P1-01-12: Mesoporous Silicon Particles for the Presentation of Tumor Antigens and Adjuvant for Anti-Cancer Immunity.

Abstract

Abstract Custom-made vaccines based on personalized tumor antigens are realistic options for secondary therapy, with the patient's excised tumor providing antigens. Overlap in the personalized repertoire of tumor antigens among patients also provides insight into targets for preventative cancer vaccines. Nanotechnology provides carriers for shielded delivery of antigens and presentation of immunostimulatory molecules. Rapid uptake of particles by phagocytic immune cells and migration to lymphatic tissue for antigen presentation provides opportunities to elicit tumor specific immune responses. Dendritic cells (DC) are the master antigen presenting cells (APC) for efficient processing and presentation of antigens. We have tested the ability of mesoporous silicon particles (pSi) to function as substrates for DC and to activate cells via engagement of surface toll-like receptors (TLR). pSi particles, surface labeled with lipopolysaccharide (LPS) or monophosphoryl lipid (MPL), were presented to bone marrow-derived DC. This resulted in rapid uptake of particles, with an enormous capacity for number of particles internalized per cell. Confocal microscopy studies supported higher uptake of LPS and MPL conjugated as compared to unlabeled pSi. pSi particle uptake into DC was also supported by electron microscopy imaging. TLR ligands induced morphological changes in GM-CSF stimulated cells consistent with maturation towards a DC phenotype. As expected, LPS conjugation to particles resulted in significant toxicity. MPL conjugated pSi showed little or no toxicity to DC and showed improved particle uptake into DC with morphological changes consistent with maturation towards a mature DC phenotype.The impact of cytokine cocktail on DC maturation and its impact on particle uptake were also examined. Flow cytometry analysis supported greater uptake of pSi by DC stimulated with GM-CSF and IL-4 compared to GM-CSF alone, with reduced uptake in the presence of TNF-alpha. Consistent with findings reported by others, addition of TNF-alpha to the cell media also resulted in higher levels of expression of costimulatory molecules by DC, compared to cells stimulated with GM-CSF alone. Thus immature DC are better able to internalize particle-based vaccines, with cytokine or TLR-driven maturation enhancing expression of costimulatory molecules for more effective antigen presentation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-12.