Mesothelin/GPC3/GUCY2C-CAR-T Cells Against Cancers

Study Overview
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Brief Summary
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The second generation of mesothelin targeted CAR-T cells that secret a fusion protein of IL21 and scfv against PD1 have been constructed and their anti-cancer function has been verified by multiple in vitro and in vivo studies. Clinical studies will be performed to test anti-cancer function of the CAR-T cells for immunotherapy of human cancer patients with Mesothelin expressions. In this phase I study, the safety, tolerance, and preliminary efficacy of the Mesothelin-CAR-T cell immunotherapy on human cancers will firstly be evaluated.

Detailed Description
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Choose appropriate patients with advanced pancreatic cancer or other cancers, with written consent for this study; Perform biopsy to determine the expression of Mesothelin of the tumors by western blotting or IHC; Collect blood from the patients and isolate mononuclear cells, activate the T cells and transfect the T cells with Mesothelin targeting CAR, amplify the transfected T cells as needed, test the quality and killing activity of the CAR-T cells and then transfer them back the patients via systemic or local injections, and follow up closely to collect related results as required; To enhance the killing capability, cotreatment the patients with PD1/PDL1/CTLA4 antibodies may be applied; Evaluate the clinical results as needed.

Official Title
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Mesothelin/GPC3/GUCY2C Targeted CAR-T for Immunotherapy of Pancreatic Cancer: Phase I Clinical Trial

Conditions
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Pancreas Cancer, CAR-T Cell Therapy, Mesothelin, Solid Tumor, Adult

Intervention / Treatment
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* Biological: CAR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Patients with advanced cancer that expresses Mesothelin protein; 2. Life expectancy >12 weeks; 3. Adequate heart, lung, liver, kidney, and blood function; 4. Available autologous transduced T cells with greater than or equal to 20% expression of Mesothelin-CAR determined by flow-cytometry and killing of Mesothelin-positive targets greater than or equal to 20% in cytotoxicity assay; 5. 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; Severe virus infection such as HBV, HCV, HIV, et al; Known HIV positivity; 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. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Use engineered CAR-T cells to kill cancer cells with mesothelin overexpression.
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: CAR-T cells|Transfer CAR-T cells into patients for anti-ancer therapy.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Dose Limiting Toxicity | A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the Mesothelin-CAR T cells, which is irreversible, or life threatening or hematologic or non-hematologic Grade 3-5. | six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients with best response as either complete remission or partial remission. | 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. | six months | 
| Median CAR-T cell persistence | Median CAR-T cell persistence will be measured by quantitative rt-PCR. | Six years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreas Cancer, CAR-T, Mesothelin, Solid Tumor