Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia

被引：476

作者：

Orlando, Elena J. ^{[1
]}

Han, Xia ^{[2
]}

Tribouley, Catherine ^{[2
]}

Wood, Patricia A. ^{[2
]}

Leary, Rebecca J. ^{[1
]}

Riester, Markus ^{[1
]}

Levine, John E. ^{[3
]}

Qayed, Muna ^{[4
]}

Grupp, Stephan A. ^{[5
]}

Boyer, Michael ^{[6
]}

De Moerloose, Barbara ^{[7
]}

Nemecek, Eneida R. ^{[8
]}

Bittencourt, Henrique ^{[9
]}

Hiramatsu, Hidefumi ^{[10
]}

Buechner, Jochen ^{[11
]}

Davies, Stella M. ^{[12
]}

Verneris, Michael R. ^{[13
]}

Nguyen, Kevin ^{[14
]}

Brogdon, Jennifer L. ^{[1
]}

Bitter, Hans ^{[1
]}

Morrissey, Michael ^{[1
]}

Pierog, Piotr ^{[2
]}

Pantano, Serafino ^{[15
]}

Engelman, Jeffrey A. ^{[1
]}

Winckler, Wendy ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

[2] Novartis Pharmaceut, E Hanover, NJ USA

[3] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

[4] Emory Univ, Aflac Canc & Blood Disorders Ctr, Atlanta, GA 30322 USA

[5] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[6] Univ Utah, Salt Lake City, UT USA

[7] Ghent Univ Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Ghent, Belgium

[8] Oregon Hlth & Sci Univ, Portland, OR 97201 USA

[9] St Justine Univ, Hlth Ctr, Montreal, PQ, Canada

[10] Kyoto Univ, Dept Pediat, Kyoto, Japan

[11] Oslo Univ Hosp, Dept Pediat Hematol & Oncol, Oslo, Norway

[12] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA

[13] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA

[14] Navigate BioPharma Serv Inc, Carlsbad, CA USA

[15] Novartis Pharma AG, Basel, Switzerland

来源：

NATURE MEDICINE | 2018年 / 24卷 / 10期

关键词：

DNA-SEQUENCING DATA; T-CELL THERAPY; MUTATIONS; FRAMEWORK; ESCAPE;

D O I：

10.1038/s41591-018-0146-z

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19(-) relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.

引用

页码：1504 / +

页数：5

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