In a phase 1 trial, Lei et al. investigated CD19-BBz CAR NK cells, derived from cord blood and engineered to express IL-15, in 8 patients with relapsed/refractory large B cell lymphoma. Three weekly infusions of CAR-NK did not lead to cytokine release syndrome, GvHD, or neurotoxicity. The 30-day ORR was 62.5%, and 50% of patients achieved a CR. The median PFS was 9.5 months, and two patients continued to show durable responses at 25 months. CAR copies were detectable in the peripheral blood of one patient with CR for 15 months. Transcriptome analysis indicated that inhibiting CBLB-mediated ubiquitination may enhance CAR-NK cell efficacy.
Contributed by Ute Burkhardt
ABSTRACT: Chimeric antigen receptor (CAR)-modified NK (CAR-NK) cells are candidates for next-generation cancer immunotherapies. Here we generated CD19-specific CAR-NK cells with 4-1BB and CD3_ signaling endo-domains (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells using baboon envelope pseudotyped lentiviral vectors and demonstrated their antitumor activity in preclinical B cell lymphoma models in female mice. We next conducted a phase 1 dose-escalation trial involving repetitive administration of CAR-NK cells in 8 patients with relapsed/refractory large B cell lymphoma (NCT05472558). Primary end points were safety, maximum tolerated dose, and overall response rate. Secondary end points included duration of response, overall survival, and progression-free survival. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. No cases of cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Results showed an overall response rate of 62.5% at day 30, with 4 patients (50%) achieving complete response. The median progression-free survival was 9.5_months, and the median overall survival was not reached. A post hoc exploratory single-cell RNA sequencing analysis revealed molecular features of CAR-NK cells associated with therapeutic efficacy and efficacy-related immune cell interaction networks. This study met the pre-specified end points. In conclusion, CD19-BBz CAR-NK cells were feasible and therapeutically safe, capable of inducing durable response in patients with B cell lymphoma.
Author Info: (1) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Key Laboratory of Cancer Prevention and Intervention, China
Author Info: (1) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education; Biotherapy Research Center, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (2) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (3) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China. (4) Stem Cell Translational Research Center, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China. (5) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (6) Stem Cell Translational Research Center, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China. (7) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (8) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (9) Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China. (10) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (11) Department of Hematology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China. tongxiangmin@163.com. (12) Stem Cell Translational Research Center, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China. yi.eve.sun@gmail.com. (13) Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China. lab7182@tongji.edu.cn. (14) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. qianwb@zju.edu.cn. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education; Biotherapy Research Center, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. qianwb@zju.edu.cn.
