Changes of CD4+ Lymphocyte Profile in Patients with Renal Cell Carcinoma and its

$245,404P01FY2008CANIH

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

We have previously observed a strong bias in the functional polarization of tumor-specific CD4+ T cell[unreadable] responses in the peripheral blood of patients with advanced stage renal cell carcinoma (RCC), cervical[unreadable] cancer or melanoma. Notably, patients with active disseminated disease were typically characterized by[unreadable] predominant Th2- or T regulatory-type immunity to tumor antigen-derived Th epitopes, while those patients[unreadable] successfully treated and exhibiting no evidence of disease (NED) at the time of analysis, displayed[unreadable] principally Th1-type immune reactivity to these same epitopes. Virtually all patients retained Th1-type[unreadable] immunity to viral (EBV, Flu) Th epitopes, regardless of disease stage, supporting the tumor-specific nature of[unreadable] immune deviation in the CD4+ T cell compartment of these cancer-bearing patients. In the current proposal,[unreadable] we will determine mechanism(s) underlying Th immune deviation in patients with RCC, resolve means by[unreadable] which to correct such deficiencies in vitro and then translate corrective therapies into a phase l/ll clinical trial[unreadable] designed to treat patients with advanced stage RCC. Specifically, we will:[unreadable] Aim 1. Test the hypothesis that tumor-specific Th1-type immune deviation in patients with advanced stage[unreadable] RCC involves tumor-induced alterations in the balance of DC functional subsets or DC-expressed[unreadable] costimulatory molecues.[unreadable] Aim 2. Test the hypothesis that tumor-specific Th1-type immune dysfunction in RCC patients with active[unreadable] disease involves the preferential apoptosis of Th1-type, but not Th2- or T regulatory-type CD4+ T cells.[unreadable] Aim 3. Test the hypothesis that aDC1-based vaccines can correct dysfunctional, antigen-specific Type-1[unreadable] immunity in vitro.[unreadable] Aim 4. Test the hypothesis that aDC1/tumor peptide-based vaccination of RCC patients with advanced[unreadable] disease will correct dysfunctional anti-RCC Type-1 CD4+ T cell responses in a phase l/ll clinical trial.

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