CRISPR-engineered T cells in patients with refractory cancer

被引：1027

作者：

Stadtmauer, Edward A. ^{[1
,2
]}

Fraietta, Joseph A. ^{[2
,3
,4
,5
,6
]}

Davis, Megan M. ^{[5
,6
]}

Cohen, Adam D. ^{[1
,2
]}

Weber, Kristy L. ^{[2
,7
]}

Lancaster, Eric ^{[8
]}

Mangan, Patricia A. ^{[1
]}

Kulikovskaya, Irina ^{[5
]}

Gupta, Minnal ^{[5
]}

Chen, Fang ^{[5
]}

Tian, Lifeng ^{[5
]}

Gonzalez, Vanessa E. ^{[5
]}

Xu, Jun ^{[5
]}

Jung, In-young ^{[4
,5
]}

Melenhorst, J. Joseph ^{[3
,5
,6
]}

Plesa, Gabriela ^{[5
]}

Shea, Joanne ^{[5
]}

Matlawski, Tina ^{[5
]}

Cervini, Amanda ^{[5
]}

Gaymon, Avery L. ^{[5
]}

Desjardins, Stephanie ^{[5
]}

Lamontagne, Anne ^{[5
]}

Salas-Mckee, January ^{[5
]}

Fesnak, Andrew ^{[5
,6
]}

Siegel, Donald L. ^{[5
,6
]}

Levine, Bruce L. ^{[5
,6
]}

Jadlowsky, Julie K. ^{[5
]}

Young, Regina M. ^{[5
]}

Chew, Anne ^{[5
]}

Hwang, Wei-Ting ^{[9
]}

Hexner, Elizabeth O. ^{[1
,2
]}

Carreno, Beatriz M. ^{[3
,5
,6
]}

Nobles, Christopher L. ^{[4
]}

Bushman, Frederic D. ^{[4
]}

Parker, Kevin R. ^{[10
]}

Qi, Yanyan ^{[11
]}

Satpathy, Ansuman T. ^{[10
,11
]}

Chang, Howard Y. ^{[10
,12
]}

Zhao, Yangbing ^{[5
,6
]}

Lacey, Simon F. ^{[5
,6
]}

June, Carl H. ^{[2
,3
,5
,6
]}

机构：

[1] Univ Penn, Dept Med, Perelman Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[3] Univ Penn, Parker Inst Canc Immunotherapy, Perelman Sch Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Ctr Cellular Immunotherapies, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA

[8] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA

[9] Univ Penn, Perelman Sch Med, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA

[10] Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA

[11] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[12] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA

来源：

SCIENCE | 2020年 / 367卷 / 6481期

基金：

美国国家卫生研究院;

关键词：

DOUBLE-STRAND BREAKS; LYMPHOCYTES; PD-1; GENOME; PERSISTENCE; NY-ESO-1; INDUCTION; RECOGNIZE; LEUKEMIA; AFFINITY;

D O I：

10.1126/science.aba7365

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, TCR alpha (TRAC) and TCR beta (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 programmed cell death protein 1 (PD-1; PDCD1), 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.

引用

页码：1001 / +

页数：79

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