It is widely accepted that effective activation of T cells requires both antigenic and costimulatory signals. However, the practical approaches to translate this principle to clinical treatment of cancers are not well established. The overall goal of this study is to explore new and effective treatment modalities for tumors in experimental mouse models by manipulation of antigen delivery and T cell costimulatory pathways. The central hypothesis to be evaluated is that the delivery of antigenic signal together with costimulatory signals can provide optimal priming, expansion and differentiation of T cells leading to therapy of advanced tumors. To test this, the applicant will first determine the optimal delivery of both cytolytic T lymphocyte epitope peptides and 4-1BB costimulation leading to the regression of advanced tumors. He will address whether combined treatment leads to activation of antigen-specific T cells by increasing priming in peripheral lymphoid organs by enhancing expansion in tumor sites and by decreasing activation-induced apoptosis. Second, he will explore a novel LIGHT-HVEM costimulatory pathway for further improvement of cancer therapy by antigenic peptides and 4-1BB costimulation. Various approaches including gene transfer, recombinant LIGHT fusion protein, leucine zipper-linked LIGHT protein as well as anti-HVEM mAb will be utilized and potential mechanisms of LIGHT-HVEM in stimulating tumor immunity will be addressed. Third, he will develop pre-clinical investigations of combining antigen and costimulation in SCID mice reconstituted with a """"""""monoclonal human immune system"""""""" to test different approaches for stimulation of human T cell responses against xenografted human tumor. It is anticipated that these studies will serve as a platform for development of new approaches towards phase I clinical trials of cancer immunotherapy.
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