CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies

被引：76

作者：

Qin, Hong ^{[1
]}

Dong, Zhenyuan ^{[1
]}

Wang, Xiuli ^{[2
]}

Cheng, Wesley A. ^{[1
,4
]}

Wen, Feng ^{[1
,3
]}

Xue, Weili ^{[1
]}

Sun, Han ^{[1
]}

Walter, Miriam ^{[2
]}

Wei, Guowei ^{[1
]}

Smith, D. Lynne ^{[1
]}

Sun, Xiuhua ^{[5
]}

Fei, Fan ^{[6
]}

Xie, Jianming ^{[6
]}

Panagopoulou, Theano I. ^{[7
]}

Chen, Chun-Wei ^{[7
]}

Song, Joo Y. ^{[8
]}

Aldoss, Ibrahim ^{[9
]}

Kayembe, Clarisse ^{[10
]}

Sarno, Luisa ^{[10
]}

Muschen, Markus ^{[7
]}

Inghirami, Giorgio G. ^{[10
]}

Forman, Stephen J. ^{[2
]}

Kwak, Larry W. ^{[1
]}

机构：

[1] City Hope Natl Med Ctr, Beckman Res Inst, Toni Stephenson Lymphoma Ctr, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA 91010 USA

[2] City Hope Natl Med Ctr, Beckman Res Inst, Ctr CAR T Cell Therapy, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA 91010 USA

[3] Sichuan Univ, West China Hosp, Canc Ctr, Dept Med Oncol, Chengdu 910041, Sichuan, Peoples R China

[4] Zhengzhou Univ, Affiliated Hosp 1, Zhengzhou 450001, Henan, Peoples R China

[5] Dalian Med Univ, Affiliated Hosp 2, Dalian 116044, Peoples R China

[6] Univ Southern Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90007 USA

[7] City Hope Natl Med Ctr, Beckman Res Inst, Dept Syst Biol, Duarte, CA 91010 USA

[8] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA

[9] City Hope Natl Med Ctr, Beckman Res Inst, Gehr Family Ctr Leukemia Res, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA 91010 USA

[10] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2019年 / 11卷 / 511期

关键词：

NON-HODGKIN-LYMPHOMA; ACTIVATING FACTOR; MONOCLONAL-ANTIBODY; RECEPTOR; EXPRESSION; RESISTANT; LEUKEMIA; THERAPY; NAIVE; BR3;

D O I：

10.1126/scitranslmed.aaw9414

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell-specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient-derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants.

引用

页数：11

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