TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIES
Chimeric Antigen Receptor (CAR) T cell therapy was adopted as a clinical modality for patients with relapsed/refractory hematological malignancies. Despite the clinical efficacy of CAR-T cell therapy, a considerable fraction of patients still relapses during the first months following CAR-T cell inf...
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| Language: | English |
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Elsevier
2024-10-01
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| Series: | Hematology, Transfusion and Cell Therapy |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2531137924019989 |
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| author | MLR Carvalho CO Andrade MP Cabral-Piccin GS Kinker GAF Vitiello L Abdo RAG Cambui MH Bonamino TS Medina |
| author_facet | MLR Carvalho CO Andrade MP Cabral-Piccin GS Kinker GAF Vitiello L Abdo RAG Cambui MH Bonamino TS Medina |
| author_sort | MLR Carvalho |
| collection | DOAJ |
| description | Chimeric Antigen Receptor (CAR) T cell therapy was adopted as a clinical modality for patients with relapsed/refractory hematological malignancies. Despite the clinical efficacy of CAR-T cell therapy, a considerable fraction of patients still relapses 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. Here, screening of multiple epigenetic inhibitors revealed that targeting PRC2 consistently enhanced the cytotoxic/effector phenotype of CD8 T-cells. Notably, PRC2 inhibition promoted the differentiation of GZMB+ effector memory 19BBζ CAR-T cells and enhanced their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BBζ CAR-T cells did not exhibit any signs of dysfunctionality/exhaustion. Furthermore, TCR restimulation along with PRC2 inhibition of patient-derived anti-CD19 CAR-T cells also induced the development of GZMB+ effector memory cells and elicited potent antitumor responses against CD19+ Daudi cells. In line with this, thegene signature derived from in-house PRC2-inhibited 19BBζ CAR-T cells was enriched in tisagenlecleucel (tisa-cel) BBζCAR-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 hematological malignancies. |
| format | Article |
| id | doaj-art-a3c90adc916c4e98af573a04f9b095c8 |
| institution | OA Journals |
| issn | 2531-1379 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Elsevier |
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| series | Hematology, Transfusion and Cell Therapy |
| spelling | doaj-art-a3c90adc916c4e98af573a04f9b095c82025-08-20T02:17:45ZengElsevierHematology, Transfusion and Cell Therapy2531-13792024-10-0146S97910.1016/j.htct.2024.09.1665TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIESMLR Carvalho0CO Andrade1MP Cabral-Piccin2GS Kinker3GAF Vitiello4L Abdo5RAG Cambui6MH Bonamino7TS Medina8International Research Center, A.C.Camargo Cancer Center, São Paulo, SP, BrazilCell and Gene Therapy Program – Research Coordination, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, BrazilInternational Research Center, A.C.Camargo Cancer Center, São Paulo, SP, BrazilInternational Research Center, A.C.Camargo Cancer Center, São Paulo, SP, BrazilInternational Research Center, A.C.Camargo Cancer Center, São Paulo, SP, BrazilCell and Gene Therapy Program – Research Coordination, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, BrazilInternational Research Center, A.C.Camargo Cancer Center, São Paulo, SP, BrazilCell and Gene Therapy Program – Research Coordination, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, BrazilInternational Research Center, A.C.Camargo Cancer Center, São Paulo, SP, BrazilChimeric Antigen Receptor (CAR) T cell therapy was adopted as a clinical modality for patients with relapsed/refractory hematological malignancies. Despite the clinical efficacy of CAR-T cell therapy, a considerable fraction of patients still relapses 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. Here, screening of multiple epigenetic inhibitors revealed that targeting PRC2 consistently enhanced the cytotoxic/effector phenotype of CD8 T-cells. Notably, PRC2 inhibition promoted the differentiation of GZMB+ effector memory 19BBζ CAR-T cells and enhanced their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BBζ CAR-T cells did not exhibit any signs of dysfunctionality/exhaustion. Furthermore, TCR restimulation along with PRC2 inhibition of patient-derived anti-CD19 CAR-T cells also induced the development of GZMB+ effector memory cells and elicited potent antitumor responses against CD19+ Daudi cells. In line with this, thegene signature derived from in-house PRC2-inhibited 19BBζ CAR-T cells was enriched in tisagenlecleucel (tisa-cel) BBζCAR-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 hematological malignancies.http://www.sciencedirect.com/science/article/pii/S2531137924019989 |
| spellingShingle | MLR Carvalho CO Andrade MP Cabral-Piccin GS Kinker GAF Vitiello L Abdo RAG Cambui MH Bonamino TS Medina TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIES Hematology, Transfusion and Cell Therapy |
| title | TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIES |
| title_full | TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIES |
| title_fullStr | TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIES |
| title_full_unstemmed | TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIES |
| title_short | TARGETING PRC2 ENHANCES THE ANTITUMOR CYTOTOXIC CAPACITY OF ANTI-CD19 CAR-T CELLS AGAINST HEMATOLOGICAL MALIGNANCIES |
| title_sort | targeting prc2 enhances the antitumor cytotoxic capacity of anti cd19 car t cells against hematological malignancies |
| url | http://www.sciencedirect.com/science/article/pii/S2531137924019989 |
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