Clinical protocol. Immunization of patients with malignant melanoma with autologous CD34+ cell-derived dendritic cells transduced ex vivo with a recombinant replication-deficient vaccinia vector encoding the human tyrosinase gene: a phase I trial

Protocol title: Immunization of Patients with Malignant Melanoma with Autologous CD34+ Cell-Derived Dendritic Cells Transduced Ex Vivo with a Recombinant Nonreplicating Vaccinia Vector Encoding the Human Tyrosinase Gene: A Phase I Trial. Study Phase: Phase I. Study Design: Nonrandomized, noncontrolled, single center. Study Objectives: Primary objective: Define the safety and toxicity of DCs/MVA-hTyr vaccine in patients with measurable metastatic melanoma. Secondary objectives: (1) to determine whether immunization with DCs/MVA-hTyr vaccine induces tyrosinase and melanoma-specific immune responses such as (a) development or enhancement of T lymphocyte-mediated responses in peripheral blood; (b) measurable delayed-type hypersensitivity (DTH) response in vivo; (c) development of antityrosinase antibodies in serum of treated patients; and (d) infiltration and expansion of tyrosinase-specific T lymphocytes in the inoculation site; and (2) to document any tumor regression and/or pigmentation modification that may result from immunization against tyrosinase. Number of Subjects: The total number of patients expected to complete this study is six. Study Population: Patients with malignant melanoma stage IV or high-risk stage III with measurable metastatic melanoma. Treatment Groups: Four vaccinations containing 100 X 106 DCs/MVA-hTyr will be given four times at 2-week intervals; the 1° vaccination will be given intravenously; the 2°, 3°, and 4° vaccinations will be given subcutaneously. Duration of Study: 20 weeks. Visit Schedule: Screening visit(s) Admission to the general clinical research center and baseline studies Preparative phase with the administration of filgrastim for six consecutive days followed by leukapheresis Immunization phase Follow-up visits monthly for 3 months and then at 2-month intervals for survival and general condition until death Safety parameters: Physical examination and measurements of melanoma lesions Complete blood tests Antimelanoma T lymphocyte (both CD8+ and CD4+) responses Ophthalmology evaluation including fundoscopy and visual acuity Neurological evaluation Cardiac rhythm, including Holter. Efficacy Parameters: Tumor response and time to progression by physical examination and CT scan Progression-free survival Overall survival Hypopigmentation Immunological evaluation: Melanoma antigen-specific and/or melanoma-specific CTL precursor frequency; antigen-specific HLA class II-restricted T cell responses; anti-tyrosinase antibodies in serum of treated patients; whenever possible biopsy at the site of vaccination to evaluate the infiltrate.