CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Patients with measurable and pathologically confirmed advanced pancreatic cancer, including metastatic pancreatic cancer (who have received standard chemotherapy) and recurrent pancreatic cancer (who have received surgery and adjuvant chemotherapy previously).
* Patient's tumor must express the KRAS G12V mutation, or a G12V mutation in HRAS or NRAS, as determined by DNA or RNA sequencing methods.
* Patients must be HLA-A\*11:01.
* Patients with brain metastasis may be eligible if they are asymptomatic and there are fewer than 3 brain lesions that are each less than 1 cm in diameter.
* Patients between 18 to 75 years old are eligible.
* Patients should have good clinical performance status (ECOG 0 or 1).
* Patients must practice birth control once enrolled into the study and for up to four months after therapy.
* Patients must be seronegative for HIV antibody.
* Patients must be seronegative for hepatitis B surface antigen and core antibody (or HBV non-detectable by QPCR).
* Patients must be seronegative for hepatitis C antibody (or HCV non-detectable by QPCR).
* Baseline hematology criteria:

  * Absolute neutrophil count of at least 1000/mm\^3.
  * White blood cell count of at least 3000/mm\^3.
  * Platelet count of at least 100,000/mm\^3.
  * Hemoglobin \> 8.0 g/dL.
* Baseline chemistry criteria:

  * Serum ALT/AST less than or equal to 3.0 x ULN.
  * Total bilirubin less than or equal to 1.5 mg/dL, unless the patient has Gilbert's Syndrome in which case total bilirubin must be less than or equal to 3.0 mg/dL.
  * Serum creatinine less than or equal to 1.6 mg/dL.
* Anticipated lifespan greater than 12 weeks.
* Patients must be willing and able to comply with all study-related procedures and follow-up requirements.
* Patients must be able to understand and sign a written Informed Consent Document as well as a durable power of attorney.

Exclusion Criteria:

* Women who are pregnant or breastfeeding.
* Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease or HIV).
* Patients with active systemic infections, coagulation disorders, or any other major medical illnesses.
* Patients with concurrent opportunistic infections.
* Patients on concurrent systemic steroid therapy.
* Patients with a history of severe immediate hypersensitivity reaction to any of the medicines used in this study (e.g., cyclophosphamide, fludarabine).
* Patients with active coronary ischemic symptoms.
* Patients who are receiving any other investigational agents.

主要终点：Frequency and severity of treatment-related adverse events · Aggregate of all adverse events, as well as their frequency and severity · 18 months following cell infusion；Objective response rate · Percentage of patients who have a clinical response to treatment (objective tumor regression) · From the date of cell infusion to disease progression (up to 18 months after cell infusion).
次要终点：The percentage of TCR transduced T cells in peripheral blood；Overall survival

• TCR Transduced T cell therapy · EXPERIMENTAL · Pre-conditioning: Non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine TCR transduced T cell infusion: mutant KRAS G12V-specific TCR transduced autologous T cells (1e9\~1e11). If the participant responds to the first infusion, the second or more infusions will be considered when the disease is progressing. Anti-PD-1 therapy: anti-PD-1 will be administered if needed.

This clinical trial will evaluate the safety and activity of mutant KRAS G12V-specific TCR transduced T cell therapy for advanced pancreatic cancer patients who express the KRAS G12V mutation and HLA-A\*11:01 allele. The theoretical basis of this study is that mutant KRAS antigen-specific TCR transduced autologous Tcells will target and kill HLA-matched mutant KRAS cancer cells but not normal cells.