fewer tumors than expected expressed FGF-5, led to end of accrual to cohorts A&B

This study will evaluate the safety and side effects of two experimental vaccines in patients with kidney cancer and determine whether the vaccines "turn on" an immune response to the cancer. Each vaccine contains one of two peptides (pieces of proteins) from the fibroblast growth factor 5 (FGF-5) antigen, a protein produced by some cancer cells, and an oil-based liquid called Incomplete Freud's Adjuvant (Montanide ISA-51) that enhances the immune response to the vaccine.

Patients 16 years of age and older who have kidney cancer that has spread beyond the kidney or whose primary kidney tumor has been removed within 6 months before entering the study and are at high risk for disease recurrence may be eligible for this study. Patients must have tissue type human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2) or human leukocyte antigen serotype within HLA-A A serotype group (HLA-A3) (determined by a blood test for human leukocyte antigen (HLA) typing) and their tumors must produce the FGF-5 peptide. Candidates are screened with a physical examination, blood and urine tests, electrocardiogram (EKG), tumor biopsy (removal of a small sample of tumor for examination) in patients whose tumor is easily accessible, and scans (computed tomography (CT), bone scans) and x-rays if current scans are not available.

Participants are divided into two groups according to their HLA type (HLA-A2 or HLA-A3) to receive the vaccine appropriate for their HLA type. They are then further divided into three groups: 1) Group 1 includes patients who do not need or are ineligible for treatment with interleukin-2 (IL-2), a protein made by certain infection-fighting white cells that helps fight tumors) and patients who have previously had IL-2 therapy; 2) Group 2 includes patients who require immediate treatment with IL-2; and 3) Group 3 includes patients whose cancer has been surgically removed but who are at risk for recurrence.

Patients in Groups 1 and 3 receive two peptide injections four times a week every 3 weeks for up to a year, or until their tumor grows (or returns in patients in Group 3) or the side effects are too severe to continue. Tumors are evaluated with a physical examination and scans or x-rays every 12 weeks and blood tests are done every 3 weeks. Patients in Group 2 receive two peptide injections every day for 4 days, along with doses of IL-2 starting the day after the first peptide injection. The vaccines are given as injections under the skin of the thigh. IL-2 is infused through a vein over 15 minutes every 8 hours for up to 12 doses, depending on tolerance. The vaccine and IL-2 are repeated every 10 to 14 days, with tumor evaluations every 2 months. Patients stay in the hospital about 1 week during each treatment cycle to receive the IL-2.

All patients undergo leukapheresis, a procedure for collecting large numbers of white blood cells. Blood is collected through a needle in an arm vein and flows through a cell separator machine, where the white cells are extracted. The rest of the blood is returned to the patient through the same needle or a needle in the other arm. The white cells are examined to evaluate how the vaccines change the action of immune cells. Some patients may undergo an additional biopsy of normal skin and tumor or lymph node to look at the effects of the vaccine on the immune cells in the tumor.

Patients in Group 1 whose cancer grows and patients in Group C whose cancer returns may be offered IL-2 treatments as given to Group 2 patients, along with the peptide vaccine. If the disease responds to IL-2, the treatment may be repeated after 2 months.

Background:

Several preliminary clinical results in the treatment of cancer lend credence to the hypothesis that augmented T-cell responses will improve IL-2 therapy. A peptide vaccine derived from the melanoma/melanosomal antigen, GP100, when given with high-dose IL-2 resulted in a response rate over 30% in a small Phase II study. These results have led to efforts to identify similar T-cells and tumor-associated antigens for IL-2 responsive tumors such as renal cell cancer. Work in our laboratory generated a renal cancer-reactive T-cell clone, raised from tumor-infiltrating lymphocytes (TIL) within a renal cell cancer (RCC) metastasis undergoing spontaneous regression. This clone was HLA-A3 restricted and recognized autologous tumor as well as a number of allogeneic RCC lines also expressing HLA-A3. Expression cloning of the antigen recognized by this clone demonstrated that the RCC-associated antigen being recognized was unmutated fibroblast growth factor 5 (FGF-5). We concluded from numerous studies that FGF-5 was a tumor associated antigen over-expressed by a majority of RCC and that it had several favorable characteristics as a target for immunotherapy. At this point, having demonstrated in the laboratory that tumor-reactive T-cells generated from patients with renal cancer can recognize naturally presented FGF-5 in either the context of HLA-A2 or HLA-A3 via the minimal determinants 117-126:FGF-5 (MLSVLEIFAV) or FGF-5:172-176/217-220 (NTYASPRFK), respectively. With this study we plan to determine if vaccination with these peptides can enhance the number of FGF-5-reactive cytotoxic T lymphocytes (CTL) precursors in patients with renal cancer or affect the anticipated response rate from high-dose IL-2.

