Study on TIL for the Treatment of Advanced Hepatobiliary-Pancreatic Cancers

Inclusion Criteria:

1. Age: 18 years to 75 years;

2. Histologically diagnosed as primary/relapsed/metastasized hepatobiliary cancer orpancreatic cancers;

3. Expected life-span more than 3 months;

4. Karnofsky≥60% or ECOG score 0-2;

5. Test subjects have failed standard treatment regimens, or there are no standardtreatment regimens available.

6. Test subjects must have tumor regions eligible for biopsy or resection, or malignantbody fluid where TILs can be isolated;

7. At least 1 evaluable tumor lesion;

8. Hematology and Chemistry（within 7 days prior to enrollment）:

• Absolute count of white blood cells≥2.5×10^9/L;

• Absolute count of neutropils≥1.5×10^9/L;

• Absolute count of lymphocytes ≥0.7×109/L；

• Platelet count≥100×10^9；

• hemoglobin≥90 g/L;

• Activated partial thromboplastin time (APTT) ≤1.5xULN (Unless receivedanticoagulant therapy within the previous 3 days);

• International normalized ratio (INR) ≤1.5xULN (Unless received anticoagulanttherapy within the previous 3 days);

• Serum creatinine ≤1.5mg/dL(or ≤132.6μmol/L), or clearance rate≥50mL/min;

• Serum ALT/AST ≤3×ULN(subjects with liver metastasis ≤3×ULN);

• Totol bilirubin≤1.5×ULN;

9. no absolute or relative contraindications to operation or biopsy;

10. Test subjects with child-bearing potential must be willing to practice approvedhighly effective methods of contraception at the time of informed consent, andcontinue within 1 year after the completion of lymphodepletion；

11. Any malignant tumor-targeting therapies, including radiotherapy, chemotherapy andbiologics must cease 28 days before obtaining TILs;

12. Be able to understand and sign the informed consent document;

13. Be able to stick to follow-up visit plan and other requirements in the agreement.

Exclusion Criteria:

1. Need glucocorticoid treatment, and daily dose of Prednisone greater than 15mg (orequivalent doses of hormones) or outoimmune diseases requiring immunomodulatorytreatment;

2. Forced expiratory volume in one second (FEV1) less than 2L, diffusing capacity ofthe lung for carbon monoxide (DLCO) (calibrated) less than 40%;

3. Significant cardiovascular anomalies according to any of the following definition:New York Heart Association (NYHA) Grade III or IV congestive heart failure,clinically significant low blood pressure, uncontrollable symptomatic coronaryartery diseases, or ejection fraction less than 35%; Severe cardiac rhythm andconduction anomaly, such as ventricular arrhythmia requiring clinical intervention,second-third degree atrio-ventricular conductive block, etc.

4. Human immunodeficiency virus (HIV) infection or anti-HIV antibody positive, activeHBV or HCV infection (HBsAg positive and/or anti-HCV positive), syphilis infectionor Treponema pallidum antibody positive;

5. Severe physical or mental diseases;

6. Have a systemic active infection requiring treatment, or have positive bloodcultures(or imaging evidence of infection);

7. Having been treated within a month or being treated now with other medicines, orother biologic therapy, chemo-or radiotherapy;

8. History of allergy to chemical compound consisting of chemical and biologicsubstances resembling cell therapy;

9. Having received immunotherapy and developed irAE level greater than Level 3;

10. Previous anti-tumor treatment AE did not return to CTCAE5.0 version grade 1 or below (toxicity considered by the investigator as non-safety concerns like alopeciaexcluded);

11. Females in pregnancy or lactation;

12. History of organ transplantation, allogeneic stem cell transplantation, and renalreplacement therapy;

13. Researchers considering the test subject as having a history of other severesystemic diseases, or other reasons inappropriate for the clinical study.