Abstract 2335: Imprime PGG triggers PD-L1 expression on tumor and myeloid cells and prevents tumor establishment in combination with αPD-L1 treatment in vivo

Abstract

Abstract Immune checkpoint inhibitors, including α-PD-1/PD-L1 antibodies, have revolutionized cancer therapy, yielding compelling long-term clinical responses in cancers resistant to traditional treatment. Translational studies have reported that expression of PD-L1 on the surface of tumor or infiltrating immune cells correlates to greater objective response. However, a large number of cancer patients are still refractory to treatment with checkpoint inhibitors, suggesting that the efficacy of anti-PD-1/PD-L1 immunotherapies may be improved by combination with agents that can both activate immune responses within the tumor microenvironment and induce PD-L1 expression. Imprime PGG (Imprime), a β glucan PAMP (Pathogen Associated Molecular Pattern) is currently in clinical development in combination with tumor-targeting antibodies, anti-angiogenic antibodies and immune checkpoint inhibitors. As a PAMP, Imprime is readily recognized by, and binds to, innate immune cells, triggering a coordinated immune response that includes neutrophil activation, repolarization of M2 macrophages and dendritic cell (DC) maturation. Co-culture of M2s or DCs with T cells elicits increased PD-L1 expression on the surface of these myeloid cells, drives T cell expansion and induces interferon gamma (IFNγ) production. When exposed to the IFNγ-rich media from these co-cultures, tumor cell lines from numerous cancers (lung, breast, and pancreas) routinely upregulate surface expression of PD-L1. In vivo treatment of Imprime in tumor free mice also repolarized splenic macrophages to M1 functionality, and furthermore, enhanced the ability of antigen presenting cells to prime antigen-specific CD8 T cells. These results suggest that Imprime has the potential to enhance the efficacy of checkpoint inhibitors. We therefore evaluated anti-tumor efficacy in two distinct syngeneic murine tumor models. In the CT-26 model, treatment began when tumors reached 40-100 mm3. Though neither Imprime nor αPD-1 (clone RMP1-14) was alone effective, the combination substantially repressed tumor growth. In the MC-38 model, tumors were injected subcutaneously. Three days later, mice were randomized to treatment groups. Tumors were evident at day 29 in 17/18 vehicle-treated mice, 16/18 Imprime-treated mice and 12/18 αPD-L1 (10F.9G2)- treated mice. Remarkably, though tumors grew initially, only 3/17 mice treated with αPD-L1 + Imprime showed palpable tumors at day 29. To assess the durability of this response, these mice were re-challenged by injection of MC-38 tumor cells on the opposite flank. These mice remained tumor-free even while MC-38 tumors readily grew in age-matched, tumor-naïve, control mice. Collectively, these data show that Imprime treatment can dramatically enhance the efficacy of immune checkpoint inhibitors in syngeneic tumor models. Citation Format: Kathryn Fraser, Anissa Chan, Ross Fulton, Steven Leonardo, Adria Jonas, Xiaohong Qiu, Nadine Ottoson, Takashi Kangas, Keith Gordon, Jeremy Graff, Nandita Bose. Imprime PGG triggers PD-L1 expression on tumor and myeloid cells and prevents tumor establishment in combination with αPD-L1 treatment in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2335.