αPD1-MSLN-CAR T Cells for the Treatment of MSLN-positive Advanced Solid Tumors

Inclusion Criteria:

• Patients must have a histological or cytological diagnosis of advanced solid tumors,such as ovarian cancer，Cholangiocarcinoma，colorectal cancer; -Patients must havefailed established standard medical anti-cancer therapies；
• Greater than or equal to 18 years of age on day of signing informed consent； -Lifeexpectancy >3 months；
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 , 1 or 2;
• Subjects must meet blood coagulation parameters and have adequate venous peripheralaccess for apheresis. Patients must also have adequate mononuclear cells for CAR Tcell manufacturing；
• Staining of MSLN must be greater than 10% of the cells in the tumor tissue and withapparent expression in the membrane. PD-L1 expression must be positive. Tissueobtained for the biopsy must be ≤1 year prior to enrollment for screening, not havebeen previously irradiated or exposed to chemotherapy. If unavailable, new tissuematerial from a recently obtained surgical or diagnostic biopsy is mandatory for thistrial；
• Satisfactory organ and bone marrow function as defined by the following:

1. Adequate bone marrow function in the opinion of the Investigator forlymphocyte-depleting chemotherapy: absolute neutrophil count must be greater than ≥ 1.5×109/L, lymphocyte count must be greater than ≥ 0.5×109/L, platelets must begreater than ≥ 90×109/L, hemoglobin must be greater than ≥ 90g/L withouttransfusion within 7 days or dependency on EPO;
2. Total bilirubin must be less than or equal to two times (≤2.0x) the institutionalnormal upper limit; transaminases, serum alanine aminotransferase (ALT) oraspartate aminotransferase (AST), must be less than or equal to 2.5 times (≤2.5x)the institutional normal upper limit (≤2.5x if there is hepatic metastasis);
3. Creatinine must be less than or equal to one and one half times (≤ 1.5x) theinstitutional normal upper limit or eGFR ≥ 60ml/min/1.73m^2 [eGFR=186×（age）-0.203×SCr-1.154（mg/dl）,for female the eGFR shoud be timed by 0.742];
4. International normalized ratio (INR) or the PT is not greater than one and onehalf times (≤ 1.5) the upper limit of normal;
5. Lung function: ≤ CTCAE grade 1 dyspnea and SaO2≥ 91%;
6. Cardiac function: cardiac ejection fraction (LVEF) must be greater than fiftypercent (≥50%) by echocardiogram or MUGA one month before enrollment.

• Subjects must have measureable disease as defined by RECIST 1.1 criteria;
• Subjects sufficiently understand the trial and willingly sign the informed consent;
• For concurrent medication:

1. Systemic therapeutic corticosteroids must be stopped 72 hours before CAR-Tinfusion. However, patients using physiologic replacement doses ofcorticosteroids, or its equivalent, will be considered eligible;
2. Immunosuppressive therapy must be stopped within four (4) weeks prior toenrollment;

• Male and Female subjects agree to use approved contraceptive methods (e.g. birthcontrol pills, barrier device, intrauterine device, abstinence) during the study andfor at least 12 months following the last dose of the study cell infusion and until noCAR-T cells can be detected after two consecutive PCR tests.

Exclusion Criteria:

• Prior therapy with targeted therapy or cell therapy against MSLN；
• Prior therapy with any gene therapy (including CAR-T cell therapy) or any T celltherapy home and abroad；
• Active bacteria, viral or fungal infection, and not contained after anti-infectivetherapy (positive results in the blood ≤72 hours before infusion);
• Patient is positive for Syphilis, Human Immunodeficiency Virus (HIV) , activeHepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected);
• Patient has a medical condition such as autoimmune disease or organ transplantationthat requires chronic systemic steroid therapy or requires any other form ofimmunosuppressive medication;
• History of severe cardiac or pulmonary disease, including hypertension that cannot becontrolled by medication, and any of the conditions occurred within the past 6 months:congestive heart failure (New York Heart Association functional classification ≥3),cardiac angioplasty and stents, myocardial infarction, unstable angina, or otherclinically significant heart disease；
• Detectable clinically relevant central nervous system (CNS) metastases and/orpathology such as epilepsy/seizure, brain Ischemia/ hemorrhage, dementia, cerebellardisease, or autoimmune disease affecting central nervous system；
• Patient has a history or current evidence of any condition such as neurotic,psychiatric, immune, metabolic and infectious disease, on any therapy, or laboratoryabnormality that might confound the results of the study, interfere with the patient'sparticipation for the full duration of the study, or is not in the best interest ofthe patient to participate, in the opinion of the treating Investigator；
• Patient has a known history of a hematologic malignancy, or of another malignantprimary solid tumor concurrently, with the exception of :

1. Patients with in situ cervical cancer or breast cancer with no evidence ofdisease for ≥ 3 years after curative treatments;
2. Patients who underwent successful definitive resection of in situ cancer with noevidence of disease for ≥5 years;

• Has had chemotherapy, radioactive, small molecules, biological cancer therapy,immunotherapy or other investigational drugs within 4 weeks prior to the initiation ofthe study；
• Pregnant or breastfeeding women;
• Investigators think that patient has a history or current evidence of any condition,therapy, or laboratory abnormality that might confound the results of the study,interfere with the patient's participation for the full duration of the study andcooperation with the requirements of the trial, uncontrolled medical, psychological,familial, sociological, or geographical conditions, or is not in the best interest ofthe patient to participate