RATIONALE: Biological therapies use different ways to stimulate the immune system and stop
tumor cells from growing. Treating a person's white blood cells in the laboratory and
reinfusing them may cause a stronger immune response and kill more tumor cells.
PURPOSE: Phase I trial to study the effectiveness of biological therapy in treating patients
who have metastatic melanoma.
- Determine the maximum tolerated dose of autologous CD4+ antigen-specific T-cells for
cellular adoptive immunotherapy in patients with metastatic melanoma.
- Determine the safety and toxicity of this regimen in these patients.
- Determine the duration of in vivo persistence of adoptively transferred CD4+
antigen-specific T-cell clones in these patients.
- Determine the antitumor effects of this regimen in these patients.
OUTLINE: This is a dose-escalation study.
Patients undergo leukapheresis to collect peripheral blood mononuclear cells. CD4+
antigen-specific T-cell clones are generated over the next 2-3 months using immunogenic
peptides MART1, tyrosinase, or gp100.
Patients receive autologous CD4+ antigen-specific T-cells IV over 30 minutes.
Cohorts of 3-6 patients receive escalating doses of autologous CD4+ antigen-specific T-cells
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Patients are followed on days 1 and 3 post T-cell infusion, and then once weekly for 12
PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for this study.
- Histologically confirmed metastatic melanoma
- HLA type expressing one of the following class II alleles:
- Tumor expresses tyrosinase
- Tumor expressing NY-ESO-1 and are HLA type DP4, DP2, or DR7 allowed
- No CNS metastases
- Prior CNS involvement allowed provided there is no evidence of CNS disease at
least 2 months after treatment
- 18 to 75
- Karnofsky 70-100%
- More than 16 weeks
- WBC greater than 4,000/mm^3
- Absolute neutrophil count greater than 2,000/mm^3
- Platelet count greater than 100,000/mm^3
- Hematocrit greater than 30%
- SGOT no greater than 3 times upper limit of normal
- INR no greater than 1.5 due to hepatic dysfunction
- No significant hepatic dysfunction, defined as hepatic toxicity grade 2 or greater
- Creatinine no greater than 2.0 mg/dL OR
- Creatinine clearance at least 60 mL/min
- Calcium no greater than 12 mg/dL
- No significant cardiac abnormalities*, defined by any 1 of the following:
- Congestive heart failure
- Clinically significant hypotension
- Symptoms of coronary artery disease
- Cardiac arrhythmias present on EKG requiring drug therapy NOTE: *Patients with a
history of cardiovascular disease or any of the above abnormalities undergo a
cardiac evaluation, including a cardiac stress test and/or echocardiogram
- No clinically significant pulmonary dysfunction
- FEV1 at least 1.0 L OR
- FEV1 at least 60%
- DLCO at least 55% (corrected for hemoglobin)
- No acquired or hereditary immunodeficiency
- No autoimmune disease
- No active infection
- No oral temperature greater than 38.2 degrees C within the past 72 hours
- No systemic infection requiring chronic maintenance or suppressive therapy
- HIV negative
- No retinitis or choroiditis
- No history of seizures
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 3 months after study
PRIOR CONCURRENT THERAPY:
- No other concurrent immunotherapy (e.g., interleukins, interferons, melanoma
vaccines, IV immunoglobulin, or expanded polyclonal tumor-infiltrating lymphocytes or
lymphokine-activated killer therapy)
- At least 4 weeks since prior chemotherapy (standard or experimental) and recovered
- No concurrent systemic steroids except for toxicity management
- At least 4 weeks since prior radiotherapy
- Not specified
- At least 4 weeks since prior immunosuppressive therapy
- More than 4 weeks since prior experimental drugs and recovered
- No concurrent pentoxifylline
- No other concurrent investigational agents