Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma

Background:

• Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
• In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gray (Gy) or 12 Gy total body irradiation (TBI) objective response rates using Response Evaluation Criteria In Solid Tumors (RECIST) criteria were 49%, 52%, and 72%, respectively. Of the 20 complete regressions seen in this trial, 19 are on-going at 70 to 114 months.
• The chemotherapy alone preparative regimen required in-patient treatment and was associated with significant neutropenia and thrombocytopenia requiring multiple transfusions and treatment for febrile neutropenia.

Objectives:

• With amendment D, to determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not; both groups will receive non-myeloablative lymphoid depleting preparative regimen followed by autologous young tumor infiltrating lymphocytes (TIL) and administration of high dose aldesleukin.
• To determine the toxicity of the treatment.

Eligibility:

• Age greater than or equal to 18 and less than or equal to 70 years
• Evaluable metastatic melanoma
• Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL
• No contraindications to high-dose aldesleukin administration
• No concurrent major medical illnesses or any form of immunodeficiency

Design:

• Patients with metastatic melanoma will have lesions resected and after TIL growth is established, patients will receive ACT with TIL plus aldesleukin following high dose chemotherapy preparative regimen.
• Up to 64 patients may be enrolled over 4-5 years.

-INCLUSION CRITERIA:

• Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation and at least one other lesion that can be measured by Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
• Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of National Cancer Institute (NCI).
• 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 70 years of age.
• Ability of subject to understand and the willingness to sign the Informed Consent Document
• Willing to sign a durable power of attorney.
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2.
• Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
• Serology:

• Seronegative for human immunodeficiency virus (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 are 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 reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (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/mm(3) without the support of filgrastim
• White blood cell (WBC) greater than or equal to 3000/mm(3)
• Platelet count greater than or equal to 100,000/mm(3)
• Hemoglobin > 8.0 g/dl
• Chemistry:

• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or equal to 2.5 times the upper limit of normal
• Serum Creatinine less than or equal to 1.6 mg/dl
• Total bilirubin less than or equal to 1.5 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 grade 1 or less (except for toxicities such as alopecia or vitiligo). Patients must have progressive disease after prior treatment.

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.

• Subjects must be co-enrolled in 03-C-0277

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.
• Concurrent systemic steroid therapy.
• History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• History of coronary revascularization or ischemic symptoms.
• Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%
• Documented LVEF of less than or equal to 45%, note: testing is required in patients with:

• Age greater than or equal to 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 history of ischemic heart disease or chest pain.
• Patients who are receiving other investigational agents
• Documented forced expiratory volume (FEV1) less than or equal to 60% predicted tested in patients with:

• A prolonged history of cigarette smoking (20 pack (pk)/year of smoking within the past 2 years).
• Symptoms of respiratory dysfunction