Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CART-Cell Therapy for Liver Cancer
Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CART-Cell Therapy for Liver Cancer
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DOI：
10.1158/1078-0432.ccr-16-1203
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发表时间：
2017-01-01
影响因子：
11.5
通讯作者：
Liu, Cheng
中科院分区：
文献类型：
--
作者：
Liu, Hong;Xu, Yiyang;Liu, Cheng
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.
