My career goal is to design and apply novel immunological approaches for treatment of advanced tumors of the head and neck. Patients with untreated and/or unresectable squamous cell carcinoma of the upper aerodigestive tract are particularly challenging to treat as they are often systemically immunosuppressed. Initial attempts to overcome this immunosuppression have utilized an approach termed adoptive immunotherapy. Adoptive immunotherapy involves injecting tumor cells into lymph nodes to generate tumor-specific T-cells, harvesting the T-cells, expanding and activating them ex vivo and infusing them into patients. Despite initial promise, adoptive transfer has met with only limited success, largely due to lack of efficient stimulation of tumoricidal T-cells. We hypothesize that the effectiveness of adoptive immunotherapy can be extended by in vivo priming of T-cells with dendritic cells (DC) loaded with tumor-derived heat shock proteins (HSP). Recently, it has been shown that HSP shuttle antigenic peptides to intracellular sites where MHC-peptide complexes are selected/assembled. When HSP are extracted from tumor cells, they carry nonselected intracellular peptides, e.g. tumor antigens, and such HSP have been successfully used for the induction of tumor-specific immunity. In this study, we will """"""""educate"""""""" DC ex vivo by loading with tumor specific HSP and subsequently use this DC/HSP vaccine for stimulation of tumoricidal T cells.
The specific aims of this proposal are to determine the efficacy of HSP-educated DC (DC/HSP) in stimulating a tumor-specific immune response; to determine the role of DC/HSP in preventing spontaneous tumor metastasis in murine melanoma model and to evaluate the role of DC/HSP in priming T cells derived from tumor-draining lymph nodes for use in adoptive immunotherapy. Successful accomplishment of these goals will provide scientific basis for improvement of adoptive immunotherapy of cancer and for development of clinical trials for treatment of patients suffering form advanced squamous cell carcinoma of the upper aerodigestive tract.
