CAR-T Cell Immunotherapy for HCC Targeting GPC3

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to preliminarily evaluate the safety and efficacy of CAR-T cell immunotherapy for GPC3 positive hepatocellular carcinoma.

Detailed Description
-----------------
Chimeric antigen receptor (CAR) is a recombinant receptor with both antigen-binding and T cell activating functions. Chimeric antigen receptor T cell Immunotherapy has more advantages compared with conventional immunotherapy, especially in dealing with patients of hematologic malignancies and solid malignant tumors.This study design a novel specific Chimeric antigen receptor targeting glypican-3(GPC3) antigen.After CAR-T cell infusion,At periodic intervals, the investigators will evaluate clinical symptoms Improved conditions of this disease.Through this study,the investigators will evaluate the safety and efficacy of CAR-T cell immunotherapy in treating with GPC3 positive malignant glioma patients.

Official Title
-----------------
Chimeric Antigen Receptor-Modified T Cell (CAR-T) Immunotherapy for Hepatocellular Carcinoma (HCC) Targeting Glypican-3 (GPC3)

Conditions
-----------------
GPC3 Positive Hepatocellular Carcinoma, CAR-T Cell Immunotherapy

Intervention / Treatment
-----------------
* Biological: CAR-T cell immunotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age:18-70 years. Gender:both. GPC3 high expression hepatocellular carcinoma patients. Non diffuse hepatocellular carcinoma，no extrahepatic metastasis or portal vein vascular invasion. Degree of liver cirrhosis：class A or class B 7 according to Child-puge grading standard. Routine blood test：white blood cell count（WBC)>=3×10^9/L, Lymphocyte percentage>=15%, hemoglobinHbo（Hb）>=90g/L, prothrombin time（PT） prolongation<=50% normal value, Cluster of differentiation 3(CD3) positive T cell count>=0.8×10^9/L. Liver and Pancreatic function：Alanine aminotransferase/Aspartate transaminase(ALT/AST)<=5 times of the normal value, total bilirubin(TBiL)<=3.0mg/dL, albumin(ALB)>=35g/L, prothrombin time(PT):International Normalized Ratio(INR)<=1.7 or prothrombin time(PT) prolongation<=4s, Serum lipase<=1.5 times of the normal value, Serum amylase<=1.5 times of the normal value. Renal function：Serum creatinine(SCr)<=221μmol/L(2.5mg/L). Karnofsky Performance Status(KPS)>=60；Expected survival time>=12 weeks. Peripheral venous access ；no contraindication of lymphocyte separation. No other serious complications. Voluntarily signed informed consent. Exclusion Criteria: Pregnant and lactating women. Lymphocyte separation or peripheral venous access cannot be performed in patients . Patients in the active stage of infection or with coagulation disorders. Patients with a previous history of hepatic coma. Patients with severe gastrointestinal ulcers or gastrointestinal bleeding. Patients with organ transplantation or waiting for organ transplantation. Patients with anticoagulant therapy. Patients with antiplatelet therapy. Serum sodium(Na)<125 mmol/L. Serum potassium(K)<3.5 mmol/L(except patients up to the standards after the use of supplements). Patients with organ failure： cardiac function：level three or above according to New York Heart Association (NYHA) criteria. liver function:class C or above according to Child-puge grading standard. renal function:Chronic kidney disease(CKD) phase 4 or more; renal insufficiency phase Ⅲ or more. pulmonary function：severe respiratory failure symptoms, involving other organs. Brain function:central nervous system abnormalities or disturbance of consciousness. Patients with non controlled infectious diseases,for example,HIV positive, syphilis, hepatitis A, hepatitis B, hepatitis C, hepatitis E virus (HEV) positive etc. Patients used corticosteroids or other immunosuppressive agents in the past 4 weeks. Patients with autoimmune disease. Patients with previous history of gene therapy. The actual transfection rate of T cells was lower than 30% or the proliferation was less than 5 times after costimulation. Patients participated in other drug trials in the past 4 weeks. Patients received radiation treatment in the past 4 weeks. Patients do not meet the criteria above.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR-T cell immunotherapy<br>Enrolled patients will receive CAR-T cell immunotherapy with a novel specific Chimeric antigen receptor aiming at GPC3 antigen by infusion. | Biological: CAR-T cell immunotherapy<br>* This CAR-T cell immunotherapy with a novel specific Chimeric antigen receptor aiming at GPC3 antigen.<br>|
| No Intervention: no intervention<br>no intervention | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological assessment | Radiological assessment of the therapeutic effect by systemic or local computed Tomography(CT) or positron emission tomography scan. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of CAR-T cell immunotherapy (adverse events) | After CAR-T cell infusion,we will observe the potential adverse events related to the T-cell infusion such as high fever,jaundice, kidney failure and so on. | 4 weeks | 
| Peripheral blood tumor markers | tested regularly to reflect the role of the Chimeric Antigen Receptor-Modified T Cell in the removal of residual tumor cells. | 3 months | 
| CAR-T cell testing | The level of CAR-T cells will be tested regularly by Real-time Quantitative Polymerase Chain Reaction Detecting System(qPCR) or Flow cytometry to evaluate the proliferation in vivo and long-term survival. | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
glypican-3(GPC3), chimeric antigen receptor-modified T cell(CAR-T), hepatocellular carcinoma(HCC)