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Background: Single-input anti-CD19 CAR T-cells have demonstrated clinical efficacy for relapsed or refractory (R/R) non-Hodgkin B-cell lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite excellent response rates, over 50% of CD19 CAR T-cell recipients relapse. Preclinical data show engineering of bispecific anti-CD19/CD20 CAR T-cells via lentiviral transduction effectively targets tumor cells and overcomes antigen escape (Zah E et al., Cancer Immunol Res, 2016). Based on these promising preclinical results and the limitations of single-input anti-CD19 CARs, we investigated the bispecific anti-CD19/CD20 CAR naïve/memory T-cells in a phase I dose-escalation clinical trial for patients with R/R NHL/CLL (NCT04007029). Methods: This trial includes patients who have measurable disease after 2 lines of therapy for diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL), and after 3 lines of therapy for mantle cell lymphoma (MCL), follicular lymphoma (FL), CLL and small lymphocytic leukemia (SLL). Eligible participants received lymphodepleting chemotherapy with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for three days, followed by anti-CD19/CD20 CAR T-cell infusion. The CAR T-cell infusion will be given with standard "3+3" dose escalation to determine the maximum tolerated dose (MTD), with a dose range of 5 x 107 to 6 x 108 CAR-positive cells per patient. Results: To date, three patients received treatment on cohort 1 with 5 x 107 CD19/CD20 CAR T-cells for R/R MCL, FL and PMBCL, with an average age of 49.3 (range, 29-60) and a mean of 3.7 prior regimens (range, 3-4). All 3 patients' lymphomas were CD19+/CD20+ on tissue biopsy prior to CAR infusion and all 3 received bridging chemotherapy. The infusion was well tolerated and no major infusion reactions occurred. Peak expansion was noted on day 14. No dose limiting toxicities were identified. The maximum grade CRS was 1 and there was no ICANS. At the 6.0-month cutoff date, 2 of the 3 patients remain in ongoing complete remission. Unfortunately, one patient developed progressive disease 0.5 months after CAR infusion, yet remains alive after treatment with immunotherapy. Both of the responders continue to demonstrate ongoing CAR T-cell persistence and B-cell aplasia by 3.0 and 6.0-month follow up, respectively. Conclusions: Here we demonstrate impressive responses in 2 of 3 patients at the 5 x 107 CD19/CD20 CAR T-cell dosages. Bispecific CD19/CD20 CAR T-cell therapy appears to be safe and effective in patients with R/R NHL and CLL and obviates the challenges with the single antigen directed CARs by decreasing risk of target antigen loss and expression downregulation. A longer follow up period is required to determine the impact of modifying naïve/memory T cells and the durability of response. The trial continues to enroll patients and additional clinical and translational data are being collected on the initial patient cohort. Disclosures Timmerman: Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; Valor: Research Funding; Merck: Research Funding; Spectrum Pharmaceuticals: Research Funding; BMS: Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Genmab: Current equity holder in publicly-traded company. Chen:Kalthera Therapeutics: Other: Co-founder; Notch Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gritstone Oncology: Membership on an entity's Board of Directors or advisory committees. Larson:BMS, Bioline, Celgene, Juno, Janssen: Research Funding; TORL Biotherapeutics: Current equity holder in private company.

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.

Four patients who manifested an association between chronic liver disease and lymphoma are reported. Three of them had nonalcoholic cirrhosis and one had chronic cholangitis. Non-Hodgkin's lymphoma developed long after the presence of liver disease had been established in three of the patients. The fourth patient died of hepatic coma and Hodgkin's disease was discovered incidentally at autopsy. Drugs could not be incriminated in the development of either cirrhosis or lymphoma in any of the patients. A review of the literature is presented, and the view that the association between chronic liver disease and lymphoma is not coincidental is supported.