RRC ID 57812
Author Liu Y, Di S, Shi B, Zhang H, Wang Y, Wu X, Luo H, Wang H, Li Z, Jiang H.
Title Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma.
Journal J Immunol
Abstract 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.
Volume 203(1)
Pages 198-207
Published 2019-7-1
DOI 10.4049/jimmunol.1800033
PII jimmunol.1800033
PMID 31142602
MeSH 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
IF 4.718
Times Cited 12
Human and Animal Cells HuH-7