Objectives:

The primary objective for patients with renal cell carcinoma will be to determine overall response rates and toxicity of peptide vaccination with HLA-A2 and HLA-A3- binding peptides from FGF-5 in HLA-appropriate patients, and to explore the effect of such vaccination on the response rate to high-dose IL-2. The primary objective for patients who are receiving vaccination in the adjuvant setting will be to evaluate the immunologic responses and toxicity of FGF-5 peptide vaccination who are likely to receive repeat vaccination prior to requiring IL-2. The secondary objective is to evaluate the immunologic responses to FGF-5 peptide vaccination.

Eligibility:

Patients who are HLA-A2+ or HLA-A3+, must be age greater than or equal to 16, and have an expected survival greater than three months. For cohort A and B, patients must have measurable metastatic renal cancer and FGF-5 tumor expression. For cohort C, patients are required to have had a Stage III primary tumor (i.e. T3/T4 or N1/N2) excised within the last 6 months.) Patients in cohorts A and B must have tumor sites safely accessible for biopsy or indications for resection of a site of tumor (e.g. an indicated nephrectomy or symptomatic metastasis) and be willing to undergo biopsy, and have FGF-5 expression determined by reverse transcription polymerase chain reaction (RT-PCR) and will only be eligible if it is detectable. Patients must meet specific safety laboratory criteria. May not have undergone other systemic therapies for their cancer in the past 3 weeks (6 weeks for nitrosureas), not have any major medical illnesses, or require systemic steroid therapy.

Design:

Patients will first be divided into cohorts with measurable metastatic disease (Cohorts A and B) or high-risk loco-regional disease (Cohort C). Patients with measurable metastatic disease will then be separated into those who require immediate IL-2 therapy (Cohort B) or those who do not (cohort A).

Cohort A will begin receiving vaccination with HLA-appropriate peptide emulsified in Montanide ISA-51 or Montanide® (Registered Trademark) ISA 51 VG daily for four days every 3 weeks and will continue this for up to a year, or until tumor progression is documented. At that point, those ineligible for high-dose IL-2 or who have had previous IL-2 as an inpatient (considered high dose at doses greater than or equal to 600,000 IU/kg) will be taken off of study, and those still eligible for IL-2 who have not yet received it, will have high-dose intravenous bolus IL-2 (720,000 IU/kg/dose every 8 hours up to 12 doses) added to their peptide vaccination regimen. Two cycles, separated by 10-14 days, will be given during every two-month period (constitutes a course.). Patients in Cohort A crossing over to vaccination plus IL-2 therapy, will receive peptide in MONTANIDE ISA-51 or Montanide® (Registered Trademark) ISA 51 VG vaccination the day prior to starting an IL-2 cycle (instead of every 3 weeks, to accommodate the IL-2 regimen) and repeated daily for three additional days (for a total of four days) during IL-2 administration.

Patients in Cohort B will begin with high-dose bolus IL-2 therapy in two cycles within every two month period, with each cycle preceded by a peptide in MONTANIDE ISA-51 or Montanide® (Registered Trademark) ISA 51 VG vaccine the day prior to starting each IL-2 cycle with peptide in MONTANIDE ISA-51 or Montanide® (Registered Trademark) ISA 51 VG repeated daily for three additional days (for a total of four days) during IL-2 administration.

Patients in Cohort C will undergo the same HLA-appropriate vaccination with peptide and MONTANIDE ISA-51 or Montanide® (Registered Trademark) ISA 51 VG daily for four days every 3 weeks and continue for up to 6 months or until disease relapse is documented. At the time of relapse, eligible patients in Cohort C will receive treatment with high-dose bolus IL-2 and continuing peptide vaccination using the same schedule as specified for the Cohort A crossover arm above.

For patients in cohort A on peptide vaccine alone, evaluation will be performed every 3 months during the first 6 months of therapy and if stable, every 3-6 months thereafter. For cohorts A and B during peptide vaccine plus high-dose IL-2 therapy, evaluation will be performed every 2 months while on IL-2, and every 3-6 months for stable patients off therapy. For cohort C, evaluations will be performed every 3 months for the first year and every 6-12 months thereafter.

