Immune priming with the EZH2 inhibitor tazemetostat in B-cell lymphomas receiving CAR T-cell therapy.

7035 Background: While chimeric antigen receptor (CAR) T cells have shown efficacy in B cell lymphomas, most patients (pts) still relapse. Preclinical studies have shown that inhibiting histone methyltransferase EZH2 prevents T cell exhaustion, promotes a T-cell memory phenotype, and sensitizes immune-based approaches. Methods: We administered the EZH2 inhibitor tazemetostat in pts receiving standard-of-care CART for diffuse large B cell, follicular, or mantle cell lymphoma (DLBCL, FL, MCL). Pts received tazemetostat for ≥7 days prior to apheresis and continued to lymphodepletion. Following CART, pts resumed tazemetostat at count recovery and continued for up to 12 mo (6 mo in pts with complete remission [CR]). Peripheral blood mononuclear cells were collected Day -24 and Day -5. To evaluate the immunomodulatory effects of priming, high parameter flow cytometry, RNA-seq with cell deconvolution, differential gene expression patterning, and functional gene signature scoring using ssGSEA were compared. Results: 13 pts enrolled (7 DLBCL, 5 FL, 1 MCL). Median prior lines of therapy were 2 (1-4), and 85% were refractory to the last therapy. EZH2 mutations were present in 2 pts. 4 pts had TP53 mutation or deletion, 4/7 DLBCL pts had MYC translocation and 3 had transformed disease. Five pts received axi-cel, 5 liso-cel, 2 tisa-cel, and 1 brexu-cel. All successfully completed CART manufacturing. The ORR was 100%, including 77% in CR (DLBCL 71%, FL 100%). At a median follow up of 18 months, 54% remain progression-free, and 77% remain alive. Ten pts (77%) experienced CRS, with 1 grade 3 CRS. 6 pts had transient grade 1-2 ICANS. Grade 3+ neutropenia was seen in 77%. Three pts experienced grade 3 infections. The most common AEs were gastrointestinal and almost exclusively grade 1-2. Comparing baseline and pre-CART samples, pts experienced a 14% and 20% increase in NK cells and CD16+ monocytes (p < 0.03) and a 14% and 53% decrease in Tregs and CD14+ monocytes (p < 0.02). Increases in the expression of functional gene signatures associated with MHC-I antigen presentation (p = 0.010), antigen-specific T cell activation (p = 0.019), and cellular cytotoxicity (p = 0.043) were also observed. Parallel reductions in signatures associated with tolerogenic dendritic cells (p = 0.011), myeloid suppression (p = 0.043), and coagulation (p = 0.030) were also seen. There was no observed negative impact on CART transduction efficiency, activation, or expansion. Conclusions: Addition of the EZH2 inhibitor tazemetostat is associated with high clinical efficacy and peripheral immune remodeling. Increases in lymphocyte activation and cytotoxicity along with decreases in myeloid tolerogenicity and immunosuppression could potentially augment CART expansion and persistence. Additional immune correlates are ongoing, and randomized studies are planned to validate this approach. Clinical trial information: NCT05934838 .