Medical treatment for RCC has primarily focused on biological therapies designed to mobilize immune effector cells that recognize and destroy cancer. Treatment with interleukin-2 (IL-2) and interferon alpha (IFNalpha), either singly or in combination, have shown dramatic clinical efficacy in a minority of metastatic RCC patients. The absence of benefit in the majority of patients may be due to tumor resistance and/or inadequate effector cell response. In vitro and animal studies show that dendritic cells (DC) are powerful initiators of cellular and humeral immune response and have therapeutic benefit in cancer models. Preliminary human studies suggest DC therapies have clinical and biological effectiveness in RCC patients. However, evidence suggests that immune inhibitory pathways may limit effectiveness of immunotherapy, including DC vaccines. The primary goal of combination immunotherapies is to successfully exploit complementary pathways of immune activity. DC vaccine, IL-2, and IFNalpha influence different pathways of immune activation and inhibition. DC vaccines can initiate, and at times sustain, an effective anti-tumor immune response. IL-2 induces T-cell activation and proliferation, and can overcome the negative inhibitory action of CTLA-4 on activated T-cells. IFNalpha enhances DC and T-cells function as well as tumor immunogenicity by inducing expression of MHC molecules and tumor associated antigens. We hypothesize that combined sequential DC vaccine and IL-2/IFNalpha therapy will decrease tumor-specific immune inhibition and increase tumor-specific immune activation in RCC patients. We propose to test this hypothesis in a phase H clinical trial of 33 RCC patients. Primary tumor removed as standard care will be processed for autologous vaccine. Eligible and consented patients with metastatic RCC will undergo leukapheresis to obtain peripheral blood monocyte derived DCs. DCs loaded with autologous tumor lysate administered by ultrasound guided injection into inguinal lymph nodes will be combined with IL-2 and IFNalpha therapy. We propose to determine 1) the objective clinical response rate to treatment, 2) the toxicity profile of this combined therapy, 3) the treatment related tumor-specific immune response and 4) the relationship of tumor-specific immune response and objective clinical response.
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