Overview

The primary aim of this study is to evaluate the efficacy of KRAS mutant antigen specific TCR-T cells in the treatment of patients with advanced pancreatic cancer.

The secondary aim is to evaluate the pharmacokinetic/pharmacodynamic characteristics of TCR-T cell therapy in patients with advanced pancreatic cancer and the survival of TCR-T cells.

The investigators will evaluate the changes of tumor microenvironment after treatment of advanced pancreatic cancer with KRAS mutant antigen specific TCR-T cells; Evaluating the correlation between cytokines and the occurrence of CRS and neurotoxicity

Eligibility

Inclusion Criteria：

1. Age greater than 18 years old；
2. Pathological diagnosis of recurrent/metastatic pancreatic cancer (except intracranial metastasis). Patients who have had prior therapy with at least one standard treatment regimen remain in stable or progressive disease states and refuse subsequent chemotherapy;
3. Mutations in KRAS G12V or G12D and expression of matched HLA -A*11:01 subtypes are confirmed in previous tumor or biopsy tissues；
4. Expected survival duration of more than 3 months；
5. Eastern Cooperative Oncology Group( ECOG )score ≤2；
6. All participants voluntarily participate in this study and sign an informed consent. And the subjects have good compliance and can cooperate with investigators follow-up study.
7. Patients at least have had at least one measurable lesion as defined by RECIST v1.1 criteria；
8. Female participants can not be pregnant or lactating and their serum or urine human chorionic gonadotropin tests must be negative within 72 hours prior to study enrollment；All subjects must be using a medically accepted means of contraception ( (e.g., oral contraceptives, intrauterine device) during the course of this study and for at least 3 months after completion of study therapy.
9. Organ function and bone marrow reserve are in good condition, and the following requirements must be met:

        1)Absolute neutrophil count≥1.5×10⁹/L；2)Platelet
        count≥50×10⁹/L；3)Hemoglobin≥90g/L；4)Bilirubin < 1.5 times upper limit of normal（Bile duct
        obstruction due to tumor compression were excluded)；5)Serum creatinine ≤ 1.5 times the
        upper limit of normal range or creatinine clearance ≥ 60 mL/min.6)Serum alanine
        aminotransferase or aspartate aminotransferase is < 2.5 times the upper limit of the normal
        value (ULN) (if patients with liver metastasis, ≤5 times the ULN).7)Coagulation function
        normalised：INR≤1.5，PTT<1.2 times the upper limit of normal（Tumor - related anticoagulant
        therapy was excluded).
        Exclusion Criteria:
          1. Intracranial metastasis or Patients with moderate or severe hydrothorax need drain
             placement to relieve symptoms.
          2. Active pulmonary tuberculosis
          3. Human immunodeficiency virus (HIV) positive；
          4. Active Hepatitis B or Hepatitis C infection；
          5. Pregnant women and lactating females；
          6. Previous or concurrent history of other malignant tumors. Exceptions include
             curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy;
          7. Patients with central nervous metastases；
          8. Serious, uncontrolled comorbidities that may affect protocol compliance or interfere
             with interpretation of results，or any serious medical condition that may affect the
             safety of the subjects ;
          9. History of clinically significant respiratory diseases or other respiratory diseases
             that seriously affect Pulmonary function;
         10. Any active autoimmune disease,any condition requiring steroid hormones or
             immunosuppressive therapy( including but not limited to systemic lupus erythematosus,
             sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory
             bowel disease, etc., require > 10 mg/D of prednisone or equivalent hormone）
         11. A history of organ transplantation；
         12. A history of myocardial infarction and severe arrhythmia within six months；Ineligible
             also includes uncontrolled hypertension, coronary heart disease, stroke, liver
             cirrhosis, nephritis and other serious complications;
         13. Those who have a history of psychotropic drug abuse and cannot quit or have a history
             of psychiatric impairment；
         14. Participants with an allergic constitution, known sensitivity to human serum albumin,
             cyclophosphamide, fludarabine and interleukin 2;
         15. Those with bleeding or thromboembolic tendency：bleeding symptoms of clinical
             significance or a clear tendency to bleeding within 2 weeks prior to entering the
             study. And those with hereditary or acquired bleeding and thrombotic tendencies；
             serious arterial/venous thromboembolic events occurred in the previous 6 months;
         16. Other severe, acute or chronic medical or mental illnesses that in the investigator's
             judgement will might be increase the risk associated with the patient's participation
             in the study or interfere with interpretation of research results.