Study of CRISPR-Cas9 Mediated PD-1 and TCR Gene-knocked Out Mesothelin-directed CAR-T Cells in Patients With Mesothelin Positive Multiple Solid Tumors.
Study of CRISPR-Cas9 Mediated PD-1 and TCR Gene-knocked Out Mesothelin-directed CAR-T Cells in Patients With Mesothelin Positive Multiple Solid Tumors.
Multiple solid tumors have positive targets of mesothelin expressed on the surfaces of the
 tumor cells, we use the technique of CRISPR-Cas9 to knocked out the PD-1 and TCR of chimeric
 antigen receptor (CAR) T cells to effect the immuno-microenvironment around tumors.
1. To evaluate the feasibility and safety of CRISPR-Cas9 mediated PD-1 and TCR gene-knocked
 out chimeric antigen receptor (CAR) T cells in patients with mesothelin positive
 multiple solid tumors.

 2. To evaluate the duration of in vivo persistence of transferred CAR-T cells.

 3. To observe and measure anti-tumor responses for patients with detectable mesothelin
 positive tumor lesions.
Inclusion Criteria:

 1. Histologically confirmed with mesothelin positive multiple solid tumors.

 2. Failure of at least one prior standard of care chemotherapy for advanced stage
 disease.

 3. Subjects must have measureable disease as defined by RECIST 1.1 criteria or modified
 RECIST criteria.

 4. Patients > 18 years of age.

 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

 6. Life expectancy > 12 weeks.

 7. Satisfactory organ and bone marrow function as defined by the following (of note, the
 minimal blood counts should be in the absence of transfusion or cytokine support):

 i. Absolute neutrophil count > 1,000/μl ii. Platelets >75,000/μl iii. Hemoglobin > 9
 g/dL iv. Bilirubin < 2.0x the institutional normal upper limit unless secondary to
 bile duct obstruction by tumor v. Creatinine < 1.5x the institutional normal upper
 limit vi. Albumin ≥2 vii. Serum alanine aminotransferase (ALT) or aspartate
 aminotransferase (AST) < 5x the institutional normal upper limit viii. Cardiac
 ejection fraction of >55% as measured by resting echocardiogram, with no significant
 pericardial effusion.

 8. Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤
 1.5 and a PTT < 1.2 time the upper limit of normal unless the patient is
 therapeutically anti-coagulated for history of cancer-related thrombosis and has
 stable coagulation parameters.

 9. Ability to understand and the willingness to provide written informed consent.

 10. Male and Female subjects of reproductive potential agree to use approved contraceptive
 methods (e.g. birth control pills, barrier device, intrauterine device, abstinence)
 and abstain from other methods of conception during the study and for 6 months
 following the study cell infusion or proof of sterility.

 Exclusion Criteria

 1. Sarcomatoid MPM histology which is known in the literature to not express mesothelin;
 biphasic MPM is also excluded.

 2. This refers to non-commercially approved investigational drugs different than those
 used in this protocol.Participated in any other trial in which receipt of an
 investigational study drug occurred within 28 days prior to enrollment and anticipated
 treatment with another investigational product while on study.

 3. Anticipated need for systemic chemotherapy within 2 weeks before apheresis and
 infusion of CART-meso cells.

 4. Active invasive cancer other than the one of the three cancers in this study. Patients
 with active non-invasive cancers (such as non-melanoma skin cancer, superficial
 cervical and bladder and prostate cancer with PSA level < 1.0) are not
 excluded.CART-meso in mesothelin expressing cancers

 5. HIV, HCV, or HBV infections

 6. Active autoimmune disease (including but not limited to: systemic lupus
 erythromatosis, Sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple
 sclerosis, inflammatory bowel disease, etc.) requiring immunosuppressive therapy
 within the past 4 weeks, with exception of thyroid replacement.

 7. Patients with ongoing or active infection.

 8. Planned concurrent treatment with systemic high dose corticosteroids. Patients may be
 on a stable low dose of steroids (<10mg equivalent of prednisone) for chronic
 respiratory conditions.

 9. Patients requiring supplemental oxygen therapy.

 10. Prior therapy with gene modified cells.

 11. Previous experimental therapy with SS1 moiety, murine or chimeric antibodies (human
 and humanized antibodies are allowed).

 12. History of allergy to murine proteins

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

 14. Any clinically significant pericardial effusion; CHF (NY Heart Association Grade
 II-IV) or cardiovascular condition that would preclude assessment of mesothelin
 induced pericarditis or that may worsen as a result of toxicities expected for this
 study. This determination will be made by a cardiologist.

 15. Any clinically significant pleural or peritoneal effusion that cannot be drained with
 standard approaches. An indwelling drainage device placed prior to enrollment is
 acceptable.

 16. Pregnant or breastfeeding women. Female study participants of reproductive potential
 must have a negative urine pregnancy test of enrollment. A serum pregnancy test will
 be performed within 2 weeks before infusion.