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

in Cancer cell by 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

TLDR

  • EZH2 inhibitors can enhance CAR-T cell efficacy by directly affecting CAR-T cells and rendering lymphoma B cells immunogenic, improving immunotherapy outcomes in B cell lymphoma patients.
  • The study suggests that EZH2 inhibition is a safe and effective approach for improving immunotherapy outcomes in B cell lymphoma patients.
  • The findings of this study are currently being evaluated in two clinical trials to improve immunotherapy outcomes in B cell lymphoma patients.

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.

Overview

  • The study aimed to develop syngeneic models of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) to understand response and resistance to T cell-based immunotherapies.
  • The study used EZH2 inhibitors to reprogram these models to re-express T cell engagement genes and render them highly immunogenic.
  • The primary objective of the study was to improve immunotherapy outcomes in B cell lymphoma patients by enhancing the efficacy of CAR-T cells.

Comparative Analysis & Findings

  • EZH2 inhibitors reduced regulatory T cells, promoted memory CAR CD8 phenotypes, and reduced exhaustion in CAR-T cells.
  • Intravital 2-photon imaging showed increased CAR-T recruitment and interaction within the tumor microenvironment, resulting in improved lymphoma cell killing.
  • EZHi inhibition did not harm tumor-controlling T cells or CAR-T cells, suggesting a safe and effective approach.

Implications and Future Directions

  • The study suggests that EZH2 inhibition can enhance CAR-T cell efficacy by directly affecting CAR-T cells and rendering lymphoma B cells immunogenic.
  • The findings of this study are currently being evaluated in two clinical trials (NCT05934838 and NCT05994235) to improve immunotherapy outcomes in B cell lymphoma patients.
  • Future research directions may include exploring the combination of EZH2 inhibition with other immunotherapies to further improve treatment outcomes.
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