Clinical trial NCT03198546: GPC3-CAR-T Cells for Immunotherapy of Cancer With GPC3 Expression
Official title: CAR-T Cell Targeting GPC3 for Immunotherapy of Hepatocellular Carcinoma: Phase I Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Immunotherapy
CAR
GPC3 Gene Inactivation
T Cell
Squamous Cell Lung Cancer
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
Lead sponsor: Second Affiliated Hospital of Guangzhou Medical University
Sponsor class: OTHER
Collaborators: name: Hunan Zhaotai Yongren Medical Innovation Co. Ltd.
name: Guangdong Zhaotai InVivo Biomedicine Co. Ltd.
name: First Affiliated Hospital, Sun Yat-Sen University
First posted: 2017-06-26
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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. -

Primary outcomes:
measure: Number of Patients with Dose Limiting Toxicity
timeFrame: three months
Secondary outcomes:
measure: Percent of Patients with best response as either complete remission or partial remission.
timeFrame: three months
measure: Median CAR-T cell persistence
timeFrame: Five years
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Sun Yat-sen University
state: Guangdong
city: Guangzhou
country: China
facility: The Second Affiliated Hospital of Guangzhou Medical University
state: Guangdong
Study officials:
affiliation: Second Affiliated Hospital of Guangzhou Medical University
name: Zhenfeng Zhang, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jiang Z, Jiang X, Chen S, Lai Y, Wei X, Li B, Lin S, Wang S, Wu Q, Liang Q, Liu Q, Peng M, Yu F, Weng J, Du X, Pei D, Liu P, Yao Y, Xue P, Li P. Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma. Front Immunol. 2017 Jan 11;7:690. doi: 10.3389/fimmu.2016.00690. eCollection 2016.
citation: Pang N, Shi J, Qin L, Chen A, Tang Y, Yang H, Huang Y, Wu Q, Li X, He B, Li T, Liang B, Zhang J, Cao B, Liu M, Feng Y, Ye X, Chen X, Wang L, Tian Y, Li H, Li J, Hu H, He J, Hu Y, Zhi C, Tang Z, Gong Y, Xu F, Xu L, Fan W, Zhao M, Chen D, Lian H, Yang L, Li P, Zhang Z. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol. 2021 Jul 29;14(1):118. doi: 10.1186/s13045-021-01128-9.