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CRISPR-engineered T cells in patients with refractory cancer. Science (New York, N.Y.) Stadtmauer, E. A., Fraietta, J. A., Davis, M. M., Cohen, A. D., Weber, K. L., Lancaster, E. n., Mangan, P. A., Kulikovskaya, I. n., Gupta, M. n., Chen, F. n., Tian, L. n., Gonzalez, V. E., Xu, J. n., Jung, I. Y., Melenhorst, J. J., Plesa, G. n., Shea, J. n., Matlawski, T. n., Cervini, A. n., Gaymon, A. L., Desjardins, S. n., Lamontagne, A. n., Salas-Mckee, J. n., Fesnak, A. n., Siegel, D. L., Levine, B. L., Jadlowsky, J. K., Young, R. M., Chew, A. n., Hwang, W. T., Hexner, E. O., Carreno, B. M., Nobles, C. L., Bushman, F. D., Parker, K. R., Qi, Y. n., Satpathy, A. T., Chang, H. Y., Zhao, Y. n., Lacey, S. F., June, C. H. 2020

Abstract

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase I clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRa (TRAC) and TCRß (TRBC) were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding PD-1 (PDCD1), was performed to improve anti-tumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Though chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene-editing for cancer immunotherapy.

View details for DOI 10.1126/science.aba7365

View details for PubMedID 32029687