Revised Abstract: Vaccination with MHC class I restricted epitopes elicit CD8+ cytotoxic T cells (CTL). In contrast, the use of unfractionated tumor as antigenic material should provide both MHC class I and class II epitopes leading to a diverse immune response involving many clones of CD4 T cells and CTL. Hence we test whether dendritic cells loaded with dying allogeneic melanoma cells can elicit melanoma-specific CD4 and CD8 T cell responses in stage IV melanoma. We will use monocyte derived DC (MDC) to elicit CD4 and CD8 T cells specific for multiple melanoma TAA. We will establish: 1) the ability of CD4 and CD8 cells from healthy volunteers and from patients with stage IV melanoma to mount melanoma-specific immunity in vitro, 2) the ability of HLA-A2.1 stage IV patients to mount melanoma-specific CD4 and CD8 responses after administration of CDC loaded with either melanoma peptides or dying melanoma cell bodies in a two-center randomized clinical trial including 48 patients Our 5 aims can be summarized as follows:
Aim 1 : To identify optimal maturation conditions for MDC pulsed with dying melanoma cells.
Aim 3 : To assess in vitro CD4T cell responses from stage IV melanoma patients to MDC pulsed with dying melanoma cells.
Aim 4 : To establish in vivo the safety, tolerability and immunogenicity of mature MDC loaded with melanoma peptides or allogeneic dying melanoma cells in stage IV patients.
Aim 5 : To analyze melanoma-specific T cells in blood, tumor and lymph nodes of patients immunized with DC loaded with dying melanoma cells. These studies should allow us to determine the most efficient TAA preparation to use in future vaccination trials aimed at establishing clinical responses.
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