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.