Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CART-Cell Therapy for Liver Cancer

被引:194
作者
Liu, Hong [1 ]
Xu, Yiyang [1 ]
Xiang, Jingyi [1 ]
Long, Li [1 ]
Green, Shon [1 ]
Yang, Zhiyuan [1 ]
Zimdahl, Bryan [1 ]
Lu, Jingwei [1 ]
Cheng, Neal [1 ]
Horan, Lucas H. [1 ]
Liu, Bin [1 ]
Yan, Su [1 ]
Wang, Pei [1 ]
Diaz, Juan [1 ]
Jin, Lu [1 ]
Nakano, Yoko [1 ]
Morales, Javier F. [1 ]
Zhang, Pengbo [1 ]
Liu, Lian-xing [1 ]
Staley, Binnaz K. [1 ]
Priceman, Saul J. [2 ,3 ,4 ]
Brown, Christine E. [2 ,3 ,4 ]
Forman, Stephen J. [2 ,3 ,4 ]
Chan, Vivien W. [1 ]
Liu, Cheng [1 ]
机构
[1] Eureka Therapeut Inc, 5858 Horton St,Suite 362, Emeryville, CA 94608 USA
[2] City Hope Natl Med Ctr, Beckman Res Inst, Dept Immunooncol & Hematol, Duarte, CA 91010 USA
[3] City Hope Natl Med Ctr, Beckman Res Inst, Hematopoiet Cell Transplantat, Duarte, CA 91010 USA
[4] City Hope Natl Med Ctr, Beckman Res Inst, Dept Hematol & Hematopoiet Cell Transplant, Duarte, CA 91010 USA
关键词
ENGINEERED T-CELLS; DENDRITIC CELLS; PHASE-I/II; IMMUNOTHERAPY; IMMUNIZATION; RESPONSES; CHEMOTHERAPY; METASTASES; BINDING;
D O I
10.1158/1078-0432.CCR-16-1203
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T-cell therapy against solid tumors. Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP(158-166) peptide complexed with human leukocyte antigen (HLA)-A*02: 01. Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01(+)/AFP(+) while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP(158)-expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6). Conclusions: This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. (C) 2016 AACR.
引用
收藏
页码:478 / 488
页数:11
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