CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* The subjects must be informed of the study before the test and voluntarily sign a written informed consent.
* Age of the patients was between 18\~70 years
* Eligible patients have histologically proven advanced liver cancer
* Eastern Cooperative Oncology Group (ECOG) performance status was 0-1
* Metastatic lesions are confirmed by PET-CT, CT, MR and/or intraoperative exploration (more than 3, at least one accessible metastasis to procure for TILs)
* Patients have at least one separate additional measurable tumour lesion according to RECIST version 1.1 standard.
* The disease has progressed after at least two previous lines of standard treatment and there is no effective treatment option available
* Adequate normal organ and marrow function were present, including absolute neutrophil count ≥ 1×10\^9/L, leukocyte count ≥ 3×10\^9/L, platelet count ≥ 75×10\^9/L, hemoglobin ≥ 80 g/L, AST and ALT ≤ 2× of upper limit of normal, Serum creatinine ≤ 1.5× upper normal limits, Serum total bilirubin ≤ 1.5× upper normal limits
* Female subjects of childbearing age must have a negative urine or serum HCG test within 7 days before cell reinfusion
* Provide at least one gram of fresh tumor tissue and 10ml of peripheral blood for whole exome sequencing and TIL isolation and culture.
* Expected survival was at least 3 months
* Child-Push liver function score grade is A within seven days before the cell reinfusion.

Exclusion Criteria:

* With previous or concurrent other active cancer (except carcinoma in situ that has been cured without onset within 5 years, or those that can be cured by adequate treatment)
* Patients with metastasis to Central Nervous System or brain
* Have received organ transplantation in the past
* Received major liver surgery within 4 weeks before the first administration (except liver metastases biopsy).
* Received local treatment of the liver or other parts within 4 weeks before the first administration (transcatheter arterial chemoembolization \[TACE\], transcatheter arterial embolization \[TAE\], hepatic artery infusion \[HAI\], radiotherapy, radioembolization or ablation). Subjects are not eligible to participate in the study if the above-mentioned treatment is carried out between the last dose of sorafenib or oxaliplatin-containing regimen and the first study administration.
* After CT angiography examination, there is severe arterial embolism or hepatic artery vascular variation.
* APTT or PT \>= 5 UNL, or with bleeding evidence in two months or bleeding history in prior to the clinical study, no matter how serious it is
* Active inflammation within 7 days after systemic antibiotics treatment
* Subjects who have undergone major surgery or severe trauma such as laparotomy, thoracotomy, and laparoscopic organ removal within 4 weeks before enrollment.
* Active coronary artery disease, serious or unstable angina pectoris, or newly diagnosed angina pectoris or myocardial infarction within 12 months prior to the clinical study
* Thrombosis or embolism event within 12 months prior to the clinical study, such as cerebrovascular accident ( including TIA) or pulmonary embolism
* Congestive heart failure of NYHA \>= Class II
* Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreated active hepatitis (hepatitis B, defined as HBV-DNA ≥ 500 IU/ml C Hepatitis, defined as HCV-RNA higher than the detection limit of the analytical method) or co-infection with hepatitis B and hepatitis C.
* Presence of any active, known or suspected autoimmune disease. Subjects in a stable state who do not require systemic immunosuppressive therapy are allowed, such as: type 1 diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, and skin diseases that do not require systemic therapy (e.g., vitiligo, psoriasis disease and hair loss).
* Any interstitial lung disease, noninfectious causes of lung inflammation, or uncontrolled systemic disease (e.g. diabetes, pulmonary fibrosis, or acute pneumonia)
* Any adverse event of CTCAE (Ver 5.0) grade 2 or higher induced by previous treatment, except anemia, hair loss, and skin pigmentation
* Pregnant or lactating women or those who are positive in pregnancy test before 1st injection
* The investigator believes that the subject has any clinical or laboratory abnormalities or compliance problems and is not suitable for participating in this clinical study.
* With serious psychological or mental abnormalities
* Joined other clinical trials in four weeks prior to this study
* Patients who have a history of hypersensitivity to cyclophosphamide and fludarabine.
* Other researchers think that they are not suitable for enrollment.

主要终点：Types and incidence of Dose-limiting toxicity (DLT) [Safety and Tolerability] · Dose-limiting toxicity (DLT) will be collected and graded according to CTCAE v5.0 · 1 month；Types and incidence of adverse events (AEs) ,serious adverse events (SAEs) [Safety and Tolerability] · AE will be collected and graded according to CTCAE v5.0 · Up to 24 months；Maximum tolerated dose [Safety and Tolerability] · Evaluate the maximum tolerated dose of TILs in patients with advanced liver cancer · 1 month
次要终点：Progression-free Survival (PFS)；Disease Control Rate (DCR)；Objective response rate (ORR)；Overall Survival (OS)

• Treatment (autologous tumor infiltrating lymphocytes) · EXPERIMENTAL · Post-NMA lymphodepletion, patients are infused with their autologous TIL followed by IL-2 administration.

Single-arm, open-label, interventional study evaluating adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) infusion followed by IL-2 after a non-myeloablative(NMA) lymphodepletion preparative regimen for the treatment of patients with advanced liver cancer.