RATIONALE: Vaccines made from peptides may make the body build an immune response to kill tumor cells.

PURPOSE: This randomized phase II trial is studying four different vaccines using melanoma peptides from cytotoxic T cells and helper T cells to see how well they work in treating patients with metastatic melanoma.

OBJECTIVES:

• Compare the cytotoxic T-cell response to each of 12 melanoma peptides restricted by HLA-A1, -A2, or -A3 in patients with metastatic melanoma vaccinated with or without these 12 melanoma peptides and with or without helper peptides.
• Compare the helper T-cell response to each of 6 melanoma helper peptides restricted by HLA-DR molecules in patients treated with these vaccinations.
• Determine whether the addition of 6 melanoma helper peptides to a vaccine containing multiple class I MHC-restricted peptides augments T-cell responses to the class I restricted peptides in these patients.
• Determine, preliminarily, whether booster vaccination maintains immune response in patients treated with these vaccinations.
• Compare the rates of clinical response and survival in patients treated with these vaccinations.
• Determine, preliminarily, whether cellular immune response correlates with clinical response and survival rates in patients treated with these vaccinations.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to HLA type (HLA-A1 vs HLA-A2 vs HLA-A1 and -A2 vs HLA-A3) and planned sentinel immunized node biopsy (yes vs no). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Arm II: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 1 tetanus helper peptide emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Arm III (closed to accrual as of 5/19/08): Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Arm IV: Patients receive 2 injections of multi-epitope peptide vaccine comprising 6HP emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

In all arms, patients continue therapy in the absence of unacceptable toxicity or disease progression necessitating other urgent therapy.

Patients are evaluated at 8 and 12 weeks. Beginning 2-3 weeks after the week-12 evaluation, patients with no evidence of disease progression may receive booster vaccinations according to their randomized treatment arm. Patients receive booster vaccination ID and SC once weekly for 3 weeks. Treatment repeats every 9 weeks for 1 course, every 12 weeks for 2 courses, and then every 24 weeks for 2 courses OR for up to 2 years (whichever comes first) provided the patient does not require an urgent change in therapy.

After completion of study treatment, patients are followed every 6 months for 2 years and then for survival for 5 years from study randomization.

PROJECTED ACCRUAL: A total of 176 patients (44 per treatment arm) will be accrued for this study within 3 years.

• Biological: incomplete Freund's adjuvant
• Biological: melanoma helper peptide vaccine
• Biological: multi-epitope melanoma peptide vaccine
• Biological: sargramostim
• Biological: tetanus peptide melanoma vaccine

• Experimental: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Experimental: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 1 tetanus helper peptide emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Experimental: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
• Experimental: Patients receive 2 injections of multi-epitope peptide vaccine comprising 6HP emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

DISEASE CHARACTERISTICS:

• Histologically confirmed stage IV melanoma

  • Multiple primary melanomas allowed
  • Metastasis may be from a cutaneous, mucosal, ocular, or unknown primary site
• Measurable disease by RECIST criteria
• Must have 2 extremities uninvolved with tumor

• Must have at least 2 intact (undissected) axillary and/or inguinal lymph node basins

  • Prior sentinel node biopsy may not have violated the integrity of a nodal basin

    • This extremity may still be considered for vaccination
• HLA-A1, -A2, or -A3 positive

• Prior brain metastases allowed provided all of the following are true:

  • No more than 3 brain metastases
  • Metastatic lesions no greater than 2 cm
  • Surgically resected or treated with gamma-knife or stereotactic radiosurgery
  • No disease progression in the brain for the past 3 months
  • More than 30 days since prior steroids for the management of brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC at least 4,000/mm^3
• Platelet count at least 100,000/mm^3
• Lymphocyte count at least 700/mm^3

Hepatic

• SGOT and SGPT no greater than 2 times upper limit of normal (ULN)
• Bilirubin no greater than 2 times ULN
• Alkaline phosphatase no greater than 2 times ULN
• Lactic dehydrogenase no greater than 2 times ULN

Renal

• Creatinine no greater than 1.8 mg/dL

Immunologic

• No known or suspected major allergy to any components of the study vaccine
• No significant detectable infection
• No immunosuppression conditions

• No prior or active autoimmune disorder requiring cytotoxic or immunosuppressive therapy, except for any of the following:

  • Presence of laboratory evidence of autoimmune disease (e.g., positive ANA titer) without symptoms
  • Clinical evidence of vitiligo or other forms of depigmenting illness
  • Mild arthritis requiring nonsteroidal anti-inflammatory medication
• No autoimmune disorder with visceral involvement

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No recent (within the past year) or concurrent addiction to alcohol or illicit drugs
• No other malignancy within the past 5 years except nonmetastatic squamous cell or basal cell skin cancer, ductal or lobular carcinoma in situ of the breast, or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 4 weeks since prior sargramostim (GM-CSF), interferon alfa-2b, or interleukin-2
• No prior vaccination with any of the study peptides

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics

• More than 30 days since prior systemic corticosteroids, including any of the following:

  • Therapeutic doses of oral steroids (e.g., prednisone or dexamethasone)

  • Steroid inhalers (e.g., Advair)

    • Topical steroids and nasal steroids with low systemic absorption (e.g., fluticasone) or steroids with low systemic absorption (e.g., triamcinolone hexacetonide) injected into a joint space allowed
• No concurrent corticosteroids
• No concurrent topical or systemic steroids

Radiotherapy

• See Disease Characteristics
• No prior radiotherapy to measurable disease
• At least 4 weeks since prior local control or palliative radiotherapy and recovered
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• Recovered from prior major surgery
• No concurrent surgery