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Background Approved CAR-T cell therapies for lymphoma and myeloma have been successful at targeting CD19 and BCMA using scFv-based CARs. Although response rates are high, a significant number of patients fail to respond or relapse afterwards. CAR-T failure has been linked to T cell exhaustion, immune dysregulation, and/or epitope loss. To overcome this, we developed a novel autologous BAFF ligand-based CAR-T cell product (LMY-920) targeting the three BAFF receptors (BAFFR/BR3, TACI and BCMA). These are attractive tumor-associated antigens being variably expressed in all B-cell NHL subtypes, CLL and MM, and are important for B-cell survival, reducing the chance of antigen escape. BAFF ligand interactions are lower affinity than scFv, potentially reducing T-cell exhaustion. The novel TcBuster transposon system is utilized to improve manufacturing timelines, efficiency, cost, and safety.Methods Patients undergo leukapheresis and LMY-920 CAR-T cells are manufactured using the BAFF-CAR transposon construct. Patients then receive fludarabine (30 mg/m 2/d) and cyclophosphamide (500 mg/m2/d) lymphodepletion for 3 days. LMY-920 is administered intravenously in a 3+3 dose escalation from 1-8 x 106 BAFF-CAR-T cells/kg. Response is assessed using the Lugano, iwCLL or IMWG criteria. CAR-T expansion and biologic characteristics are assessed.Results Five patients have been treated with 1-2 x 10 6 BAFF-CAR-T cells/kg, 2 patients each with mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL) and one with MM. Patients had received 2 – 4 prior lines of therapy and all were refractory. Two patients experienced grade 1 CRS (fever), but no ICANS was reported. All patients experienced grade 3 or higher hematologic toxicity that recovered prior to day 28, and grade 1-2 fatigue. There have been no dose limiting toxicities and dose escalation continues. Responses included 2 complete responses (DLBCL), 1 partial response (MM) and 2 stable disease (MCL). Of note, the responding MM patient had plasma cell leukemia (PCL). Further, one of the DLBCL patients in complete response had received prior axicabtagene ciloleucel (anti-CD19) CAR-T cells as well as anti-CD20 bispecific antibodies, with lymphoma cells resulting in CD19 and CD20 antigen loss.Conclusions This study demonstrates successful use of a novel transposon-engineered BAFF ligand-based CAR-T cell product. Excellent safety and efficacy were observed, including in patients with challenging clinical scenarios such as PCL, prior CAR-T failure and epitope loss, as hypothesized. This product is also being evaluated in a clinical trial in systemic lupus erythematosus ( NCT06340750).Acknowledgements Branden S. Moriarity and Beau R. Webber co-directed this work.Trial Registration NCT05546723, NCT05312801, NCT06916767Ethics Approval The study obtained ethics approval from Case Comprehensive Cancer Center, Cleveland Clinic’s Institutional Review Board (24-424/MOD01553645), and participants gave informed consent before taking part.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.