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Molecular & Cellular Analysis Technologies
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Metastatic melanoma patients currently have a dismal diagnosis, and treatment at the metastatic stage is generally ineffective. The long-term objective of this research project is to develop a novel treatment and vaccination approach for cancer in general, and melanoma in particular, based on immunotherapy. Ex vivo antigen delivery for immunotherapy is laborious and expensive, and is thus not affordable to many of those in need. The investigators propose to develop an antigenic entity that can be applied on the skin, with direct antigen delivery to skin dendritic cells and without the need for in vitro cell manipulations. Thus, the major practical objective of this study is to establish the proof of principle that topically delivered tumor associated antigens can elicit effective anti-tumor responses, and can be used for cancer immunotherapy. Specific Alms The study will be based on two antigenic proteins derived from melanoma: the first is a hydrophilic recombinant gp100 protein, and the second is a multiepitope polypeptide that comprises 3', repeats of 4 HLA-A2 melanoma peptides derived from 3 different melanoma proteins. In order to allow and to improve topical transdermal delivery, the antigens will be genetically fused to potential carrier molecules. One of these is E. coli heat labile enterotoxin, a molecule recently shown to act as carrier and adjuvant. Another is a novel haptotactic C-terminal fibrinopeptide (Haptide). During the first phase of the project, R21, the new antigenic entities will be cloned, expressed, and purified. Novel in vitro models using human skin will be used to evaluate transcutaneous passage of molecules, Langerhans' cells activation and mobilization, and stimulation of specific cytotoxic T cells. The rationale for the milestones that will determine continuation to the second phase, R33, is based on the efficacy of antigen delivered transcutaneously to stimulate the immune system in human in vitro models, and will allow for the selection of the molecules that will be further evaluated in depth in vivo models. In the R33 phase, specific immune responses of splenic T cells from vaccinated mice will be evaluated, tumor models will be established in mice, and the response to vaccination will be determined. Finally, the most effective molecule/s will be produced under GMP or GMP-like conditions for phase I/II clinical trials in a subsequent study. Public Health The success of this project would allow topical application of an immunostimulant for treatment of melanoma and other cancers and would thus significantly simplify treatment, eliminating the need for hospitalization and even day-care and without the need for a specialized laboratory. As a result, one could treat a much larger number of patients, with the potential to clinically evaluate new antigens and immunotherapeutic modalities, improving the life quality and expectancy of metastatic melanoma patients