• Safety [ Designated as safety issue: Yes ]
  
• Toxicity [ Designated as safety issue: Yes ]
  
• Antitumor efficacy [ Designated as safety issue: No ]
  
• Duration of in vivo persistence of adoptively transferred CD8+ antigen-specific T-cell clones in the presence or absence of transferred CD4+ T cells [ Designated as safety issue: No ]
  
• Influence of low-dose aldesleukin in enhancing the in vivo persistence of transferred CD4+ and CD8+ T cells [ Designated as safety issue: No ]
  

OBJECTIVES:

• Assess the safety and toxicity of cellular adoptive immunotherapy in melanoma patients using autologous CD4+ and CD8+ antigen-specific T-cell clones.
• Evaluate the antitumor effects of CD4+ and CD8+ antigen-specific T cells in patients with metastatic melanoma.
• Determine the duration of in vivo persistence of adoptively transferred CD8+ antigen-specific T-cell clones in the presence or absence of transferred CD4+ T cells.
• Determine the influence of low-dose aldesleukin in enhancing the in vivo persistence of transferred CD4+ and CD8+ T cells.

OUTLINE: Patients undergo leukapheresis to provide peripheral blood mononuclear cells which will serve as a source of responder and stimulator cells for the in vitro generation of antigen-specific T cells over approximately 3-4 months. Patients may receive therapy during this time.

Patients receive an initial infusion of antigen-specific CD8+ cytotoxic T-lymphocyte clones over 30-60 minutes to provide a baseline for assessing the contribution of CD4+ helper T-cell clones to augmenting persistence and function of CD8+ T cells. The second infusion (given 3-4 weeks after the first) will consist of the same dose of CD8+ T cells as the first infusion, together with antigen-specific CD4+ T-cell clones. All infusions will be preceded by 48 hours with a single infusion of low-dose cyclophosphamide.

The first 6 patients will receive infusions without aldesleukin (IL-2). If no serious adverse toxicities are observed, then the next 6 patients will receive both first and second infusions with a 14-day course of low-dose IL-2 subcutaneously twice daily.

After completion of study therapy, patients are followed every 3 months.

DISEASE CHARACTERISTICS:

Inclusion criteria:

• Histopathologically documented metastatic melanoma
• Tumor expresses targeted antigen and restricting allele against which CD4+ and CD8+ T-cell clones can be generated
• Evidence of measurable residual disease by clinical examination or imaging studies
• History of CNS metastases with no current evidence of active disease allowed

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Prognosis < 6 months
• Karnofsky performance status 70-100%
• Life expectancy > 16 weeks
• WBC > 2,500/μL
• ANC > 1,000/μL
• Platelet count > 80,000/μL
• Hematocrit > 28%
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Exclusion criteria:

• Active infections or oral temperature > 38.2°C within the past 72 hours or systemic infection requiring chronic maintenance or suppressive therapy
• HIV seropositive

• None of the following is permitted prior to T-cell infusion:

  • Serum creatinine > 2.0 mg/dL
  • Hepatic toxicity ≥ grade 2 of whatever origin

  • Clinically significant pulmonary dysfunction, as determined by medical history and physical examination

    • Patients with FEV_1 < 60% of normal or DLCO (corrected for hemoglobin) < 55% are excluded

  • Significant cardiovascular abnormalities, as defined by any of the following:

    • Congestive heart failure
    • Clinically significant hypotension
    • Symptoms of coronary artery disease
    • Cardiac arrhythmias on EKG requiring drug therapy
    • Ejection fraction < 50%
  • Serum calcium > 12 mg/dL
  • History of seizures

PRIOR CONCURRENT THERAPY:

• No chemotherapeutic agents (standard or experimental), radiation therapy, or other immunosuppressive therapies < 3 weeks prior to T-cell therapy

  • Patients with bulky disease may undergo 1-2 courses of cytoreductive chemotherapy but treatment will be discontinued ≥ 3 weeks prior to T-cell therapy
  • Patients should have recovered fully from all previous treatment-related toxicities
• No other concurrent experimental drugs within the 3 weeks prior to T-cell infusion
• No concurrent steroids
• No concurrent systemic corticosteroids (except as outlined for management of toxicity of nontransduced cytotoxic T lymphocytes), immunotherapy (e.g., interleukins, interferons, melanoma vaccines, or intravenous immunoglobulin, expanded polyclonal tumor-infiltrating lymphocytes, or lymphokine-activated killer cell therapy), pentoxifylline, or other investigational agents during T-cell infusion