We have previously observed a strong bias in the functional polarization of tumor-specific CD4+ T cellresponses in the peripheral blood of patients with advanced stage renal cell carcinoma (RCC), cervicalcancer or melanoma. Notably, patients with active disseminated disease were typically characterized bypredominant Th2- or T regulatory-type immunity to tumor antigen-derived Th epitopes, while those patientssuccessfully treated and exhibiting no evidence of disease (NED) at the time of analysis, displayedprincipally Th1-type immune reactivity to these same epitopes. Virtually all patients retained Th1-typeimmunity to viral (EBV, Flu) Th epitopes, regardless of disease stage, supporting the tumor-specific nature ofimmune deviation in the CD4+ T cell compartment of these cancer-bearing patients. In the current proposal,we will determine mechanism(s) underlying Th immune deviation in patients with RCC, resolve means bywhich to correct such deficiencies in vitro and then translate corrective therapies into a phase l/ll clinical trialdesigned to treat patients with advanced stage RCC. Specifically, we will:
Aim 1. Test the hypothesis that tumor-specific Th1-type immune deviation in patients with advanced stageRCC involves tumor-induced alterations in the balance of DC functional subsets or DC-expressedcostimulatory molecues.
Aim 2. Test the hypothesis that tumor-specific Th1-type immune dysfunction in RCC patients with activedisease involves the preferential apoptosis of Th1-type, but not Th2- or T regulatory-type CD4+ T cells.
Aim 3. Test the hypothesis that aDC1-based vaccines can correct dysfunctional, antigen-specific Type-1immunity in vitro.
Aim 4. Test the hypothesis that aDC1/tumor peptide-based vaccination of RCC patients with advanceddisease will correct dysfunctional anti-RCC Type-1 CD4+ T cell responses in a phase l/ll clinical trial.
Showing the most recent 10 out of 110 publications
