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

Yusuke Isshiki; Xi Chen; Matt Teater; Ioannis Karagiannidis; Henna Nam; Winson Cai; Cem Meydan; Min Xia; Hao Shen; Johana Gutierrez; Vigneshwari Easwar Kumar; Sebastián E. Carrasco; Madhu M. Ouseph; Samuel Yamshon; Peter Martin; Ofir Griess; Efrat Shema; Patrizia Porazzi; Marco Ruella; Renier J. Brentjens; Giorgio Inghirami; Roberta Zappasodi; Amy Chadburn; Ari M. Melnick; Wendy Béguelin

doi:10.1016/j.ccell.2024.11.006

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

Yusuke Isshiki, Xi Chen, Matt Teater, Ioannis Karagiannidis, Henna Nam, Winson Cai, Cem Meydan, Min Xia, Hao Shen, Johana Gutierrez, Vigneshwari Easwar Kumar, Sebastián E. Carrasco, Madhu M. Ouseph, Samuel Yamshon, Peter Martin, Ofir Griess, Efrat Shema, Patrizia Porazzi, Marco Ruella, Renier J. BrentjensGiorgio Inghirami, Roberta Zappasodi, Amy Chadburn, Ari M. Melnick, Wendy Béguelin

Department of Immunology and Regenerative Biology

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	49-68.e9
Number of pages	30
Journal	Cancer Cell
Volume	43
Issue number	1
Early online date	5 Dec 2024
DOIs	https://doi.org/10.1016/j.ccell.2024.11.006
State	Published - 13 Jan 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CAR-T
DLBCL
EZH2
T cell immunotherapy
bispecific antibodies
follicular lymphoma

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2024.11.006

Cite this

Isshiki, Y., Chen, X., Teater, M., Karagiannidis, I., Nam, H., Cai, W., Meydan, C., Xia, M., Shen, H., Gutierrez, J., Easwar Kumar, V., Carrasco, S. E., Ouseph, M. M., Yamshon, S., Martin, P., Griess, O., Shema, E., Porazzi, P., Ruella, M., ... Béguelin, W. (2025). EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function. Cancer Cell, 43(1), 49-68.e9. https://doi.org/10.1016/j.ccell.2024.11.006

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title = "EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function",

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.",

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author = "Yusuke Isshiki and Xi Chen and Matt Teater and Ioannis Karagiannidis and Henna Nam and Winson Cai and Cem Meydan and Min Xia and Hao Shen and Johana Gutierrez and \{Easwar Kumar\}, Vigneshwari and Carrasco, \{Sebasti{\'a}n E.\} and Ouseph, \{Madhu M.\} and Samuel Yamshon and Peter Martin and Ofir Griess and Efrat Shema and Patrizia Porazzi and Marco Ruella and Brentjens, \{Renier J.\} and Giorgio Inghirami and Roberta Zappasodi and Amy Chadburn and Melnick, \{Ari M.\} and Wendy B{\'e}guelin",

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doi = "10.1016/j.ccell.2024.11.006",

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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 & Béguelin, W 2025, 'EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function', Cancer Cell, vol. 43, no. 1, pp. 49-68.e9. https://doi.org/10.1016/j.ccell.2024.11.006

TY - JOUR

T1 - EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function

AU - Isshiki, Yusuke

AU - Chen, Xi

AU - Teater, Matt

AU - Karagiannidis, Ioannis

AU - Nam, Henna

AU - Cai, Winson

AU - Meydan, Cem

AU - Xia, Min

AU - Shen, Hao

AU - Gutierrez, Johana

AU - Easwar Kumar, Vigneshwari

AU - Carrasco, Sebastián E.

AU - Ouseph, Madhu M.

AU - Yamshon, Samuel

AU - Martin, Peter

AU - Griess, Ofir

AU - Shema, Efrat

AU - Porazzi, Patrizia

AU - Ruella, Marco

AU - Brentjens, Renier J.

AU - Inghirami, Giorgio

AU - Zappasodi, Roberta

AU - Chadburn, Amy

AU - Melnick, Ari M.

AU - Béguelin, Wendy

PY - 2025/1/13

Y1 - 2025/1/13

N2 - 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.

AB - 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.

KW - CAR-T

KW - DLBCL

KW - EZH2

KW - T cell immunotherapy

KW - bispecific antibodies

KW - follicular lymphoma

UR - http://www.scopus.com/inward/record.url?scp=85213495863&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2024.11.006

DO - 10.1016/j.ccell.2024.11.006

M3 - مقالة

C2 - 39642889

SN - 1535-6108

VL - 43

SP - 49-68.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

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

Abstract

UN SDGs

Keywords

All Science Journal Classification (ASJC) codes

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