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50% of patients with relapsed/refractory (R/R) B-cell lymphomas (BCL) who initially respond to CD19 CAR T therapy will relapse either due to poor CAR-T persistence or CD19 antigen escape. Preclinical data demonstrate that engineering of bispecific anti-CD19/CD20 CAR in naïve/memory T-cells (TN/MEM) via lentiviral transduction effectively targets tumor cells, overcomes antigen escape and enhances CART persistence (Zah E et al., Cancer Immunol Res, 2016). We conducted a first-in-human phase 1 clinical trial with bispecific CD19/CD20 CAR T-cells for patients with R/R BCL (NCT04007029). Patients with measurable disease after 2 or more lines of therapy for DLBCL and PMBCL, and 3 or more lines of therapy for MCL, FL and CLL were included. Autologous leukocytes obtained by leukapheresis were sorted for CD14-/CD25-/CD62L+ TN/MEM cells, followed by lentiviral transduction of the bispecific CD19/CD20 CAR. Following Cy-Flu lymphodepletion, patients are infused with CD19/CD20 CAR TN/MEM cells, at doses ranging from 5 x 107 and 2 x 108 CAR positive cells. 5 patients are included in the analysis, 4 in the first cohort and 1 in the second cohort. All patients had CD19/CD20+ B cell malignancy on tissue biopsy prior to CAR-T. Patients had previously received a median of 4 prior lines of therapy, and 4 received bridging therapy. Infusions were well tolerated, and no dose limiting toxicities were identified. All patients had grade 1 CRS, with median onset 8 days (range 7-11) after infusion. No patient had immune effector cell-associated neurotoxicity syndrome (ICANS). Peak expansion was noted on day 14. Median follow up is 11.1 months (95% CI 2.1-14.8), with 4 of patients in ongoing complete remission. The 1 patient who did not respond had early disease progression, with CD19 and CD20 negative mediastinal lymphoma at day 14 after CAR infusion. Median progression-free survival (PFS) and overall survival (OS) were not reached and all responders demonstrate ongoing CAR T-cell persistence and B-cell aplasia by data cutoff. Bispecific CD19/CD20 CAR in naïve/memory T-cells are safe and effective in patients with R/R BCL. To our knowledge, this is the first study that potentially obviates the challenges of the commonest causes of relapse after CAR T-cell therapy, poor CAR-T persistence and antigen escape mechanisms, by means of modifying naïve/memory T cells and dual antigen targeting, respectively. Patient and Treatment CharacteristicsID12345DiagnosisMCLFLPMBCLFLFLSexMMFMFAge6058296235Prior lines of therapy44343Stage44442EECOG01100Bridging therapy?YesYesYesYesNoDosage, x 106 CART50505050200Max CRS/ICANS gradeGrade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Required treatment for CRS/ICANS?NoNoNoNoNoBest Response to CARTCRCRNone; refractoryCRCRPFS (months)14.811.10.54.82.1OS (months)14.811.16.24.82.1Subsequent Follow-upAlive, ongoing remissionAlive, ongoing remissionNo response to CART; died from infectious complications after subsequent therapy with nivolumab and brentuximab.Alive, ongoing remissionAlive, ongoing remission Citation Format: Sanaz Noelle Ghafouri, Christopher Walthers, Mobina Roshandell, Brenda Ji, Jacqueline Trent, Jia Ming Chen, Jacob Naparstek, Caitlin Harris, Thomas Schweppe, Karla K. Nawaly, Monica Mead, Sven de Vos, Patricia Young, Caspian Oliai, Gary Schiller, John M. Timmerman, Yvonne Y. Chen, Sarah Larson. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T-cells for the treatment of relapsed or refractory B-cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT007.