UCLM802 (Anti-Mesothelin CAR-T) Cell Injection in Patients With Mesothelin-positive Advanced Malignant Solid Tumors

Inclusion Criteria:

1. Subjects are≥18 years old (including cut-off value), gender is not limited.
2. Solid tumors that histological diagnosis of malignancy refractor to, or relapsingafter standard therapy, including but not limited to mesothelioma, pancreatic cancer,biliary tract cancer, lung cancer, ovarian cancer, gastric cancer, bowel cancer,thymic carcinoma, esophageal cancer, breast cancer, endometrial cancer. Subjects havefailed with standard treatment or cannot tolerate treatment recommended by clinicaltreatment guidelines form relevant international and domestic authoritativeorganization (Chinese Anti-Cancer Association(CACA), Chinese Society of ClinicalOncology(CSCO), National Health Commission, etc.)
3. At least one measurable lesion according to RECIST v1.1.
4. Mesothelin should be positive confirmed by Immunohistochemistry/Immunocytochemistry (IHC/ICC) in tumor tissue samples.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy ≥ 3 months.
7. Adequate function defined as: Hematological functions: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L (Patientsshould not receive G-CSF support within 7 days before laboratory examination);Absolute Lymphocyte Count (ALC) ≥ 0.5 × 10^9/L; Hemoglobin (HGB) ≥ 80 g/L (Patientsshould not be transfused red cells within 7 days before the laboratory examination);Platelet count (PLT) ≥ 75 × 10^9/L (Patients should not receive transfusion supportwithin 7 days before the laboratory examination). Hepatic functions: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN); AST and ALT of patients with liver metastasis ≤ 5 × ULN; Total bilirubin (TBIL) ≤ 1.5 × ULN; TBIL of patients with liver metastasis must ≤ 3.0 × ULN; TBIL of patients with Gilbert's Syndrome ≤ 3.0 × ULN and Direct bilirubin (DBIL) ≤ 1.5 × ULN. Coagulation functions: International normalized ratio (INR) ≤ 1.5 × ULN; Activatedpartial thromboplastin time (APTT) ≤ 1.5 × ULN (Except for patients who are receivingtherapeutic anticoagulants.). Renal functions: Serum creatinine (Cr) ≤ 1.5 × ULN; or Creatinine clearance rate (Ccr) ≥ 60 mL/min. Cardiac functions: Left ventricular ejection fraction (LVEF) > 45%; Pulmonaryfunction: Oxygen saturation (SpO2) > 92%.
8. Female participants of childbearing potential must undergo a pregnancy test and theresults must be negative. Female participants of childbearing potential or maleparticipants whose sex partner has childbearing potential must be willing to useeffective methods of contraception from screening period to at least 1 year afterinfusion.
9. Participants must be able to understand the protocol and be willing to enroll thestudy, sign the informed consent, and be able to comply with the study and follow-upprocedures.

Exclusion Criteria:

