EZH2 INHIBITION ENHANCES T CELL IMMUNOTHERAPIES BY INDUCING LYMPHOMA IMMUNOGENICITY AND IMPROVING T CELL FUNCTION (CUT&RUN)

While T cell immunotherapies have demonstrated effectiveness in a subset of patients with diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), they are currently administered without guidance regarding whether the underlying biology or immunology is conducive to a durable response. Moreover, mechanisms explaining CAR-T resistance in B cell lymphomas remain largely unknown, and suitable systems to study lymphomas are currently unavailable, making it infeasible. To address these unmet needs, we developed syngeneic animal models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that treatment of these models with EZH2 inhibitors reprogrammed them to re-express T cell engagement genes and rendered them highly immunogenic. Notably, EZH2 inhibitors did not exhibit deleterious effects on T cells. Instead, they promoted a memory CAR CD8 phenotype and reduced exhaustion, resulting in a superior elimination of lymphoma B cells and decreased tumor burden. Intravital 2-photon imaging of transformed FL bearing mice showed that EZH2 inhibition increased the recruitment of CAR-T into the tumor microenvironment and enhanced the quality of interactions with lymphoma cells, leading to increased killing. Therefore, inhibition of EZH2 enhances CAR-T cell activity through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This offers an innovative approach for enhancing the prognosis of patients with refractory B cell lymphomas, and is currently under evaluation in a clinical trial (NCT05934838)