Overview
The third/fourth generation of CAR-T cells that target GPC3 (GPC3-CART cell) and/or soluble TGFβ (GPC3/TGFβ-CART )have been constructed and their anti-HCC function has been verified by multiple in vitro and in vivo studies. Clinical studies will be performed to test the anti-cancer function by the GPC3/TGFβ-CAR-T cells in human HCC patients with GPC3 expression. In this phase I study, the safety, tolerance, and preliminary efficacy of the GPC3/TGFβ-CAR-T cell immunotherapy on human will firstly be tested.
Description
- Choose appropriate patients with advanced hepatocellular carcinoma,with written consent for this study;
- Perform biopsy to determine the expression of GPC3 of the tumor by western blotting or IHC;
- Collect blood from the patients and isolate mononuclear cells, activate the T cells and transfect the T cells with GPC3/TGFβ targeting CAR (or/and scfv/cytokines-secreting), amplify the number of transfected T cells as needed, test the quality and killing activity of the GPC3/TGFβ-CART cells and then transplant back the patients via systemic or local infusions (via artery or intra-tumor), and follow up closely to collect related results as needed;
- To enhance the killing capability, CD4+ T cells are genetically engineered to express TGFβ-CAR and secret IL7/CCL19 and/or SCFVs against PD1/CTLA4/Tigit; CD8+T cells are constructed to express GPC3-DAP10-CAR with knockdown of PD1/HPK1;
- Evaluate the clinical results as needed.
- Will also perform the similar clinical trial on lung squamous carcinoma with the GPC3 expression.
Eligibility
Inclusion Criteria:
- patients with advanced HCC,which express GPC3 protein.
- Life expectancy >12 weeks
- Child-Pugh-Turcotte score <7
- Adequate heart,lung,liver,kidney function
- Available autologous transduced T cells with greater than or equal to 20% expression of GPC3 CAR determined by flow-cytometry and killing of GPC3-positive targets greater than or equal to 20% in cytotoxicity assay
- Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent. -
Exclusion Criteria:
- Had accepted gene therapy before;
- Tumor size more than 25cm;
- Severe virus infection such as HBV,HCV,HIV,et al
- Known HIV positivity
- History of liver transplantation
- Active infectious disease related to bacteria, virus,fungi,et al
- Other severe diseases that the investigators consider not appropriate;
- Pregnant or lactating women
- Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day)
- Other conditions that the investigators consider not appropriate. -