Abstract SY03-03: Modulating innate and adaptive immunity through the manipulation of dendritic cells

Abstract

Abstract Dendritic cells (DC) are potent antigen presenting cells used in clinical trials to treat cancer and infectious diseases such as HIV. We have performed two types of clinical trials to evaluate their immunogenicity in vivo. First, we compared DC to conventional vaccine adjuvants. HLA-A2+ resected melanoma patients were enrolled into a randomized clinical trial to compare vaccines comprised of six HLA-A2-restricted peptide antigens and a foreign protein, KLH, either pulsed onto cytokine-matured, monocyte-derived DCs or emulsified in the mineral oil adjuvant Montanide ISA 51. The frequency, magnitude and quality of antigen-specific cellular immune responses in peripheral blood were found to be greater in patients receiving the Montanide vaccine. Furthermore, the primed cells were functionally superior, indicating a need to improve current DC-based vaccine approaches. Preclinical studies in mice were undertaken to evaluate the mechanism by which DC prime T cells. Contrary to previous assumptions, we found that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches will focus on creating DC vaccines that are more effective at directly priming T cells, by altering maturation factors, or abrogating the tumor induced suppression of endogenous DCs In a second approach, we used TLR agonists targeting TLR 7, 8 and/or 9 to prime immunity to melanoma associated antigens in a series of clinical trials. They include imiquimod, resiquimod and CpG, agonists for TLR7 and/or TLR 8 and TLR9 respectively. These adjuvants when combined with the cancer testis antigen NY-ESO-1, induced integrated immune responses which were characterized by the induction of both CD4+ and CD8+ T cell immunity as well as antigen-specific antibodies in patients with resected melanoma. Strategies to optimize these various approaches to induce immunity in cancer and other chronic diseases will be discussed. Citation Format: Nina Bhardwaj. Modulating innate and adaptive immunity through the manipulation of dendritic cells [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY03-03