Preclinical Evaluation of Novel Dendritic Cell-Based Prostate Cancer Vaccines; Annual summary rept. 1 Jan-31 Dec 2007

摘要

To enhance DC-based vaccines, we used the combination of a synthetic ligand-inducible CD40 receptor (iCD40) along with TLR-4 ligation in human monocyte-derived DCs. The iCD40 receptor permits targeted, reversible activation of CD40 in vivo, potentially bypassing the essential role of CD4+ T cells for activation of DCs. As a rigorous preclinical study of this approach, we evaluated key parameters of DC activation and function. While neither iCD40 nor TLR4 signaling alone led to high levels of IL-12p70 and IL-6, using iCD40 in combination with lipopolysaccharides (LPS) led to strongly synergistic production of both. Furthermore, this approach led to high expression of DC maturation markers, epitope-specific cytotoxic T cell and TH1 responses, as well as DC migration in vitro. Moreover, use of iCD40-modified and LPS- stimulated DCs led to targeted expansion of autologous T cells against the attractive tumor-associated antigen, prostate-specific membrane antigen (PSMA), supporting this technology as a potent strategy for DC-based prostate cancer immunotherapy.