Protocol Number: 03-C-0162

Title:

Treatment of Patients with Metastatic Melanoma Using Tumor Infiltrating Lymphocytes (TIL Cells) Transduced with an Interleukin-2 (SBIL-2) Gene following the Administration of a Nonmyeloablative But Lymphocyte Depleting Regimen

Number:

03-C-0162

Summary:

This study will examine the safety and effectiveness of gene therapy for creating special tumor-fighting cells to treat patients with metastatic melanoma (melanoma that has spread from the primary tumor site). A gene for interleukin-2 (IL-2) will be inserted into cells from the patients' tumors. This gene makes the IL-2 protein, which is a growth factor for tumor-fighting white cells called T-cells. The cells with the IL-2 gene will be grown in culture and then given back to the patient.

Patients 18 years of age and older with metastatic melanoma who have been treated with IL-2 and have progressive disease may be eligible for this study. Candidates will be screened with blood tests, scans, and x-rays to evaluate the tumor. Participants will undergo the following procedures:

- Biopsy and culture of tumor cells. For the biopsy, a small area of skin is numbed and a piece of tumor is removed with a needle or a small incision. The tumor cells are grown in the laboratory for about 40 days.

- IL-2 gene insertion into cells. IL-2 genes are inserted into the tumor cells using a virus that has been rendered incapable of causing an infection.

- G-CSF administration and leukapheresis. Injections of G-CSF are given under the skin once a day for 5 days, followed by leukapheresis. G-CSF is a hormone that causes white cells to increase in number, allowing more cells to be collected through leukapheresis. For leukapheresis, whole blood is drawn from a needle in an arm vein and circulated through a machine that separates it into its components. The white cells are removed, and the plasma and red cells are given back to the patient through a vein in the other arm.

- Chemotherapy. Patients receive two anti-cancer drugs, cyclophosphamide and fludarabine, through a catheter (flexible plastic tube) placed into a vein in the arm, upper chest, or neck. The cyclophosphamide is given over 1 hour for 2 days and the fludarabine is given for 30 minutes for 5 days. The drugs are intended not to treat the tumor, but to see if they improve the functioning of the IL-2 gene-modified white cells. Patients who have HLA-A201 blood type may additionally receive vaccine(s) following chemotherapy to increase the body's immune response to the tumor. Each vaccine consists of peptides (pieces of protein) from melanoma tumors, either gp 100, MART-1 or both, and an adjuvant called Montanide ISA-51. The injections are given the morning of the cell infusion (see below) and every other day for a total of 3 days of injections.

- Cell infusions. The gene modified cells are given through the catheter over 30 minutes the day after the last dose of chemotherapy. Patients are monitored closely for side effects and are given medicines as needed to treat and prevent as many side effects as possible.

Patients whose tumors do not respond to treatment may receive additional gene modified cells along with high-dose IL-2. The IL-2 is given as a 15-minute infusion through one of the catheters every 8 hours for up to 5 days after each cell infusion. Four to six weeks after the treatment regimen, patients return to the clinic for a 2-day follow-up evaluation. They may have additional treatments with gene-modified cells, with or without chemotherapy or IL-2 infusions. The additional regimens will be designed according to the patient's response to previous cell infusions.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA - CELL HARVEST:

a. Patients must have metastatic melanoma.

b. Age greater than or equal to 18 years.

c. Clinical performance status of ECOG 0 or 1.

d. Life expectancy of greater than three months.

e. 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.)

f. Seronegative for hepatitis B and C antigen.

INCLUSION CRITERIA - CELL INFUSION:

a. Patients must have tumor available for biopsy or must have expandable SBIL-2 transduced TIL available.

b. Patients must have evaluable metastatic melanoma that is refractory to standard therapy including high dose IL-2 therapy.

c. Patients may not have brain metastases.

d. Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.

e. Clinical performance status of ECOG 0,1 at the time of chemotherapy induction.

f. Absolute neutrophil count greater than 1000/mm(3).

g. Platelet count greater than 100,000/mm (3).

h. Hemoglobin greater than 8.0 g/dl.

i. Serum ALT/AST less than three times the upper limit of normal.

j. Serum creatinine less than or equal to 1.6 mg/dl.

k. Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a bilirubin less than 3.0 mg/dl.

l. Must sign a durable power of attorney.

m. Patients who have progressive disease while receiving prior immunization to melanoma antigens or who have received prior anti-CTLA-4 antibody, or prior cellular therapy, with or without myeloablation may be eligible for this protocol, as long as all toxicities (except vitiligo) are resolved.

EXCLUSION CRITERIA - CELL HARVEST:

a. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system.

EXCLUSION CRITERIA: CELL INFUSION:

a. Has had prior systemic therapy within the past four weeks at the time of the start of the preparative regimen.

b. Women of child-bearing potential who are pregnant will be excluded because of the potentially dangerous effects of the preparative chemotherapy on the fetus.

c. Life expectancy of less than three months.

d. Requires steroid therapy.

e. Seropositive 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.)

f. Seropositive for hepatitis B or C antigen.

g. Seronegative for Epstein-Barr virus (EBV).

h. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, such as abnormal stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive or restrictive pulmonary disease.

i. Any form of primary or secondary immunodeficiency. Must have recovered immune competence after chemotherapy or radiation therapy as evidenced by normal lymphocyte counts (greater than 500/mm(3), and absence of 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.)

j. History of severe immediate hypersensitivity reaction.

Special Instructions: Currently Not Provided

Keywords:

Cancer

Immunotherapy

Gene Therapy

Cytokines

Clinical Response

Recruitment Keywords:

None

Conditions:

Melanoma

Investigational Drug(s):

IL-2

gp100: 209-217(210M)

MART-1:26-35(27L)

Montanide

Retronectin

SBIL-2

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001 May 17;411(6835):380-4. Review. PMID: 11357146

Topalian SL, Rosenberg SA.Tumor-infiltrating lymphocytes: evidence for specific immune reactions against growing cancers in mice and humans. Important Adv Oncol. 1990;:19-41. Review. No abstract available. PMID: 2182519

Schwartzentruber DJ, Topalian SL, Mancini M, Rosenberg SA. Specific release of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IFN-gamma by human tumor-infiltrating lymphocytes after autologous tumor stimulation. J Immunol. 1991 May 15;146(10):3674-81. PMID: 1902860

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