Safety and efficacy of transposon, BAFF-ligand directed chimeric antigen receptor T cells (LMY-920) with pre-apheresis obinutuzumab for patients with Relapsed/Refractory chronic lymphocytic leukemia and small lymphocytic lymphoma

Abstract Background and Significance: Despite major therapeutic advances including BTK and BCL2 inhibitors, patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) face limited treatment options after targeted therapy failure. Anti-CD19 CAR T cells show modest activity in CLL, with lisocabtagene maraleucel demonstrating only 57% overall response and 18% complete response rates in BTK/BCL2 inhibitor-treated patients. CLL cells express BAFF receptors (BAFF-R, TACI, BCMA) universally, and BAFF signaling promotes CLL cell survival through BTK-independent pathways. Additionally, CLL-associated T cell dysfunction limits CAR-T efficacy which may be overcome by pre-apheresis B cell depletion. We are conducting a trial with LMY-920, a BAFF ligand-based chimeric antigen receptor (CAR)-T cell therapy targeting all three BAFF receptors, manufactured using the TcBuster transposon system for improved manufacturing efficiency and safety with obinutuzumab intended to improve T cell quality and enhance CAR-T product function. Study Design and Methods: This is an open-label, dose escalation study (NCT 06916767) conducted at Cleveland Clinic, University Hospitals of Cleveland and The Ohio State University. Dose escalation of LMY-920 (2 - 8 x 106 cells/kg) is done using a 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose. Major inclusion criteria include histologically confirmed CLL/SLL relapsed after ≥2 prior therapies including both BTK and BCL2 inhibitors (i.e. “double refractory”), active disease per iwCLL criteria, ECOG performance status ≤2, and adequate organ function. Key exclusion criteria include CNS involvement, active malignancy, cardiovascular instability, active infection, and autoimmune disease requiring immunosuppression. The treatment protocol involves: (1) pre-apheresis B cell depletion with obinutuzumab (100mg day 1, 900mg day 2) starting 14-21 days before leukapheresis; (2) standard leukapheresis and LMY-920 manufacturing over 8-11 days using transposon technology; (3) lymphodepletion with fludarabine (30 mg/m²/day) and cyclophosphamide (500 mg/m²/day) for 3 days beginning on day -5; and (4) LMY-920 infusion on day 0 at escalating doses from 2×10⁶ to 8×10⁶ BAFF CAR-T cells/kg. Up to 18 patients will be enrolled across dose escalation and expansion cohorts. Primary endpoints include determination of recommended phase 2 dose and safety profile. Secondary endpoints assess objective response rate, complete response rate, duration of response, progression-free survival, and overall survival per iwCLL criteria. Correlative studies will evaluate BAFF CAR-T persistence, cytokine profiles, T cell functionality, receptor expression, circulating tumor DNA, and the impact of pre-apheresis obinutuzumab on T cell populations and CAR-T product characteristics. Long-term safety follow-up continues for 15 years per gene therapy guidelines. Conclusion: Targeting ubiquitously expressed BAFF receptors with optimization of the starting T cell material through pre-apheresis B cell depletion for patients with double refractory disease is designed to overcome current limitations of CAR-T therapy for CLL/SLL