Brief Summary:

This is a study in which pancreatic cancer patients receive a immunotherapy with CART-meso cells administered at 3 days after one dose of cyclophosphamide. CART-meso cells are patients' own T cells lentivirally transduced to express anti-mesothelin scFv fused to TCRζ and 4-1BB costimulatory domains.The lymphodepletion with cyclophosphamide may prolong the persistence of CART cells.

Pancreatic Cancer

​

​

Biological: CART-meso cells

Detailed Description:

This study is being conducted to assess the safety and efficacy of immunotherapy with CART-meso cells in dose escalation design. The trial will begin in Cohort 1 and progress to Cohorts 2, depending upon dose limiting toxicity (DLT) assessment .

Subjects will be enrolled serially, but infusions will be staggered to allow assessment of DLTs for determination of cohort progression, expansion, or dose de-escalation.

Cohort 1 subjects will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced CART-meso cells after conditioning chemotherapeutic regimen.

Cohort 2 subjects will receive a single dose of 1-3x10^8 /m^2 lentiviral transduced CART-meso cells cells after conditioning chemotherapeutic regimen.

Dose limiting toxicity is defined as any adverse reactions at level 3 or above that may be associated with CART-meso within 4 weeks after infusion.

Arms and Interventions

Arm

Experimental: CART-meso cells

A single dose of CART-meso T cells will be administered intravenously.The dose is 1-3×10^7/m^2 CART positive cells(chort 1)or 1-3×10^8/m^2 CARTpositive cells(chort 2).

Intervention

Biological: CART-meso cells

CART-meso is a 2nd CAR, with mesothelin as target protein, 4-1BB as co- stimulator. The infusion will be scheduled to occur 3 (±1) days after a single dose of 1.5 grams/m^2 of cyclophosphamide, which will be administered according to standard procedures, Thereby enhancing the efficacy of anti-tumor, reducing the potential of side effects.

Primary Outcome Measures  :

1. Safety of CART-meso infusion: number of adverse events [ Time Frame: 60 months ]

Number of Adverse Events evaluated with NCI CTC AE, version 4.0[Safety evaluation]

Secondary Outcome Measures  :

1. Clinical response of CART-meso [ Time Frame: 60 months ]

Number of patients with tumor response including overal remission ,complete ression,progression-free survival，progressive disease ,etc.

2. CAR-T cell detection [ Time Frame: 60 months ]

Detection of transferred T cells in peripheral blood or bone marrow using multi-parameter flow cytometer.

Criteria

Inclusion Criteria:

·       Signed informed consent

·       Unresectable or metastatic pancreatic cancer

·       Persistent cancer after at least one prior standard of care chemotherapy for advanced stage disease

·       18 - 70 years of age

·       ECOG performance status of 0 or 1

·       Life expectancy greater than 3 months

·       Satisfactory organ and bone marrow function

·       Meets blood coagulation parameters

·       Male and Female subjects of reproductive potential agree to use approved contraceptive methods

Exclusion Criteria:

·       Participation in a therapeutic investigational study within 4 weeks prior to the screening visit

·       Anticipated need for systemic chemotherapy within 2 weeks before apheresis and infusion

·       Active invasive cancer other than pancreatic cancer

·       HIV, HCV, or HBV infections

·       Active autoimmune disease requiring immunosuppressive therapy within 4 weeks prior to screening visit, with exception of thyroid replacement

·       Ongoing or active infection

·       Planned concurrent treatment with systemic high dose corticosteroids

·       Patients requiring supplemental oxygen therapy

·       Prior therapy with gene modified cells

·       Previous experimental therapy with SS1 moiety, murine or chimeric antibodies

·       History of allergy to murine proteins

·       History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)

·       Clinically significant pericardial effusion, CHF, or cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study

·       Pregnant or breastfeeding women