Imprime PGG (Imprime), a soluble yeast 1,3/1,6 β-glucan, is being developed as a novel cancer immunotherapy in conjunction with anti-tumor antibodies in several cancers. Randomized Phase 2 clinical trials of Imprime in the 1st-line treatment of stage IV non-small cell lung cancer have shown promising efficacy in both objective tumor response and survival.
Mechanistic work has revealed that Imprime acts to stimulate a coordinated, anti-cancer immune response in conjunction with antibody therapy. Imprime represents a pathogen associated molecular pattern (PAMP) and, as such, can be efficiently and effectively recognized by cells of the innate immune system, triggering macrophage repolarization, neutrophil activation, monocyte-derived dendritic cell maturation, NK cell activation and, via cross-talk with the adaptive immune system, expansion of CD4 and CD8 T cells.
As PAMPs have been shown to stimulate dendritic cells (DCs), which are critical for generating robust and durable anti-tumor responses, we sought to better understand the effects of Imprime on DCs. Here we demonstrate that Imprime binds to various DC subsets, stimulating the critical antigen presenting functional activity of these DC subsets. Following i.v. administration in mice, Imprime bound both classical splenic DCs, including CD8α+ cross-presenting DCs, and migratory DC subsets within peripheral lymph nodes. In vitro treatment of human whole blood showed binding in the inflammatory DC subset (Lin-HLA-DR+CD11c+CD16+) as well as the classical (Lin-HLA-DR+CD11c+CD1c+) DC subset. Binding of Imprime to both mouse and human DCs resulted in the upregulation of MHC class II and the co-stimulatory molecules CD80/86 that are critical for antigen presentation and T cell activation. Furthermore, in vivo treatment of mice with Imprime in combination with H-2Kb-restricted OVA257-264 peptide resulted in enhanced expansion of adoptively transferred OVA-specific OT-I CD8 T cells. In contrast to mice immunized with OVA peptide alone, which did not generate a functional CD8 T cell response, Imprime co-administration resulted in functional OT-I capable of ex vivo degranulation and production of the cytokines IFN-γ and IL-2. These data suggest that, in addition to previous studies showing Imprime primes monocytes, macrophages, and neutrophils, Imprime also enhances T cell activation and expansion by directly stimulating dendritic cell maturation and efficient antigen presentation. These data demonstrate that Imprime PGG treatment may enhance the adaptive immune response necessary for durable tumor control and, together with previously published data, indicate that Imprime PGG treatment triggers an orchestrated anti-cancer immune response involving both the innate and adaptive immune systems.
Citation Format: Ross B. Fulton, Steven M. Leonardo, Kyle S. Michel, Michael E. Danielson, Keith B. Gorden, Jeremy R. Graff. Imprime PGG, a soluble β-glucan, binds to and activates dendritic cells resulting in enhanced T cell priming, expansion, and cytokine production. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B019.