Title |
Targeting Alpha-Fetoprotein (AFP)–MHC Complex with CAR T-Cell Therapy for Liver Cancer
|
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Published in |
Clinical Cancer Research, January 2017
|
DOI | 10.1158/1078-0432.ccr-16-1203 |
Pubmed ID | |
Authors |
Hong Liu, Yiyang Xu, Jingyi Xiang, Li Long, Shon Green, Zhiyuan Yang, Bryan Zimdahl, Jingwei Lu, Neal Cheng, Lucas H. Horan, Bin Liu, Su Yan, Pei Wang, Juan Diaz, Lu Jin, Yoko Nakano, Javier F. Morales, Pengbo Zhang, Lian-xing Liu, Binnaz K. Staley, Saul J. Priceman, Christine E. Brown, Stephen J. Forman, Vivien W. Chan, Cheng Liu |
Abstract |
The majority of tumor-specific antigens are intracellular and/or secreted and therefore previously 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 major histocompatibility complexes (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. We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158-166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. 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-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 anti-tumor activity (n=6). This study demonstrates that CAR T cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent anti-tumor 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 12 | 25% |
United Kingdom | 2 | 4% |
Spain | 2 | 4% |
Mexico | 1 | 2% |
Chile | 1 | 2% |
Germany | 1 | 2% |
Russia | 1 | 2% |
South Africa | 1 | 2% |
China | 1 | 2% |
Other | 4 | 8% |
Unknown | 22 | 46% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 40 | 83% |
Scientists | 4 | 8% |
Science communicators (journalists, bloggers, editors) | 2 | 4% |
Practitioners (doctors, other healthcare professionals) | 2 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 139 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 29 | 21% |
Researcher | 18 | 13% |
Other | 16 | 12% |
Student > Master | 13 | 9% |
Student > Bachelor | 13 | 9% |
Other | 14 | 10% |
Unknown | 36 | 26% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 26 | 19% |
Medicine and Dentistry | 21 | 15% |
Immunology and Microbiology | 20 | 14% |
Agricultural and Biological Sciences | 18 | 13% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 4% |
Other | 13 | 9% |
Unknown | 35 | 25% |