Met-Targeting Chimeric Antigen Receptor (MetCAR) T-Cell Therapy in Hepatocellular Carcinoma
Abstract
Our project addresses two fiscal year 2018 Peer Reviewed Cancer Research Program Topic Areas: (1) Liver Cancer and (2) Immunotherapy. Hepatocellular carcinoma (HCC) is the most malignant type of liver cancer without effective treatments. Pathologically, hepatitis B or C virus (HBV/HCV) infection induces hepatitis, which triggers the activation of hepatocyte growth factor (HGF) as a repair mechanism, functioning through its receptor Met. However, the rapid growth of hepatocytes in turn facilitates viral replication. The repetitive cycle of liver injury and repair ultimately leads to HGF/MET pathway alteration, which is a major cause of HCC. Because Met expression correlates with a short survival in HCC patients, targeting Met is becoming a promising strategy for treating malignant HCC. While Met inhibitors are entering clinical trials showing promising results, the long term efficacy and toxicity remain elusive. Novel strategies to improve Met-targeting therapeutics are needed soon. The objective of this application is to develop Met-targeting immunotherapy for treating malignant HCC. Given the recent breakthrough in cancer immunotherapy, genetically modifying T cells with chimeric antigen receptors (CAR T cell) is becoming a practical approach for treating cancer. While CAR-T cell therapy targeting leukemia and glioblastoma have shown encouraging clinical results; however, T cell therapy for targeting Met in advanced HCC has not been established to date. Recently, we have developed an approach for generating Met-targeting CAR T cells, providing a strong rationale to evaluate their therapeutic efficacy using preclinical HCC models. We also will study the mechanisms regulating the MetCAR-T cells activity, which is essential for improving the antitumor efficacy in future. Our project is designed for the Focus Area to fill in the gap of developing novel therapeutic reagents for treating advanced HCC. By the end of the funding period, we expect that MetCAR-T cells may specifically and potently inhibit Met-positive HCC in preclinical models. For the long-term, we expect the outcomes of this study may guide human clinical trials and benefit Veterans healthcare. In this regard, Veterans diagnosed with advanced HCC with Met overexpression will be enrolled into the trial for MetCAR-T cell therapy. We anticipate that MetCAR-T cell therapy will effectively suppress HCC growth in these Veteran patients, providing prolonged survival benefit. U.S. Veterans have a higher rate of HCC due to the higher rates of HBV/HCV infection. Both active duty Service members and the Veterans exposed to HBV/HCV infection will benefit from our study. If successful, our study may change clinical outcome by offering a new T cell-based immunotherapy for treating advanced liver cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910811
Entities
People
- Qian Xie
Organizations
- East Tennessee State University
- United States Army