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. In clinical studies, including randomized Phase 2 clinical trials in the 1st-line treatment of stage IV non-small cell lung cancer with bevacizumab, Imprime treatment has shown promising efficacy in both objective tumor response rates and survival. Mechanistic studies in humans have now demonstrated that Imprime, a fungal pathogen associated molecular pattern (PAMP), forms an immune complex with endogenous anti-β-glucan antibodies (ABA), which is then opsonized by complement. This immune complex binds complement receptor 3 (CR3) and FcγRIIA on innate immune cells (macrophages, monocytes and neutrophils). In numerous syngeneic and xenogeneic mouse tumor models, Imprime treatment in combination with an anti-tumor antibody reduced tumor growth and prolonged survival beyond that observed with antibody alone. We sought to understand better the anti-tumor effect elicited by Imprime binding to these innate immune effector cells by exploring both phenotypic and functional changes driven by Imprime binding to neutrophils, monocytes and macrophages.
Neutrophils were isolated from human whole blood treated with Imprime or vehicle. Imprime treatment elicited an activated phenotype as demonstrated by downregulation of CD88 (C5aR) and CD62L (L-Selectin), along with the upregulation of CR1 and CR3. These surface changes coincided with functional changes as well. Neutrophils from Imprime-treated whole blood showed a profound increase in the generation of reactive oxygen species (ROS) when stimulated with phorbol myristate acetate (PMA). Similarly, Imprime- treated neutrophils exhibited further enhanced ROS production when co-cultured specifically with B cell lymphoma cells (Raji) that had been coated with the anti-CD20 antibody rituximab. ROS were not generated by vehicle-treated neutrophils nor when Imprime-treated neutrophils were co-cultured with Raji B cells that had not been coated with antibody. These data support the notion that that Imprime specifically “primes” neutrophils enhancing the recognition of, and responsiveness to, antibody-coated tumor cells.
Monocytes showed similar “priming” effects post Imprime treatment, including downmodulation of CD88, upregulation of CR1 and CR3, and enhanced ROS production in response to PMA co-treatment. Differentiation of monocytes to macrophages, post Imprime treatment of human whole blood, enabled enhanced antibody-dependent cellular phagocytosis (ADCP) of multiple B cell lymphoma cell lines decorated with the anti-CD20 antibodies rituximab, ofatumumab and obinatuzumab.
Collectively, these data highlight the impact of Imprime on key cell lineages of the innate immune system, priming neutrophils, monocytes and macrophages to better recognize and exert cytotoxic effector functions in response to antibody- coated tumor cells.
Citation Format: Steven M. Leonardo, Adria Jonas, Nadine Ottoson, Xiaohong Qiu, Anissa Chan, Jeremy Graff, Nandita Bose, Keith Gorden. Imprime PGG, a soluble yeast β glucan, primes innate immune effector cells to recognize and eradicate tumor cells. [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 A98.