The maximal accrual possible would be 210 patients (Cohort A with 80 patients, Cohort B with 66 patients and Cohort C with 64 patients), and maximal enrollment could take up to 5 years.

• INCLUSION CRITERIA

Patients will be screened for inclusion on this study while participating in the Surgery Branch protocol 99-C-0128: Evaluation for the National Cancer Institute (NCI) Surgery Branch Clinical Research Protocols

Patients with clear cell renal carcinoma must fall into one of the two following groups:

For cohort A and B, patients must have measurable metastatic renal cancer and fibroblast growth factor 5 (FGF-5) tumor expression. For cohort C, patients are required to have had a Stage III primary tumor (i.e. T3/T4 or N1/N2) excised within the last 6 months.

Patients must be greater than or equal to 16.

Expected survival must be greater than three months

Patients in cohorts A and B must have tumor sites safely accessible for biopsy or indications for resection of a site of tumor (e.g. an indicated nephrectomy or symptomatic metastasis) and have FGF-5 expression determined by RT-PCR (reverse transcription polymerase chain reaction) and will only be eligible if it is detectable.

Must be human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2+) or HLA-A3+.

Serum creatinine of 2.0 mg/dl or less.

Bilirubin 1.6 mg/dl or less, except in patients with Gilbert's syndrome who must have a total bilirubin less than 3.0 mg/dl.

White blood cell (WBC) 3000/mm or greater.

Platelet count 90,000mm^3 or greater.

Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less then three times normal.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients of both genders must be willing to practice effective birth control during this trial and for three months after active treatment on this trial.

Patients who have received previous low dose interleukin-2 (IL-2) (less than 600,000 IU/kg Food and Drug Administration (FDA) approved dosing regimen) will be eligible.

For cohort A for each human leukocyte antigen (HLA) type, if there are no clinical responses to vaccine alone in the first 12 patients enrolled, subsequent patients must be eligible to receive high-dose IL-2.

Patients must be able to understand and sign the informed consent document.

Eligibility for administration of IL-2.

Patients must meet the following criteria to be eligible to receive IL-2:

Patients may not have active major medical illnesses such as cardiac ischemia, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

Patients with recent prolonged history of cigarette smoking or symptoms of respiratory dysfunction must have a normal pulmonary function test as evidenced by a forced expiratory volume in 1 second (FEV1) greater than 60% predicted.

Patients with electrocardiogram (EKG) abnormalities, symptoms of cardiac ischemia or arrhythmias or age greater than 50 years will have a normal stress cardiac test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine echocardiogram or other stress test).

Patients must be willing to sign a durable power of attorney (DPA).

Serum creatinine of 2.0 mg/dl or less.

Total bilirubin 2.0 mg/dl or less, except in patients with Gilbert's syndrome who must have a total bilirubin less than 3.0 mg/dl.

White blood cell (WBC) 3000/mm^3 or greater.

Platelet count 90,000 mm^3 or greater.

EXCLUSION CRITERIA:

Patients will be excluded:

Who are not willing or able to be biopsied.

Who are undergoing or have undergone in the past 3 weeks any other form of therapy for their cancer, or have undergone nitrosurea therapy within the past 6 weeks. All patients toxicities must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or local radiotherapy within the past 3 weeks as long as all toxicities have recovered to a grade 1 or less.

Have active systemic infections, coagulation disorder, or other major medical illnesses of the cardiovascular or respiratory symptoms or any known immunodeficiency disease (Immune competence will be defined as lymphocyte count greater than 500 (grade 3 toxicity in Common Toxicity Criteria (CTC) 3); white blood cell (WBC) 1000; and absence of opportunistic infections).

Who require systemic steroid therapy.

Who are pregnant (because of possible side effects on the fetus) or who are breastfeeding, or who are unwilling/unable to practice effective birth control.

Who are known to be positive for hepatitis BsAG, or human immunodeficiency virus (HIV) antibody, or hepatitis C antibody (unless antigen negative), (because of possible immune effects of these conditions).

Who have had a known allergic reaction to Incomplete Freund's Adjuvant (MONTANIDE ISA-51) or hypersensitivity to any agent used on this protocol.

Who have a fresh tumor specimen with no evidence of FGF-5 expression on a technically adequate RT-PCR assessment.

47 months