CRISPR-engineered T cells in patients with refractory cancer

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 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two g...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2020-02, Vol.367 (6481)
Main Authors: Stadtmauer, Edward A, Fraietta, Joseph A, Davis, Megan M, Cohen, Adam D, Weber, Kristy L, Lancaster, Eric, Mangan, Patricia A, Kulikovskaya, Irina, Gupta, Minnal, Chen, Fang, Tian, Lifeng, Gonzalez, Vanessa E, Xu, Jun, Jung, In-Young, Melenhorst, J Joseph, Plesa, Gabriela, Shea, Joanne, Matlawski, Tina, Cervini, Amanda, Gaymon, Avery L, Desjardins, Stephanie, Lamontagne, Anne, Salas-Mckee, January, Fesnak, Andrew, Siegel, Donald L, Levine, Bruce L, Jadlowsky, Julie K, Young, Regina M, Chew, Anne, Hwang, Wei-Ting, Hexner, Elizabeth O, Carreno, Beatriz M, Nobles, Christopher L, Bushman, Frederic D, Parker, Kevin R, Qi, Yanyan, Satpathy, Ansuman T, Chang, Howard Y, Zhao, Yangbing, Lacey, Simon F, June, Carl H
Format: Article
Language:English
Subjects:
Adoptive Transfer
Aged
Apoptosis
Autoimmunity
Bone marrow
Cancer
Cancer immunotherapy
Cell Engineering
Cell therapy
Clinical trials
CRISPR
CRISPR-Associated Protein 9
CRISPR-Cas Systems
Editing
Efficiency
Female
Gene Editing
Genes
Genome editing
Genomes
Genomics
Humans
Immune response
Immune system
Immunogenicity
Immunotherapy
Lymphocytes
Lymphocytes T
Male
Middle Aged
Multiple myeloma
Mutation
Patients
Persistence
Programmed Cell Death 1 Receptor - genetics
Proteins
Receptors, Antigen, T-Cell, alpha-beta - genetics
Safety engineering
Sarcoma
T cell receptors
T-Lymphocytes - immunology
T-Lymphocytes - transplantation
Technology
Toxicity
Transgenes
Tumors
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Summary: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 1 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, TCRα ( ) and TCRβ ( ), 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 programmed cell death protein 1 (PD-1; ), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although 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.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.aba7365