Administration of adjuvants (eg, granulocyte-macrophage colonystimulating factor [GM-CSF] or Tolllike receptor [TLR] ligands) may further bolster the immune response. Dendritic Cell Tyrphostin AG-1478 chemical structure vaccines Vaccines consisting of autologous antigen-presenting cells, including DCs manipulated to enhance the presentation of tumor antigens to CTLs, have

advanced to mature stages of clinical development. DCs are efficient APCs that express several costimulatory molecules that participate in the activation of T cells.7 Mature DCs can be generated in the laboratory by exposing multipotent CD34+ hematopoietic progenitor cells first to stem cell factor (SCF) Inhibitors,research,lifescience,medical and FLT3 ligand and second to GM-CSF, interleukin (IL)-4 and tumor necrosis Inhibitors,research,lifescience,medical factor (TNF)-α or by exposing myeloid progenitor CD14+ cells to GM-CSF and IL-4, which can then be pulsed with the TAA. The desired results are APCs/DCs

presenting both MHC-I- and MHC-II-derived TAA on the cell surface. The most common ex vivo technique is to pulse DCs with TAA proteins or peptides, Inhibitors,research,lifescience,medical which are then phagocytosed, processed, and presented by the DCs, or with messenger RNA (mRNA) of the TAA or derived from tumor cells, enabling the cell’s own genetic machinery to produce the TAA proteins, enhancing presentation by the MHC-I pathway. The optimal method of production, and the route and schedule of administration of DC vaccines, are unknown and may vary depending on the target cancer type. Sipuleucel-T Sipuleucel-T (Provenge®; APC8015, Inhibitors,research,lifescience,medical Dendreon Corp, Seattle, WA) is a cellular product consisting of autologous peripheral blood mononuclear cells obtained by leukapheresis and enriched for a CD54+ DC fraction pulsed with PA2024, a prostatic acid phosphatase (PAP)-GM-CSF construct.8 GM-CSF functions to enable efficient GM-CSF receptor-mediated uptake of the PAP antigen moiety. Following promising results in early trials, 127 previously untreated Inhibitors,research,lifescience,medical men with asymptomatic, metastatic CRPC were

randomized 2:1 in a phase III clinical trial (D9901) to receive sipuleucel-T or placebo as intravenous (IV) infusions every 2 weeks × 3.9 Crossover to the vaccine was allowed for progressing placebo patients. Eligible patients were not on steroids, had no visceral metastasis, and > 25% of cancer cells were required to be positive for the expression of PAP. The primary endpoint of time to progression (TTP) displayed a trend to statistical significance why for the superiority of sipuleucel-T (P = .052). The median overall survival was 25.9 months for those on sipuleucel-T compared with 21.4 months for those on placebo (P = .01). At the preplanned 3-year survival analysis, 34% of sipuleucel-T-treated patients were alive compared with 11% of placebo-treated patients (P = .0046). PCa-specific survival was also improved with a hazard ratio (HR) of 2.04 (P = .002).