Phase 1 assessment of novel transposon BAFF CAR-T cells (LMY-920) for non-Hodgkin lymphoma (NHL) and multiple myeloma (MM)

Abstract Background and Significance: Marked success has been achieved using scFv-based CAR-T cell therapies targeting CD19 and BCMA to treat lymphoma and myeloma. Response rates are high, but a significant number of patients fail to respond or relapse subsequently. Resistance to CAR-T cells has been associated with T cell exhaustion, immune dysregulation and/or epitope loss. We developed a BAFF ligand-based CAR-T cell therapy (LMY-920) targeting the BAFF receptors BAFFR/BR3, TACI and BCMA, to overcome these mechanisms of resistance. These are attractive tumor-associated antigens being variably expressed in all B-cell NHL subtypes, chronic lymphocytic leukemia (CLL) and MM. These receptors are important in B-cell survival and proliferation pathways, reducing the chance of antigen escape. Further, BAFF ligand interactions are of lower affinity than scFv, potentially reducing T-cell exhaustion. The TcBuster transposon system is utilized, resulting in better manufacturing timelines, efficiency, cost, and safety. Study Design and Methods: Two parallel Phase 1 open-label dose escalation trials are being conducted in NHL and MM (NCT05546723 and NCT05312801, respectively) open at the same centers in the United States. Major inclusion criteria include disease progression after 2 (NHL), 3 (MM) or more prior therapies and adequate organ function, with major exclusion criteria centering around concomitant conditions that could reduce tolerance or complicate interpretation of results. After patients are enrolled and undergo leukapheresis, LMY-920 CAR-T cells are manufactured using the BAFF-CAR transposon construct. Patients then receive lymphodepleting chemotherapy (fludarabine (30 mg/m2/d x 3) and cyclophosphamide (500 mg/m2/d x 3). LMY-920 is administered intravenously 2 days after lymphodepletion. Dose levels range from 1-8 x 106 BAFF-CAR-T cells/kg, following a 3+3 dose escalation schema (3 patients at each dose level, increased to 6 if dose-limiting toxicity is reported). Response is assessed using the Lugano or IMWG criteria. Adverse events, standard laboratory assays, circulating LMY-920 number and characteristics are also assessed. Given the hypothesized advantages of targeting BAFF receptors, enrolled patients have included those having received prior idecabtagene vicleucel (anti-BCMA) CAR-T cells, axicabtagene ciloleucel (anti-CD19) CAR-T cells, as well as anti-CD20 antibodies and bispecific antibodies, with lymphoma cells demonstrating CD19 and/or CD20 antigen loss. Clinical trials are also being conducted to assess LMY-920 in patients with CLL and autoimmune disease (systemic lupus erythematosus).