receiving commercial research grants from Incyte Corporation, Bristol-Myers Squibb, Verastem, Halozyme, Biothera, Newlink, Novartis, Arcus Biosciences, and Janssen. G.L.B. is an inventor of intellectual property related to CAR-T cells that is managed by the University of Pennsylvania.

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