First-in-Human Trial of CRISPR-Edited PD-1 Knockout T Cells in Lung Cancer
This first-in-human phase I trial treated 12 patients with advanced non-small-cell lung cancer using autologous T cells with CRISPR-Cas9 knockout of PD-1, demonstrating safety and feasibility with only grade 1/2 treatment-related adverse events. NGS-based off-target analysis showed a median mutation frequency of 0.05% across 18 candidate sites, confirming acceptable editing specificity. Median overall survival was 42.6 weeks, and while efficacy was modest, the trial establishes a safety foundation for next-generation CRISPR-based cell therapies with improved editing approaches.
The original study
Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer.
- Authors
- Lu Y, Xue J, Deng T, Zhou X, Yu K, Deng L, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't
- PMID
- 32341578
Original 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.