Back to Search
Start Over
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. 23(2)
- Publication Year :
- 2016
-
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. Experimental Design: 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. 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 AFP158-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. Clin Cancer Res; 23(2); 478–88. ©2016 AACR.
- Subjects :
- Cancer Research
medicine.medical_treatment
Receptors, Antigen, T-Cell
Human leukocyte antigen
Major histocompatibility complex
03 medical and health sciences
Mice
0302 clinical medicine
Antigen
Antigens, Neoplasm
HLA-A2 Antigen
medicine
Animals
Humans
Molecular Targeted Therapy
Antigen Presentation
biology
Liver Neoplasms
Cancer
Immunotherapy
Hep G2 Cells
medicine.disease
Xenograft Model Antitumor Assays
Chimeric antigen receptor
Hep G2
Oncology
030220 oncology & carcinogenesis
Immunology
Cancer research
biology.protein
alpha-Fetoproteins
Liver cancer
030215 immunology
T-Lymphocytes, Cytotoxic
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 23
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....c444ad4eb6d9a748f1de84ce55cb8576