• 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 ]

• Safety
• Toxicity
• Antitumor efficacy
• Duration of in vivo persistence of adoptively transferred CD8+ antigen-specific T cell clones in the presence or absence of transferred CD4+ T cells
• Influence of low-dose aldesleukin in enhancing the in vivo persistence of transferred CD4 and CD8 T cells

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Biological therapies, such as cellular adoptive immunotherapy, may stimulate the immune system in different ways and stop tumor cells from growing. Aldesleukin may stimulate white blood cells to kill tumor cells. Giving cyclophosphamide together with cellular adoptive immunotherapy with or without aldesleukin may be an effective treatment for metastatic melanoma.

PURPOSE: This phase I/II trial is studying the side effects of cyclophosphamide, cellular adoptive immunotherapy, and aldesleukin and to see how well it works in treating patients with metastatic melanoma.

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. (Closed to accrual as of 1/6/09).

All patients will receive low-dose IL-2 subcutaneously twice daily on days 1-14. Treatment repeats every 28 days for 2 courses.

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

• Biological: aldesleukin
• Biological: therapeutic autologous lymphocytes
• Drug: cyclophosphamide
• Procedure: autologous hematopoietic stem cell transplantation

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