Immunization of Patients With Renal Cancer Using HLA-A2 and HLA-A3-Binding Peptides From Fibroblast Growth Factors 5 (FGF-5)
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.
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
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.
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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
Overall response is defined as the best response (e.g. complete response...) recorded from the start of treatment until disease progression/recurrence. Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions. Progressive disease is at least a 20% increase in the sum of LD of target lesions since the treatment started or the appearance of new lesion. Stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.
3 years and 9 months
James Yang, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
|National Cancer Institute (NCI)||Bethesda, Maryland 20892|