Abstract A168: The LSD1 specific inhibitor INCB059872 enhances the activity of mechanistically distinct immunotherapeutic agents in the syngeneic 4T1 mouse mammary tumor model
Authors: Lee Sang Hyun , Diamond Melody , Chadderton Antony , Condamine Thomas , Liu Huiqing , Roman Valerie , Lu Jin , Zhang Yan , Soloviev Maxim , He Chunhong , Wu Liangxing , Koblish Holly , Burn Timothy , Combs Andrew , Yeleswaram Swamy , Roberts Alan , Yao Wenqing , Hollis Gregory , Huber Reid , Scherle Peggy , Ruggeri Bruce 
Published: August 2018

Abstract
Despite the successes of immune checkpoint blockade for the treatment of a variety of cancers, effective combinatorial therapy strategies are needed to achieve more durable and complete clinical responses in patients. Pharmacologically inducing a more permissive tumor microenvironment to enhance patient responsiveness to immune modulatory therapies may offer a rational approach to address this medical need. In particular, targeting immune suppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and polymorphonuclear (PMN) cells in the tumor microenvironment may enhance the effectiveness of immune checkpoint blockade. Since MDSCs abundantly infiltrate syngeneic 4T1 mammary tumors compared with other commonly used syngeneic tumor models, this model was chosen for testing the hypothesis that the modulation of MDSC activity enhances antitumor activity driven by adaptive immunity. We have recently demonstrated (#4635, AACR 2017) that the selective Lysine Specific Demethylase 1 (LSD1) inhibitor, INCB059872, redirected myeloid differentiation toward monocyte/macrophages in vitro and in vivo and reduced the PMN-MDSC population in the syngeneic 4T1 murine mammary tumor model. The combination of INCB059872 and PD1/PDL1 axis blockade enhanced antitumor activity and was well tolerated in this model. In this study, we further tested if modulation of MDSCs with INCB059872 could enhance the effect of mechanistically distinct immunotherapeutic agents. The combination of INCB059872 with agonist anti-OX40 or anti-GITR T cell costimulatory monoclonal antibodies significantly augmented antitumor efficacy in the 4T1 model. These results consistently demonstrated that the inhibition of immune suppressive MDSCs increased antitumor activity of immune checkpoint modulatory monoclonal antibodies. Next, we tested the combination of INCB059872 with small-molecule inhibitors targeting the tumor microenvironment. The combination of INCB059872 with highly selective small-molecule immunotherapeutic inhibitors such as epacadostat (IDO1 inhibitor) and ruxolitinib (JAK1/JAK2 inhibitor) demonstrated similar marked increases in antitumor efficacy. The studies to understand mechanism of enhanced activity are under way. In summary, consistent with previous findings, the combination of INCB059872 with a variety of mechanistically distinct immunotherapeutic agents significantly enhanced antitumor efficacy in the syngeneic 4T1 murine mammary tumor model. These results strongly support the hypothesis that reshaping the tumor microenvironment by redirecting myeloid differentiation as a result of LSD1 inhibition enhances the responsiveness of the tumor microenvironment to immunotherapies, supporting the therapeutic rationale for the combination of an LSD1 inhibitor with various immunotherapeutic agents to improve clinical responses in cancer patients.
Citation Format: Sang Hyun Lee, Melody Diamond, Antony Chadderton, Thomas Condamine, Huiqing Liu, Valerie Roman, Jin Lu, Yan Zhang, Maxim Soloviev, Chunhong He, Liangxing Wu, Holly Koblish, Timothy Burn, Andrew Combs, Swamy Yeleswaram, Alan Roberts, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri. The LSD1 specific inhibitor INCB059872 enhances the activity of mechanistically distinct immunotherapeutic agents in the syngeneic 4T1 mouse mammary tumor model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A168.