Related Experiment Video
Updated: Mar 16, 2026
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer
Hong Liu1, Yiyang Xu1, Jingyi Xiang1
1Eureka Therapeutics Inc., Emeryville, California.
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.
Insights
Chimeric antigen receptor (CAR) T-cell therapy can target intracellular liver cancer antigens. This study shows AFP-CAR T cells effectively eliminate tumors expressing the alpha-fetoprotein (AFP) peptide-MHC complex.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Most tumor antigens are intracellular or secreted, limiting conventional CAR T-cell therapy.
- Peptide-MHC complexes on tumor surfaces present intracellular antigens for potential targeting.
Purpose of the Study:
- To investigate if peptide-MHC complexes can be targeted by CAR T-cell therapy.
- To evaluate alpha-fetoprotein (AFP) as a target for liver cancer immunotherapy.
Main Methods:
- Generated a chimeric antigen receptor (AFP-CAR) targeting the AFP peptide-MHC complex (AFP158-166/HLA-A*02:01).
- Tested AFP-CAR T-cell activity against liver cancer cells in vitro and in vivo models.
Main Results:
- AFP-CAR T cells selectively killed HLA-A*02:01+/AFP+ liver cancer cells.
- Demonstrated significant tumor regression and growth inhibition in mouse models (Hep G2, SK-HEP-1).
- Confirmed robust antitumor activity in an established liver cancer xenograft model.
Conclusions:
- CAR T-cell immunotherapy targeting intracellular/secreted tumor antigens is effective.
- This approach broadens targets for solid tumor immunotherapy, offering a new strategy for liver cancer treatment.
