GPC3-CAR-T Cells for Immunotherapy of Cancer With GPC3 Expression

Sponsor

Second Affiliated Hospital of Guangzhou Medical University (Other)

Overall Status

Recruiting

CT.gov ID

NCT03198546

Collaborator

Hunan Zhaotai Yongren Medical Innovation Co. Ltd. (Other), Guangdong Zhaotai InVivo Biomedicine Co. Ltd. (Other), First Affiliated Hospital, Sun Yat-Sen University (Other)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma Immunotherapy CAR GPC3 Gene Inactivation T Cell Squamous Cell Lung Cancer	Biological: GPC3 and/or TGFβ targeting CAR-T cells	Phase 1

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

CAR-T Cell Targeting GPC3 for Immunotherapy of Hepatocellular Carcinoma: Phase I Clinical Trial

Actual Study Start Date :

Jul 1, 2017

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

Aug 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: CAR-T cell therapy group Appropriate patients who could benefit from the GPC3 and TGFβ targeting CAR-T cell therapy against HCC are chosen to be the CAR-T cell therapy group.	Biological: GPC3 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.

Arm

Intervention/Treatment

Other: CAR-T cell therapy group

Appropriate patients who could benefit from the GPC3 and TGFβ targeting CAR-T cell therapy against HCC are chosen to be the CAR-T cell therapy group.

Biological: GPC3 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.

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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. -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The First Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong	China	510072
2	The Second Affiliated Hospital of Guangzhou Medical University	Guangzhou	Guangdong	China	510260