Targeting PRC2 Enhances the Cytotoxic Capacity of Anti-CD19 CAR T Cells against Hematologic Malignancies

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Rodrigues Carvalho, Maria Leticia ; de Oliveira Andrade, Clara ; Cabral-Piccin, Mariela Pires ; Kinker, Gabriela Sarti ; Vitiello, Glauco Akelinghton Freire ; Goncalves Cambui, Raylane Adrielle ; de Macedo Abdo, Luiza ; Mannarino Correia, Eduardo ; da Silva Elias, Bruno Dalbelo ; Araujo, Emmanuel Vinicius Oliveira ; Chaves, Alexandre Silva ; Pereira, Pedro Henrique Barbosa ; Hajdu, Karina Lobo ; Rondinelli, Amanda ; Fagotti Gusmao, Arianne ; Marques Pierre, Maria Luisa ; Brasil-Costa, Igor ; Pouza Zanella, Caroline ; Moreira Lemos, Marta Maria ; Batista, Marjorie Vieira ; Filho, Jayr Schmidt ; Arrowsmith, Cheryl ; Cordeiro de Lima, Vladmir Claudio ; Bonamino, Martin Hernan ; da Silva Medina, Tiago

• Document type: Journal article
• Source: Cancer Research; v. 85, n. 12, p. 16-pg., 2025-06-16.

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is increasingly being adopted as a clinical modality for patients with relapsed/refractory hematologic malignancies. Despite the clinical efficacy of CAR T-cell therapy, a considerable fraction of patients still relapse during the first months following CAR T-cell infusion. The limited CAR T-cell efficiency is thought to relate to epigenetic mechanisms involved in T-cell suppression and dysfunction. In this study, screening of multiple epigenetic inhibitors revealed that targeting polycomb repressive complex 2 (PRC2) consistently induced the development of granzyme B+ effector memory CD8 T cells. Notably, PRC2 inhibition also promoted the long-term persistence of granzyme B+ effector memory 19BB zeta CAR T cells and enhanced sustainably their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BB zeta CAR T cells did not exhibit signs of exhaustion over time. Furthermore, TCR restimulation along with PRC2 inhibition promoted the differentiation of patient-derived anti-CD19 effector memory CAR T cells with enhanced cytotoxic features and elicited potent antitumor responses. In line with this, the gene signature derived from in-house PRC2-inhibited 19BB zeta CAR T cells was enriched in tisagenlecleucel BB zeta CAR T-cell therapy responders with large B-cell lymphoma. Collectively, our results demonstrated that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR T cells against hematologic malignancies.Significance: Selective inhibition of PRC2 endows 19BB zeta CAR T cells with cytotoxic and effector memory features that are associated with improved antitumor activity and better response to CAR T-cell therapy. (AU)

• FAPESP's process: 22/00747-8 - Evaluation of the antitumoral activity of CD39+ T cells in patients with clear cell renal cell carcinoma
• Grantee: Emmanuel Vinicius Oliveira Araujo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/10299-7 - PIWIL4 as a central regulator of endogenous retroviral elements in Gastric Cancer: implications for immunopathogenesis and immunotherapy?
• Grantee: Glauco Akelinghton Freire Vitiello
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/25129-2 - Comprehensive characterization of T cells in Pancreatic Ductal Adenocarcinomas
• Grantee: Gabriela Sarti Kinker
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/50943-1 - INCT 2014: on Oncogenomics and Therapeutic Inovations
• Grantee: Dirce Maria Carraro
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/14034-8 - Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets
• Grantee: Tiago da Silva Medina
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 21/00643-5 - Characterization of chromatin and transcriptional landscapes of T cells from diffuse-type gastric adenocarcinoma patients as a tool to discover immunotherapy targets
• Grantee: Maria Letícia Rodrigues Carvalho
• Support Opportunities: Scholarships in Brazil - Master