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Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Jan 15; Vol. 23 (2), pp. 478-488. Date of Electronic Publication: 2016 Aug 17. - Publication Year :
- 2017
-
Abstract
- 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.<br />Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP <subscript>158-166</subscript> peptide complexed with human leukocyte antigen (HLA)-A*02:01.<br />Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01 <superscript>+</superscript> /AFP <superscript>+</superscript> 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 <subscript>158</subscript> -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).<br />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. Clin Cancer Res; 23(2); 478-88. ©2016 AACR.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Antigen Presentation immunology
Antigens, Neoplasm immunology
HLA-A2 Antigen genetics
HLA-A2 Antigen immunology
Hep G2 Cells
Humans
Liver Neoplasms immunology
Liver Neoplasms pathology
Mice
Molecular Targeted Therapy
Receptors, Antigen, T-Cell genetics
T-Lymphocytes, Cytotoxic drug effects
Xenograft Model Antitumor Assays
alpha-Fetoproteins antagonists & inhibitors
alpha-Fetoproteins genetics
Immunotherapy
Liver Neoplasms therapy
Receptors, Antigen, T-Cell immunology
alpha-Fetoproteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 23
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 27535982
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-16-1203