Abstract A99: Imprime PGG, a soluble yeast β-glucan, induces dendritic cell maturation, upregulating co-stimulatory and activation markers to enhance antigen presentation and T cell priming
Authors: Fulton Ross B. , Chan Anissa SH , Leonardo Steven M. , Jonas Adria B. , Qiu Xiaohong , Ottoson Nadine C. , Kangas Takashi O. , Michel Kyle S. , Danielson Michael E. , Graff Jeremy R. , Bose Nandita , Gorden Keith 
Published: May 2016

Imprime PGG (Imprime), a soluble yeast 1,3/1,6 β-glucan, is being developed as a novel cancer immunotherapy in combination with monoclonal antibody therapy. 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 as a pathogen-associated molecular pattern (PAMP) to broadly activate the innate immune system, resulting in priming of monocytes and neutrophils, inhibition of immunosuppressive M2 macrophage polarization, and enhanced NK cell activity. Here, we demonstrate that Imprime also binds to various dendritic cell (DC) subsets and promotes DC maturation as well as subsequent T cell activation and acquisition of effector functions. In humans, in vitro treatment of whole blood with Imprime shows binding to CD16+ inflammatory DCs as well as CD1c+ classical DCs. Following i.v. administration in mice, Imprime binds resident and migratory DC subsets within secondary lymphoid organs. In both human and mouse, Imprime increases DC expression of the co-stimulatory molecules CD80/86 as well as MHC class II. Importantly, Imprime-mediated maturation of DCs enhances T cell responses: in mice, immunization with antigen in the presence of Imprime increases the magnitude of the antigen-specific CD8 T cell response as well as improves their ability to degranulate and produce IFN-γ and IL-2. Additionally, we show that Imprime imparts long-lasting effects on human monocytes that sensitize them to subsequent danger signals. Monocytes that are exposed to Imprime in human whole blood prior to their isolation and week-long differentiation into monocyte-derived DCs with GM-CSF and IL-4 show increased upregulation of CD83, CD86, and MHC class II after being matured with LPS and TNF-α. This increased maturation state translates into improved priming and expansion of allogeneic CD4 and CD8 T cells in a mixed-lymphocyte reaction. Altogether, we demonstrate that Imprime behaves as a PAMP to bridge the innate and adaptive immune systems. In a cancer setting, these data suggest that Imprime treatment in conjugation with agents that relieve immunosuppression (e.g. checkpoint inhibitors) could result in superior anti-tumor immunity.

Citation Format: Ross B. Fulton, Anissa SH Chan, Steven M. Leonardo, Adria B. Jonas, Xiaohong Qiu, Nadine C. Ottoson, Takashi O. Kangas, Kyle S. Michel, Michael E. Danielson, Jeremy R. Graff, Nandita Bose, Keith Gorden. Imprime PGG, a soluble yeast β-glucan, induces dendritic cell maturation, upregulating co-stimulatory and activation markers to enhance antigen presentation and T cell priming. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A99.