Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma

• Published in: The Journal of immunology (1950) 2019-07, Vol.203 (1), p.198-207
• Main Authors: Liu, Ying, Di, Shengmeng, Shi, Bizhi, Zhang, Honghong, Wang, Yi, Wu, Xiuqi, Luo, Hong, Wang, Huamao, Li, Zonghai, Jiang, Hua
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - therapy; Glypicans - genetics; Glypicans - immunology; Glypicans - metabolism; HEK293 Cells; Humans; Immunotherapy, Adoptive - methods; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-12 - metabolism; Liver Neoplasms - immunology; Liver Neoplasms - therapy; Lymphocytes, Tumor-Infiltrating - physiology; Lymphocytes, Tumor-Infiltrating - transplantation; Mice; Mice, Inbred C57BL; Protein Engineering; Receptors, Antigen, T-Cell, alpha-beta - genetics; T-Cell Antigen Receptor Specificity - genetics; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1800033

Adoptive immunotherapy based on chimeric antigen receptor-modified T (CAR-T) cells has been demonstrated as one of the most promising therapeutic strategies in the treatment of malignancies. However, CAR-T cell therapy has shown limited efficacy for the treatment of solid tumors. This is, in part, because of tumor heterogeneity and a hostile tumor microenvironment, which could suppress adoptively transferred T cell activity. In this study, we, respectively, engineered human- or murine-derived-armored glypican-3 (GPC3)-specific CAR-T cells capable of inducibly expressing IL-12 (GPC3-28Z-NFAT-IL-12) T cells. The results showed that GPC3-28Z-NFAT-IL-12 T cells could lyse GPC3 tumor cells specifically and increase cytokine secretion compared with GPC3-28Z T cells in vitro. In vivo, GPC3-28Z-NFAT-IL-12 T cells augmented the antitumor effect when encountering GPC3 large tumor burdens, which could be attributed to IL-12 increasing IFN-γ production, favoring T cells infiltration and persistence. Furthermore, in immunocompetent hosts, low doses of GPC3-m28Z-mNFAT-mIL-12 T cells exerted superior antitumor efficacy without prior conditioning in comparison with GPC3-m28Z T cells. Also, mIL-12 secretion decreased regulatory T cell infiltration in established tumors. In conclusion, these findings demonstrated that the inducible expression of IL-12 could boost CAR-T function with less potential side effects, both in immunodeficient and immunocompetent hosts. The inducibly expressed IL-12-armored GPC3-CAR-T cells could broaden the application of CAR-T-based immunotherapy to patients intolerant of lymphodepletion chemotherapy and might provide an alternative therapeutic strategy for patients with GPC3 cancers.