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)
Year: 2025
Type: conference-abstract
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.
Source: Blood
Authors: Jingwei Yu, Linlin Cao, Lanfang Li, Jing Ming, Zhengzi Qian, Dandan Fan, Lihua Qiu, Xianming Liu, Jiayi Han, Jian Li, Pu Wang, Qing Dai, Yafeng Zhang, Wenjie Wang, Da Xu, Yue Zhu, Cong Feng, Xiaoyu Feng, Jin Liu, Lemei Jia, Ning Chen, Yinrui Jiang, Liping Sun, Qi Zhou, Nan Wang, Yongxin Luo, Kaiyang Ding, Huilai Zhang
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417011000