A phase 1 study of lucar-G39D: A novel anti-CD20/CD19 dual-CAR allogeneic gamma delta T cells in adults with relapsed / refractory B-cell non-Hodgkin lymphoma (NHL)

Abstract Introduction: Autologous CD19-targeted chimeric antigen receptor (CAR)-T cell therapies have demonstrated clinical benefit for patients with R/R B-NHL; however, many patients are unable to receive these potentially life-saving therapies due to aggressive disease progression, manufacturing constraints, or limited access. A bispecific CAR-T targeting CD19 and CD20 may enhance efficacy by overcoming heterogeneous antigen expression and CD19-negative relapse. LUCAR-G39D is a first-in-class allogeneic γδ CAR-T cell therapy targeting both CD19 and CD20. (NCT06395870) Methods: This ongoing multicenter phase I clinical trial evaluates the safety and preliminary efficacy of LUCAR-G39D in adults with R/R B-NHL. Key eligibility criteria include presence of measurable lesions, expression of CD19 and/or CD20 on tumor cells, and ≥ 2 (or refractory to 1) prior lines of systemic therapy. All patients received moderate conditioning therapy with fludarabine (30mg/m2) and cyclophosphamide (500mg/m2) per day for 3-4 days followed by a single infusion of LUCAR-G39D at dose level 1 (DL1):30×106, DL2:100×106, DL3:200×106, or DL4:400×106CAR-T cells. Accelerated titration (DL1 only) followed by BOIN dose escalation was adopted. Patients who completed the 30-day DLT period were considered DLT evaluable. Treatment-emergent adverse events were graded by CTCAE v5.0; immune effector cell-associated neurologic syndrome and cytokine release syndrome (CRS) were assessed per ASTCT criteria. Objective response rates (ORR) were evaluated per Lugano 2014 criteria. CAR-T cell pharmacokinetics (PK) were assessed by qPCR. Results: As of 29 April 2025, 12 patients were dosed; 10 patients completed at least 30 days follow up or at least 1 efficacy evaluation, 10 were efficacy evaluable and 9 DLT evaluable (1 withdrawal due to PD). Of these 10 patients, the median age was 58 years (range 19-70) and 5(50%) were male. Six (60%) patients had diffuse large B-cell lymphoma, 1(10%) patient had primary mediastinal large B-cell lymphoma, and 3 (30%) had follicular lymphoma. At baseline, 10(100%) patients were CD20(+) and 6(60%) patients were CD19(+); CD19 status was unavailable for the remaining 4(40%) due to insufficient material. Four (40%) patients were IPI≥3, 3(30%) patients were triple-hit lymphoma, the median tumor burden was 1188(531-6431) mm2, and 7(70%) had stage III/IV disease. The median number of prior therapies was 3 (range 1-6). One, 4, 3, and 2 patients received DL1, DL2, DL3, or DL4, respectively. One patient at DL2 was re-dosed with the same dose level. LUCAR-G39D was well tolerated without DLT, neurotoxicity, or GvHD. CRS occurred in 4/10 (40%) patients: 2(20%) Grade 1, 1(10%) Grade 2, and 1(10%) Grade 3, with median duration 5 days (range, 3-7). Infections occurred in 5/10(50%) patients including 1(10%) Grade 1, 3(30%) Grade 2, and 1(10%) Grade 3. Of the infections, there was only 1 Grade 3 event (pneumonia); it was also the only serious adverse event and resolved post-treatment. The most common Grade 3 or Grade 4 adverse events (incidence ≥20%) included decreased neutrophil count (100%), decreased lymphocyte count (100%), decreased white blood cell (100%), and decreased platelet count (20%). No fetal adverse events occurred. PK expansion was detected in 80% (8/10) of patients for all dose levels (100% [2/2] at DL4). The median Cmax was 1999 copies/μg gDNA (range 59-164768), with a median Tmax of 5.5 days. ORR was 70% (7/10), and the complete response rate was 30%(3/10) for all patients (3 patients had deepening efficacy from Days 30-90). Both patients at DL4 achieved a response by the first efficacy evaluation. As of the cut-off date, all 7 responders were still in response and active follow up, the longest last to Day 270 (range 30-270). At a median follow-up time of 3.52 months (range 0.8-8.8), the 6-month rate of PFS was 75% (range 29.8%-93.4%). Following LUCAR-G39D, 7 of 8 patients (88%) with paired baseline and Day30 ctDNA samples had decreased ctDNA levels (median, –98%; range –23% to –100%), consistent with radiographic responses. Conclusions: LUCAR-G39D γδ CAR-T cells showed a manageable safety profile and good expansion in patients with NHL. Preliminary efficacy showed encouraging response rate and sustained durability in patients; this therapeutic strategy warrants further investigation.