Using melanoma peptide loaded CD34-DCs, a composite vaccine composed of Langerhans cells and? Interstitial DCs, we have demonstrated that DC vaccines can induce tumor-specific immunity, as well as? some clinical responses. Two major questions arise: 1) Why is the composite vaccine efficient? and 2) How? can the therapeutic immunogenicity of DC vaccines be improved? With this in mind, AIM 1 will test the? hypothesis that composite DC vaccines loaded with killed allogeneic melanoma cells will have superior? therapeutic efficacy, because of i) presentation of multiple tumor antigen epitopes to both CD4 and CDS T? cells, and ii) strong allogeneic help. This will be a Phase l/ll single arm clinical trial which Primary Objective? is induction of melanoma antigen-specific CD8+T cells and Secondary Objective is induction of objective? clinical responses. The trial is powered based on the rate of induction of melanoma-specific CD8+T cell? immunity and will accrue up to 51 metastatic melanoma patients. Interim analyses will be conducted after 9? and 24 patients are enrolled to assess toxicity and immunogenicity. Immune responses will be assessed? using EPIMAX strategy. The 2 main quantitative assays involve melanoma antigen-specific IFN-gamma? release (effector memory cells) and cell proliferation (CFSE and flow cytometry; recall memory) by T cells in? short term PBMCs cultures with selected melanoma antigen-peptides.
AIM2 will assess the helper functions? of melanoma antigen-specific CD4+T cells in patients vaccinated with composite DCs loaded with killed? allogeneic melanoma cells. We want to establish an assay to measure the ability of melanoma-antigen? specific CD4+T cells to prime melanoma-antigen specific CD8+T cells.
AIM 3 will determine which DC? subset present in composite DCs vaccines primes melanoma antigen-specific CD4+T cells that help CD8+T? cells.
AIM 4 will test the hypothesis that further activation of myeloid DC vaccines, indirectly through the? activation of pDCs or exposure to IFN-a, will increase their efficacy in vitro.
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