Lu et al. report the safety, feasibility, and efficacy of first-in-human phase I clinical trial of CRISPR Cas9 PD1-edited T cell infusion in patients with NSCLC. Editing frequency was low (~20%), and edited CD8+ T cells showed decreased PD-1 expression and an increase in IFNγ positivity. Sequencing showed limited off-target effect in the edited cells, and the treatment-related adverse events were of grades 1 and 2. Edited PD-1 gene and unique TCR clones were detectable in PBMCs and were persistent in a patient with stable disease. Among 12 treated patients, median PFS was 7.7 weeks and the best response was stable disease in 2 patients.
Contributed by Shishir Pant
ABSTRACT: Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.
Author Info: (1) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. radyoulu@hotmail.com. (2) Depart
Author Info: (1) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. radyoulu@hotmail.com. (2) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (3) Chengdu MedGenCell, Co., Ltd, Chengdu, China. (4) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (5) Chengdu MedGenCell, Co., Ltd, Chengdu, China. (6) Jacobi Medical Center, NYC Health Hospitals, Albert Einstein College of Medicine, New York, NY, USA. (7) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (8) Geneplus-Beijing Institute, Beijing, China. (9) Center of GCP, West China Hospital, Sichuan University, Chengdu, China. (10) ZenRhyme Consulting Service, Ltd, Shanghai, China. (11) ZenRhyme Consulting Service, Ltd, Shanghai, China. (12) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (13) National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. (14) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (15) Geneplus-Beijing Institute, Beijing, China. (16) Geneplus-Beijing Institute, Beijing, China. (17) Berry Oncology Co. Ltd, Fujian, China. (18) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (19) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (20) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (21) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. Center of GCP, West China Hospital, Sichuan University, Chengdu, China. (22) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (23) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (24) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (25) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (26) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (27) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (28) Geneplus-Beijing Institute, Beijing, China. (29) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (30) Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (31) Geneplus-Beijing Institute, Beijing, China. (32) Chengdu MedGenCell, Co., Ltd, Chengdu, China. (33) Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. (34) Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. (35) State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (36) State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China. (37) Department of Respiratory and Critical Care Medicine and Frontier Science Center of Disease Molecular Network, West China Hospital, Sichuan University, Chengdu, China. (38) State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China.
