CAR, GPC3 Gene Inactivation, Hepatocellular Carcinoma, Immunotherapy, Squamous Cell Lung Cancer, T Cell
Conditions
Keywords
Hepatocellular carcinoma, immunotherapy, CAR-T cell therapy, GPC3 or TGFβ targeting, Phase I clinical study, squamous cell lung cancer, interventional radiology, IL7-CCL19-secreting, SCFV against PD1/CTLA4/Tigit, knockdown of PD1/HPK1, DAP10
Brief summary
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.
Detailed description
1. Choose appropriate patients with advanced hepatocellular carcinoma,with written consent for this study; 2. Perform biopsy to determine the expression of GPC3 of the tumor by western blotting or IHC; 3. 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; 4. 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; 5. Evaluate the clinical results as needed. 6. Will also perform the similar clinical trial on lung squamous carcinoma with the GPC3 expression.
Interventions
BIOLOGICALGPC3 and/or TGFβ targeting CAR-T cells
Engineering GPC3 or/and TGFβ targeting CAR combined with/or without IL7/CCL19 and/or scfv against PD1/CTLA4/Tigit secreting vector into T cells with knockdown of PD1/HPK1, which are isolated from patients with advanced HCC, and then transfusing them back the patients.
Sponsors
Hunan Zhaotai Yongren Medical Innovation Co. Ltd.
Guangdong Zhaotai InVivo Biomedicine Co. Ltd.
First Affiliated Hospital, Sun Yat-Sen University
Second Affiliated Hospital of Guangzhou Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. patients with advanced HCC,which express GPC3 protein. 2. Life expectancy \>12 weeks 3. Child-Pugh-Turcotte score \<7 4. Adequate heart,lung,liver,kidney function 5. 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 6. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent. -
Exclusion criteria
1. Had accepted gene therapy before; 2. Tumor size more than 25cm; 3. Severe virus infection such as HBV,HCV,HIV,et al 4. Known HIV positivity 5. History of liver transplantation 6. Active infectious disease related to bacteria, virus,fungi,et al 7. Other severe diseases that the investigators consider not appropriate; 8. Pregnant or lactating women 9. Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day) 10. Other conditions that the investigators consider not appropriate. -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients with Dose Limiting Toxicity | three months | A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the GPC3-T2-CAR T cells, which is irreversible, or life threatening or hematologic or non-hematologic Grade 3-5. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Patients with best response as either complete remission or partial remission. | three months | Response rates will be estimated as the percent of patients whose best response is either complete remission or partial remission by combining the data from the patients. To compare with historical data, a 95% confidence interval will be calculated for the response rate. |
| Median CAR-T cell persistence | Five years | Median CAR-T cell persistence will be measured by quantitative rt-PCR. |
Countries
China
Contacts
Primary ContactZhenfeng Zhang, MD,PhD
Backup ContactPeng Li, PhD
Outcome results
None listed