CAR T therapy against AFP for the treatment of liver cancer

Purpose: 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. 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 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). Conclusions: 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.

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