More promising antitumor strategies utilize combination therapies, with each strategy targeting a separate aspect of oncogenesis. Imprime PGG® (Imprime PGG) is a soluble beta-1,3/1,6 glucose polymer being developed as an adjunct to monoclonal antibody (MAb) therapy for cancer. Imprime PGG, a pathogen- associated molecular pattern isolated from the cell wall of S. cerevisiae, has shown therapeutic antitumor and survival-enhancing effects when combined with an antitumor MAb in several in vivo syngeneic and xenogeneic tumor models. Here, we evaluated and characterized the antitumor activity and functional synergy of Imprime PGG in combination with an anti-EGFR MAb, cetuximab, in two different cancers, using an EGFR+ human pancreatic tumor line, MiaPaCa-2, and an EGFR+ human ovarian tumor line, SKOV-3. The objectives of this study were: (1) Evaluate the ability of cetuximab to activate complement as measured by iC3b opsonization on tumor cells (measured by flow cytometry using a FITC anti-human iC3b MAb); (2) Characterize tumor cells for expression of the complement regulatory proteins (CRP) CD46, CD55 and CD59 (measured by flow cytometry using fluorescently-labeled CRP-specific antibodies); (3) Evaluate tumor cytolysis following treatment with cetuximab +/- Imprime PGG in the absence and presence of human peripheral blood mononuclear cells (PBMC) (using the MTT colorimetric assay); and (4) Assess the ability of cetuximab +/- Imprime PGG to induce cytokines when tumor cells were cultured with human PBMC. Key findings include: (1) in vitro cetuximab does not induce iC3b deposition on SKOV-3 and MiaPaCa-2 tumor cells over that seen with fresh serum alone. (2) Both tumor cell lines expressed all CRPs but each to a variable extent. (3) Cetuximab did not induce CDC but did induce ADCC in the presence of PBMC, and Imprime PGG further enhanced cetuximab-induced cytolysis under these conditions. (4) The combination of cetuximab and Imprime PGG inhibited the secretion of VEGF in tumor cell/PBMC co-cultures compared to levels observed with either agent alone. These studies demonstrate antitumor synergy of Imprime PGG when combined with cetuximab that may be mediated by modulation of the tumor microenvironment. Overall, the data indicate synergy between Imprime PGG and cetuximab in vitro in inducing antitumor activity in both pancreatic and ovarian tumor cells and provide rationale for such combination strategy for therapy in cancer.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A35.