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

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 19BBζ CAR T cells and enhanced sustainably 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 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 19BBζ CAR T cells was enriched in tisagenlecleucel BBζ 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 19BBζ CAR T cells with cytotoxic and effector memory features that are associated with improved antitumor activity and better response to CAR T-cell therapy.