We found that administration of peptide-loaded CD34-DC vaccine can lead to therapeutic immunity in? metastatic melanoma. This """"""""composite vaccine"""""""" includes several DC subsets, the combination of which may? contribute to vaccine efficacy. We have also found that culturing monocytes with GM-CSF and TNF yields a? composite vaccine that is phenotypically different from the """"""""traditional"""""""" GM-CSF/IL-4 monocyte-derived DCs,? while it appears similar to CD34-DCs. Such vaccine would offer a great advantage for clinical trials as it can? be generated within 3 days and does not require G-CSF treatment of the patients. The feasibility of? administering such vaccine has already been shown with ten patients. We also found that monocyte-derived? IL4-DCs loaded with killed allogeneic melanoma cells induce clinical and immunological responses. We? hypothesize that monocyte-derived composite DC vaccines loaded with killed allogeneic melanoma cells? activated with TLR agonists ex vivo will induce clinical and immunological responses. Therefore, AIM 1 will? optimize the TNF-MDCs vaccine loaded with killed allogeneic Colo829 melanoma cells and activated via? TRLs and CD40.
AIM 2 will establish in vivo the immunogenicity of TNF-MDCs loaded with killed allogeneic? melanoma cells in patients 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.
AIM 3 will determine the breadth and? the quality of melanoma-specific CD8+T cell immunity in patients vaccinated with composite DCs loaded with? killed allogeneic melanoma cells. We will determine 1) the breadth of immune response, i.e. beyond the five? antigens selected for immunomonitoring; 2) the function of elicited CD8+T cells; and 3) the authentic killing of? melanoma tumors in vivo in the OncoHumouse.?
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