Targeting PRC2 Enhances the Cytotoxic Capacity of Anti-CD19 CAR-T Cells Against Hematological Malignancies

Abstract Chimeric antigen receptor (CAR) T cell therapy is increasingly being 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 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 19BBζ CAR-T cells and sustainably 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 signs of exhaustion over time. Furthermore, TCR restimulation along with PRC2 inhibition promoted the differentiation of patient-derived anti-CD19 CAR-T cells to a granzyme B+ effector memory phenotype with enhanced cytotoxic features that elicited potent antitumor responses. A gene signature derived from in-house PRC2-inhibited 19BBζ CAR-T cells was enriched in tisagenlecleucel (tisa-cel) BBζ CAR-T cell therapy responders with large B-cell lymphoma. Collectively, these results demonstrate that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR-T cells to improve the efficacy in treating hematological malignancies.