CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Measurable locally advanced, recurrent, or metastatic biliary tract carcinoma (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma).
* Patients with locally advanced disease should be unresectable by conventional surgical approaches.
* Patients with distant metastatic spread must be refractory to approved standard systemic therapies (such as gemcitabine, cisplatin, or equivalents) if they are eligible to receive these treatments.
* Patients must be co-enrolled on the companion protocol HCC 17-220 (Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies) and have available TIL cultures for therapy.
* Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
* Greater than or equal to 18 years of age and less than or equal to age 75
* Able to understand and sign the Informed Consent Document
* Clinical performance status of ECOG 0 or 1
* Life expectancy of greater than three months
* Patients of both genders who are of child-bearing potential must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the treatment.
* Serology:

  * Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
  * Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
* Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
* Hematology

  * Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim
  * WBC ≥ 3000/mm3
  * Platelet count ≥ 100,000/mm3
  * Hemoglobin \> 8.0 g/dl
* Chemistry

  * Serum ALT/AST ≤ to 3.5 times the upper limit of normal
  * Serum creatinine ≤ to 1.6 mg/dl
  * Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
* More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a clinically manageable level (except for toxicities such as alopecia or vitiligo). (Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less)

Exclusion Criteria:

* Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
* Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
* Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
* Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses.
* History of clinically significant major organ autoimmune disease
* Concurrent systemic steroid therapy.
* History of severe immediate hypersensitivity reaction to any of the agents used in this study.
* History of active coronary or ischemic symptoms.
* Documented LVEF of less than or equal to 45%; note: testing is required in patients with:

  * Age \> 65 years' old
  * Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or have a history of ischemic heart disease, chest pain.
* Documented FEV1 less than or equal to 60% predicted tested in patients with:

  * A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
  * Symptoms of respiratory dysfunction
* Patients who are receiving any other investigational agents.

主要终点：Objective Response Rate (ORR) · Proportion of patients with response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1): Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. The appearance ≥1 new lesion(s) is considered progression.. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. ORR (proportion of patients) = # with CR + # with PR / # with CR + # with PR + # with SD + # with PD. · Up to 24 months
次要终点：Complete response rate (CRR)；Duration of Response (DOR)；Disease control rate (DCR)；Progression-free survival (PFS)；Overall survival (OS)；EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30)；EuroQol 5 dimensions 5 levels (EQ-5D-5L)

• Tumor Infiltrating Lymphocytes (TIL) · EXPERIMENTAL · Patients with locally advanced, recurrent, or metastatic biliary tract cancers will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of up to 2x10\^11 lymphocytes infused intravenously through a central vein catheter and Aldesleukin, administered at a dose of 600,000 IU/kg (based on total body weight) as an intravenous bolus over a 15-minute period approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to a maximum of 6 doses.

This is a Phase 2 study to evaluate the efficacy, using objective response rate, of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous Tumor Infiltrating Lymphocytes (TIL) and high-dose aldesleukin in patients with locally advanced, recurrent, or metastatic biliary tract cancer. These are low-incidence cancers carry a poor prognosis. Participants will include patients with biliary tract cancers (BTC), including cholangiocarcinoma (both intrahepatic and extrahepatic) and gallbladder cancer, who are and are physically able to tolerate non-myeloablative chemotherapy and high-dose aldesleukin.