CELL INTELLIGENCE · 肿瘤细胞治疗研究

* INCLUSION CRITERIA:

  1. Measurable metastatic (stage IV) or unresectable non-small cell lung cancer (including but not limited to squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinomas) with at least one lesion that is resectable for TIL generation. (Note: neuroendocrine tumors are not eligible.)
  2. 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.
  3. All patients must have had at least one appropriate first line systemic therapy and progressed.
  4. Clinical performance status of ECOG 0 or 1.
  5. Age \>= 18 years of age and \<= 72 years of age.
  6. Patients of both sexes must be willing to practice birth control from the time of enrollment on this study and for 12 months after the last dose of combined chemotherapy for individuals of childbearing potential (IOCBP) and for four months after treatment for individuals able to father a child.
  7. Willing to sign a durable power of attorney
  8. Able to understand and sign the Informed Consent Document

I. Hematology:

* Absolute neutrophil count \> 1000/mm\^3 without support of filgrastim
* Normal WBC (\>= 2500/mm\^3).
* Hemoglobin \> 8.0 g/dl. Subjects may be transfused to reach this cut-off.
* Platelet count \>= 80,000/mm\^3

  j. 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 may be less responsive to the experimental treatment and more susceptible to its toxicities.)
* Seronegative for active hepatitis B, 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.

  k. Chemistry:
* Serum ALT/AST \<= 2.5 times the upper limit of normal.
* Serum creatinine \<= 1.6 mg/dl.
* Total bilirubin \<= 2 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin \<= 3 mg/dl.

  l. IOCBP must have a negative pregnancy test or evidence that they are not pregnant (e.g., ultrasound or serial HCG measurements) prior to the start of treatment because of the potentially dangerous effects of the treatment on the fetus.

  m. Patients must have completed any prior systemic therapy at the time of enrollment.

Note: Patients may have undergone minor surgical procedures or local radiotherapy within the past 4 weeks, as long as related major organ toxicities have recovered to grade 1 or less.

n. More than two weeks must have elapsed since any prior palliation for major bronchial occlusion or bleeding at the time the patient receives the preparative regimen, and patient's toxicities must have recovered to a grade 1 or less.

o. Subjects must be co-enrolled in protocol 03-C-0277.

EXCLUSION CRITERIA:

1. Participants who are nursing because of the potentially dangerous effects of the treatment on the infant.
2. Ongoing need for pharmacological immunosuppression, including steroids
3. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other active or uncompensated major medical illnesses
4. Major bronchial occlusion or bleeding not amenable to palliation.
5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency

   Disease and AIDS).
6. 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.)
7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
8. For select patients with a clinical history prompting cardiac evaluation: last known LVEF \<= 45%.
9. For select patients with a clinical history prompting pulmonary evaluation: known FEV1 \<= 50%
10. Any of the following will exclude patients from the high-dose aldesleukin arm, but may be eligible for the low-dose aldesleukin arm:

    * Greater than 2 invasive thoracic procedures
    * Poor exercise tolerance
    * Greater than 66 years of age
    * Clinically significant patient history which in the judgment of the Principal Investigator would compromise the patient s ability to tolerate high-dose.
11. Patients who are receiving any other investigational agents.

主要终点：Response rate · Percentage of patients who have a clinical response to treatment (objective tumor regression) · 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion
次要终点：Phenotypic and functional characteristics of TIL；Frequency and severity of treatment-related adverse events；Feasibility of generating TIL from patients with NSCLC

• 1/High-Dose Aldesleukin · EXPERIMENTAL · Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus young TIL plus high-dose Aldesleukin
• 2/Low-Dose Aldesleukin · EXPERIMENTAL · Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus young TIL plus low-dose Aldesleukin

Background: The NCI Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 100 patients. In this study, we are selecting a specific subset of white blood cells from the tumor that we think are the most effective in fighting tumors and will use only these cells in making the tumor fighting cells. Objective: The purpose of this study is to see if these specifically selected tumor fighting cells can cause non-small cell lung cancer (NSCLC) tumors to shrink and to see if this treatment is safe. Eligibility: \- Adults age 18-72 with NSCLC who have a tumor that can be safely removed. Design: * Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed * Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product. * Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} * Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.