Abstract A3: Imprime PGG triggers a coordinated anti-cancer immune response in concert with anti-angiogenic antibodies, re-polarizing the immune microenvironment to suppress tumor growth

Abstract

Abstract Imprime PGG (Imprime) is a soluble, yeast-derived 1,3-1,6 β-glucan in clinical development for the treatment of cancer in combination with other anti-cancer therapies. Imprime acts as a Pathogen Associated Molecular Pattern (PAMP) and can be recognized by cells of the innate immune system. Preclinical data using human whole blood from healthy volunteers show that Imprime binding to innate immune cells triggers a coordinated immune response that includes repolarization of M2 macrophages, activation of neutrophils and maturation of dendritic cells. This response ultimately leads to cross-talk with the adaptive immune system driving T cell expansion and the production of interferon gamma (IFNγ). In a randomized phase 2 clinical study in stage IV NSCLC patients, treatment with Imprime plus bevacizumab (bev; anti-VEGF antibody), carboplatin and paclitaxel showed a median overall survival of 16.1 months versus 11.6 months in patients not receiving Imprime. We sought to explore a mechanistic understanding for this promising clinical activity. Angiogenic factors, such as VEGF, not only drive the formation of new leaky vessels but also facilitate the establishment of a suppressive immune microenvironment enabling tumor survival and growth. Recent work has shown that anti-angiogenics not only block neovascularization but may also promote a shift in the immune microenvironment, enabling immune recognition and destruction of the tumor. We therefore sought to evaluate whether Imprime, may complement the effect of anti-angiogenics on the immune microenvironment. We tested Imprime in combination with either bev or DC101 (anti-VEGFR2) in distinct NSCLC xenograft models in athymic nude mice. Once tumors reached a mean size of 100mm3, mice were treated with Imprime, bev or DC101. H1299 and H441 tumor-bearing mice were used in the bev and DC101 studies, respectively. In the bev study, Imprime plus bev induced >75% tumor growth inhibition in ∼50% of mice vs 20% in the bev alone groups. Both macrophages and neutrophils from spleen and tumor tissue of combination-treated mice showed significant upregulation of the activation marker CD86 compared to tissues from bev alone treated mice. Moreover, splenic MDSCs in combination-treated mice showed significantly increased iNOS2 expression with reduced Arg-1 expression compared to bev alone treated mice. Tumors from the Imprime plus bev groups showed significantly reduced expression of the potent immunosuppressor, TGFβ, when compared to tumors from mice treated only with bev-with the greatest reduction evident in the tumors with the greatest growth inhibition. In the H441 tumor-bearing mice treated with Imprime and DC101, a significant suppression of tumor growth compared with DC101 alone was also observed and additional mechanistic studies in this model are ongoing. These data show for the first time that Imprime-based treatment prompts a shift in the immune microenvironment of a tumor in situ, eliciting enhanced tumor growth inhibition in concert with anti-angiogenic therapy. Citation Format: Kathryn Fraser, Nadine Ottoson, Xiahong Qiu, Anissa SH Chan, Adria Jonas, Takashi Kangas, Jeremy Graff, Nandita Bose. Imprime PGG triggers a coordinated anti-cancer immune response in concert with anti-angiogenic antibodies, re-polarizing the immune microenvironment to suppress tumor growth. [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 A3.