1. Patients have received systemic therapy with cytotoxic chemicals, monoclonalantibodies, or immunotherapy within 4 weeks or 5 half-lives (which is shorter) priorto signing informed consent; Patients have received systemic glucocorticoids (prednisone at a dose of ≥10 mg per day or equivalent) or other immune-suppressivetherapy within 2 weeks prior to signing informed consent; Patients have receivedsystemic antitumor therapy with a biologic agent or other approved targetedsmall-molecule inhibitor within 1 week or five half-lives (which is shorter) prior tosigning informed consent; Patients have received Chinese herbal medicine or Chinesepatent medicine with anti-tumor indication within 1 week prior to signing informedconsent.
2. Pregnant or lactating women.
3. Patients with hepatitis B surface antigen (HBsAg) positive. Patients who is hepatitisB core antibody (HBcAb) positive and the quantification of HBV DNA in peripheral bloodis higher than the lower limit of detection. Patients who is hepatitis C virus (HCV)antibody positive and quantification of HCV RNA in peripheral blood is higher than thelower limit of detection. Patients with human immunodeficiency virus (HIV) antibodypositive, or syphilis antibody positive.
4. The toxicities caused by the prior therapy (surgery, chemotherapy, radiotherapy,targeted therapy, immunotherapy, etc.) have not recovered to grade 1 according toCTCAE, except for hair loss and peripheral sensory nerve disorders.
5. Have received any allogeneic tissue/organ transplantation (including bone marrowtransplantation, stem cell transplantation, liver transplantation, kidneytransplantation), except for the transplantation that does not requireimmunosuppressive therapy (such as: corneal transplantation, hair transplantation.)
6. Patients have received anti-mesothelin CAR-T cell therapy.
7. Patients who have history of major surgery and unrecovered severe trauma within 4weeks prior to signing informed consent; or plan to have major surgery within 12 weeksof cell therapy.
8. Presence of known central nervous system metastases, but the following patients willbe allowed: a) Asymptomatic brain metastases; b) Clinically stable (no radiographicprogression within 4 weeks before apheresis and return of any neurologic symptoms tobaseline), and with no need for corticosteroids or other treatment for brainmetastases for ≥ 4 weeks.
9. Patients with clinically significant systemic disease (such as: severe activeinfection or significant cardiac, pulmonary, hepatic, nervous system, or other organdysfunction) that evaluated by the investigator would impair the patients' ability totolerate the treatments used in this study or significantly increase the risk ofcomplications.

• Uncontrolled severe active infection (sepsis, bacteremia, viremia, etc.);
• Congestive heart failure with New York Heart Association (NYHA) functional class > 1;
• Clinically significant severe aortic stenosis and symptomatic mitral stenosis;
• Electrocardiogram QTc > 450 msec or QTc > 480 msec in patients with bundle-branchblock;
• Uncontrolled clinically significant arrhythmia within 6 months prior to signinginformed consent;
• Acute coronary syndrome (such as: unstable angina, myocardial infarction) within 6 months prior to signing informed consent;
• Drug-uncontrolled hypertension (systolic pressure ≥ 160 mmHg and/or diastolicpressure ≥ 100 mmHg) or pulmonary hypertension;
• Cerebrovascular accident occurred within 6 months prior to signing informedconsent, including transient ischemic attack (TIA), cerebral infarction, cerebralhemorrhage, subarachnoid hemorrhage;
• A history of active, chronic, or recurrent (within 1 year prior to signinginformed consent) severe autoimmune disease or immune-mediated disease requiringsteroids or other immunosuppressive therapy, including but not limited tosystemic lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory boweldisease, Hashimoto's thyroiditis, autoimmune thyroid disease, multiple sclerosis.Exceptions: hypothyroidism that can be controlled only by hormone replacementtherapy, skin diseases (such as: vitiligo, psoriasis) that do not requiresystemic treatment, coeliac disease that has been controlled;
• Any form of primary or secondary immunodeficiency, such as severe combinedimmunodeficiency (SCID);
• Possibility of bleeding from esophageal or gastric varices evaluated by theinvestigator.

10. History of severe systemic hypersensitivity reaction to the drugs/ingredients [fludarabine, cyclophosphamide, dimethyl sulfoxide (DMSO), low molecular dextran,human serum albumin (HSA), etc.] used in this study.
11. Patients have received attenuated vaccine within 4 weeks prior to signing informedconsent.
12. Patients have received other clinical trials within 4 weeks prior to signing informedconsent.
13. History of another malignancy tumor within the previous five years, except foradequately treated non-melanoma skin cancer, carcinoma in situ of bladder, stomach,colon, cervix/dysplasia, melanoma, or breast.
14. History of neuropsychiatric diseases diagnosed by the ICD-11 criteria or evaluated byinvestigator, including but not limited to epilepsy, schizophrenia, dementia, drug andalcohol addictions.
15. For any other reasons, the patients are believed not suitable for participation inthis study by investigators.