Editors' ChoiceCancer

CRISPR-engineered immune cells reach the bedside

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Science Translational Medicine  13 May 2020:
Vol. 12, Issue 543, eabb7095
DOI: 10.1126/scitranslmed.abb7095


In a clinical trial, CRISPR editing of T cells to fight lung cancer was feasible and safe.

Lung cancer is the most prevalent and fatal malignancy worldwide. Whereas the overall five-year cancer survival rates in the United States increased by 16.7% over the past five decades, lung cancer five-year survival rates only increased by 5.9%. Immune checkpoint inhibitors, such as antibodies against programmed cell death protein 1 (PD-1), are front-line anticancer treatments because PD-1 ligand on tumor cells efficiently inhibits immune responses.

Lu et al. published the results of a clinical trial, which aimed at knocking out PD-1 on T cells to confer antitumor activity against metastatic non–small cell lung cancer. The T cells were expanded ex vivo, then reinfused into 12 patients. The primary aim of the trial was to test feasibility and safety, and the secondary aims included efficiency and tracking of edited T cells. Overall, the treatment was well tolerated, with only mild to moderate adverse effects and no dose-limiting toxicities. Considerable care was taken to analyze clustered regularly interspaced short palindromic repeats (CRISPR)–induced off-target effects, and the study showed that median mutation frequency was 0.05% in off-target sites. Edited T cells were detected in the peripheral blood of 11 out of 12 patients and in tumor biopsy specimens from one patient up to 52 weeks after infusion. After infusion, two patients had stable disease, and it lasted up to 76 weeks in one patient.

This trial was performed cautiously to avoid major issues with off-target effects, and the researchers used T cells with relatively low editing rates (median of 5.8%). Nevertheless, the authors observed signs of biological activity in patients with metastatic disease who had failed several other lines of treatment. To improve biological efficiency, it will be critical to increase editing rates without increasing off-target effects. Although the off-target effects were close to background level in this study, genome-wide unbiased screens will be necessary, particularly when editing rates are boosted. A separate problem to address before broader clinical translation is T cell expansion, which failed in five patients in this study.

These early data suggest that CRISPR editing of T cells in humans is feasible and safe. Several other trials are ongoing and should help assess the potential benefit of ex vivo edited immune cells. With CRISPR-edited immune cells, it may be possible to get a better grip on metastatic lung cancer and other malignancies.

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