Abstract 2299: ET1402L1-CART, a T cell therapy targeting the intracellular tumor antigen AFP, demonstrates potent antitumor activity in hepatocellular carcinoma models

Abstract

Hepatocellular carcinoma (HCC) is the 5th most prevalent and 3rd most lethal cancer worldwide, due to limited treatment options. The lack of tumor-specific membrane targets is one of the key challenges currently facing immunotherapy for solid tumors, where on-target/off-tumor activity can lead to severe adverse responses. Most HCCs overexpress Alpha-Fetoprotein (AFP), a secreted fetal glycoprotein rarely expressed in adult tissues, making AFP an ideal target for immunotherapy. However, since AFP is only expressed intracellularly and secreted, it cannot be targeted with traditional antibodies against cell-surface antigens. To overcome this limitation, we exploited the fact that intracellular antigens, including AFP, are processed into peptides and presented by class I major histocompatibility complexes (MHCs) on the surface of tumor cells. Using an antibody discovery platform optimized for identifying candidates that bind peptide/MHC complexes, we developed ET1402L1, a fully-human scFv specifically targeting an immunogenic AFP peptide complexed with human leukocyte antigen (HLA)-A*02:01. ET1402L1 binds HLA-A*02:01/AFP with exquisite specificity and does not cross-react with naked HLA-A*02:01 molecules or with HLA-A*02:01 complexed with a panel of control peptides from endogenous human proteins. T cells engineered to express a second generation chimeric antigen receptor (CAR) constructed with ET1402L1 responded to HLA-A*02:01/AFP-expressing cells by degranulating and releasing IFN-γ, IL-2, IL-6, IL-8, IL-10, GM-CSF, and TNFα in an antigen-selective manner. In a cell killing assay, ET1402L1-CART selectively lysed HCC cells that expressed both HLA-A*02:01 and AFP, while sparing cells from multiple tissue types that were negative for either. In vivo, ET1402L1-CART demonstrated potent anti-tumor activity in multiple HCC xenograft models. While intravenous administration of ET1402L1-CART significantly inhibited the growth of established subcutaneous (s.c.) Hep G2 tumors (an HCC cell line positive for HLA-A*02:01 and AFP), intratumoral delivery resulted in rapid and prolonged tumor regression with complete regression observed in 75% of animals. These effects were recapitulated in a s.c. tumor model using another liver-derived HLA-A*02:01-positive cell line (SK-HEP-1) engineered to express the AFP peptide. Lastly, intraperitoneal injection of ET1402L1-CART led to regression of tumors in a disseminated abdominal HCC xenograft model. Our data demonstrates that CAR-T cell therapy targeting intracellular antigens via peptide/MHC complexes can effectively eradicate solid tumors in vivo. This approach expands the spectrum of antigens available for redirected T cell therapy against solid malignancies and provides a promising future therapy for HCC. A phase I clinical trial testing ET1402L1-CART in HCC patients is expected to begin in 2016. Citation Format: Hong Liu, Yiyang Xu, Jingyi Xiang, Li Long, Shon Green, Zhiyuan Yang, Jingwei Lu, Neal Cheng, Lucas H. Horan, Bin Liu, Su Yan, Pei Wang, Juan Diaz, Lian-xing Liu, Vivien Chan, Cheng Liu. ET1402L1-CART, a T cell therapy targeting the intracellular tumor antigen AFP, demonstrates potent antitumor activity in hepatocellular carcinoma models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2299.

Insights in Molecular Therapies for Hepatocellular Carcinoma

“…However, CAR-T cells face a physiological challenge in recognizing intracellularly located antigens like AFP. Specialized CAR-T cells have been engineered to address this issue by targeting the AFP-MHC complex, which presents intracellular antigens through MHC class 1 molecules [305]. These modified AFP-MHC CAR-T cells have exhibited promising anti-tumor activity in preclinical studies both in vitro and in vivo [306].…”

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