Cyclophosphamide and Fludarabine Followed by Cellular Adoptive Immunotherapy and Vaccine Therapy in Patients With Metastatic Melanoma

OBJECTIVES:

• Determine the magnitude and duration of the expansion of antigen-specific T-cells present in post-vaccination peripheral blood mononuclear cells and reinfused after immunosuppression in patients with metastatic melanoma.
• Characterize the T-cell subsets (phenotype, function, T-cell receptor repertoire) in these patients.
• Determine the tumor response in patients treated with this regimen.
• Determine the toxicity of this regimen in these patients.

OUTLINE: This is an open-label dose-finding study. Patients undergo leukapheresis to collect whole peripheral blood mononuclear cells (PBMC). Patients are then assigned to 1 of 3 treatment groups.

• Group 1 (closed to accrual as of 5/8/2007): Patients receive cyclophosphamide IV on days -7 and -6 and fludarabine IV on days -5 to -3. Patients undergo autologous PBMC infusion on day 0. Patients also receive vaccination comprising Melan-A vaccine emulsified in incomplete Freund's adjuvant (IFA) subcutaneously (SC) once every 3 weeks beginning on day 0.
• Group 2 (closed to accrual as of 8/15/2007): Patients receive cyclophosphamide IV at a higher dose than in group 1 on days -7 and -6 and fludarabine IV on days -5 to -3. Patients also receive an autologous PBMC infusion and Melan-A vaccine emulsified in IFA as in group 1.
• Group 3: Patients receive cyclophosphamide IV at 30 mg/kg on days -7 and -6. Patients also receive fludarabine 30 mg/m2 IV on days -5 to -3, autologous PBMC infusion on day 0,and Melan-A vaccine emulsified in IFA and IMP321. The first 3 patients receive 25 micrograms of IMP321, in the absence of severe 3 or 4 toxicity, the dose will be escalated to IMP321 250 micrograms.

PROJECTED ACCRUAL: A total of 9 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of metastatic melanoma
• Progressive disease after receiving prior Melan-A peptide vaccine on an immunotherapy protocol of the Ludwig Institute AND achieved a detectable immune response (increase of specific CD8^+ TET^+ Melan-A)
• Tumor must express MART-1/Melan-A antigen
• HLA-A2 positive
• Not eligible for other protocols due to progressive disease OR maximum number of vaccine injections with stable disease has been attained

PATIENT CHARACTERISTICS:

• Performance status 0-2
• Whole blood counts normal
• Pulmonary status normal
• Transaminases < 1.5 times upper limit of normal (ULN)
• Gamma-glutamyl-transferase < 1.5 times ULN
• Bilirubin normal
• Creatinine clearance > 70 mL/min
• No major uncontrolled heart disease
• No arterial hypertension

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior chemotherapy, biologic therapy, radiotherapy, and/or surgery allowed