2563 Background: CAR-T cells targeting CD19 using scFv-based CARs have been effective and approved to treat lymphoma. Response rates are high, but a significant number of patients fail to respond or relapse. This has been linked to T cell exhaustion, immune dysregulation, and/or epitope loss. To overcome this, we developed a CAR-T cell product expressing a BAFF-ligand (LMY-920). The CAR consists of truncated human BAFF on a 3rd generation CAR backbone with CD28, OX40, and CD3z intracellular signaling domains. The BAFF-ligand domain confers ability to bind the 3 BAFF receptors (BAFFR/BR3, TACI and BCMA). These are attractive tumor-associated antigens being variably expressed in all B-lineage malignancies such as B cell NHL, chronic lymphocytic leukemia (CLL), hairy cell leukemia and multiple myeloma (MM), and are important for B-cell survival, reducing the chance of antigen escape. Additionally, they are expressed on B-lineage cells involved in antibody-mediated autoimmune diseases. BAFF ligand interactions are lower affinity than scFv interactions, potentially reducing T-cell exhaustion. The novel TcBuster transposon system is used to improve manufacturing time, efficiency, cost, and safety. Methods: Patients with refractory B cell NHL are treated in this study (NCT05312801). Autologous LMY-920 CAR-T cells are manufactured, then patients receive 3 days of fludarabine (30 mg/m 2 /d) and cyclophosphamide (500 mg/m 2 /d) lymphodepletion. LMY-920 is administered intravenously in a 3+3 dose escalation design from 1-8 x 10 6 BAFF-CAR-T cells/kg. Response is assessed using the Lugano 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 in this study, 2 patients each with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), and one with marginal zone lymphoma (MZL). Patients had received 2 – 6 prior lines of therapy and all were refractory. One patient 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 (CR) (DLBCL), a partial response (MZL), a mixed response (MCL) and one stable disease (MCL). Of note, one of the DLBCL patients in CR 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: The successful use of a novel transposon-engineered BAFF ligand-based CAR-T cell product demonstrates the potential of a new direction in CAR-T cell development. Safety and efficacy were seen, including patients with prior CAR-T failure and epitope loss, as hypothesized. This product is also being evaluated in patients with CLL, MM and systemic lupus erythematosus. Clinical trial information: NCT05312801 .
Caimi et al. (Wed,) studied this question.