Based on genetic cloning approaches and protein sequencing techniques, a number of tumor associated antigens (TAA), principally melanoma antigens, have been recently identified. These TAA contain peptide sequences presented in the context of major histocompatibility complex (MHC) molecules expressed by tumor cells that are capable of being recognized by the effector T cells. The induction of T cells or adoptive transfer of T cells reactive against TAA in vivo has been associated with objective clinical responses in up to 40% of melanoma patients treated. Such approaches have thus far focused exclusively on implementing or activating CD8+ T cells in patients with melanoma. In order to provide a greater degree of utility of such therapeutic vaccines for a greater profile of patients with cancer, the applicant proposes in this competitive renewal application to prioritize the TAA identification process towards those antigens that are shared by multiple tumor cell types (i.e. multilineage) or that are expressed by non-melanocytic lineage tumors in order to provide tools for the ultimate construction of therapeutic vaccines designed for a more diverse audience of patients with cancer. This will be accomplished using a novel T cell induction system that implements the potent immunostimulatory capacity of autologous dendritic cells (DC). DCs pulsed with tumor-derived peptides or proteins, or transfected with tumor antigen cDNA, will be used to promote the expansion of HLA-restricted anti-tumor T cells in vitro. Further, the applicant will investigate and identify TAA and TAA-derived epitopes that are recognized either by CD8+ T cells or CD4+ T cells, and evaluate their anti-tumor immunogenicity in vitro. It should be stressed that this latter class of CD4+ T cell epitopes has received minimal attention in the past and will likely provide useful reagents for the optimal induction of an effective anti-tumor immune response in vivo. Such epitopes may elicit effector CD4+ T cells, promote """"""""help"""""""" for the efficient generation and maintenance of effector CD8+ T cells, or may mediate the recruitment of additional immune arms to tumor sites. The applicant believes that this information will provide him with a more complete understanding of the resident immune response directed against TAA-derived epitopes, and will ultimately facilitate the design of clinical protocols for the treatment of patients with tumors of diverse lineages.
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