Background: Although chimeric antigen receptor (CAR)-T cells produce impressive outcomes in B-cell malignancies, a substantial fraction of patients with relapsed/refractory B-cell leukemia and lymphoma treated with anti-CD19 CAR-T cell therapy (CART19) either do not respond to treatment or relapse, with poor CAR-T cell persistence or CD19 antigen escape being two key factors that limit durability of response. In order to address these factors, we initiated a clinical trial with naïve/memory T (T_N/MEM) cells engineered to express bispecific anti-CD19/CD20 CARs (CART19/20) (NCT04007029). Methods: This trial is a Phase 1, first-in-human, dose-escalation trial enrolling patients with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Following lymphodepletion chemotherapy with fludarabine and cyclophosphamide, patients received CART19/20 cell doses ranging from 50 x 10⁶ to 200 x 10⁶ CAR-positive cells. The primary endpoint was to evaluate the safety of CART19/20 as measured by adverse events and dose limiting toxicities. Secondary endpoints were efficacy as assessed by disease response, progression-free survival (PFS), overall survival (OS), and CAR transgene persistence. Results: As of February 7, 2022, dose-escalation has been completed with 9 patients enrolled and 8 patients infused (3 FL, 4 DLBCL including 2 transformed follicular and 1 primary mediastinal B cell, and 1 MCL). with CART19/20 cells on this study. The median age at the time of CART19/20 infusion was 59 and median prior lines of therapy was 3.5. All patients had stage IV disease and 7 of 9 patients required bridging therapy. Grade-1 cytokine release syndrome (CRS) occurred in 6 of 8 patients, and no patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS). Among all patients, only one dose of tocilizumab was administered to one subject, and no steroids were given. With a median follow-up of 12 months from time of CART19/20 infusion (range: 4+ to 24+ months), 7 of 8 of patients remain in a complete remission. Median PFS and OS were not reached, and all patients with a complete remission demonstrate ongoing B-cell aplasia. Conclusions: This study demonstrates that CART19/20 cells are safe and effective in patients with relapsed/refractory NHL and potentially obviates the challenges of the commonest causes of relapse after CAR-T cell therapy by means of modifying T_N/MEM cells and dual-antigen targeting, respectively. Given the strong safety and response observed, dose escalation was completed with the second dosing level (DL2) of 200 x 10⁶ CAR-positive cells, and DL1 of 50 x 10⁶ CAR-positive cells was chosen as the therapeutic dose for future trial expansion. Clinical trial information: NCT04007029.