Immunization of Patients With Renal Cancer Using HLA-A2 and HLA-A3-Binding Peptides From Fibroblast Growth Factors 5 (FGF-5)

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.