Abstract A37: Immuno-oncological efficacy of RXDX-106, a novel TAM (TYRO3, AXL, MER) family small-molecule kinase inhibitor

Abstract

Background: The TAM family of receptor tyrosine kinases (RTKs), TYRO3, AXL, and MER, have emerged as attractive targets for cancer therapy. In cancer cells, overexpression of TAM RTKs is associated with resistance and a mesenchymal phenotype. In immune cells, TAM RTKs play a key homeostatic role as negative regulators of immune responses, contributing to the evasion of cancer cells from immune surveillance. RXDX-106 is a potent and selective TAM family inhibitor in preclinical development. Previously, in several syngeneic tumor models, we have demonstrated that RXDX-106 alone inhibited tumor growth, whereas such benefit was reduced when the tumors grew in immunocompromised athymic nude mice. In addition, RXDX-106 induced favorable polarization of the tumor infiltrating immune cells towards an anti-cancer phenotype. Here we sought (1) to evaluate the efficacy of RXDX-106 as a single agent and in combination with immune checkpoint inhibitors; (2) to identify the immuno-modulatory mechanisms of action; (3) to explore the reciprocal regulation of TAM expression on cancer and immune cells in the tumor microenvironment; and (4) to decipher how pharmacological inhibition of TAM signaling pathways on both tumor and immune cells would be beneficial, given their complex regulation and intimate relationship in the tumor microenvironment. Methods and Results: In the present study, we demonstrated that tumor growth inhibition in an MC38 model was associated with a significant increase in tumor associated M1 macrophages, an increase in CD169hi antigen presenting macrophages, and upregulation of PD-L1. In addition, we observed a higher ratio of CD8+/CD4+ T cells and increased expression of CD69 and PD-1 on CD8+ T cells, all indicative of activation of cytotoxic T cells. Finally, we observed an increase in Granzyme B and IFNγ with a concomitant decrease in VEGF in tumor cell lysates, evidence supporting T cell activation and M1 polarization of macrophages. Furthermore, in a CT26 syngeneic model, we demonstrated that RXDX-106 inhibited tumor growth as a single agent, and the effect was further potentiated by combination therapy with immune checkpoint inhibitors, as evidenced by upregulation of anti-tumor gene expression patterns, upregulation of anti-tumor cytokines in the tumor cell lysates, and an increase in T cell function. Finally, in an AXL-driven tumor model, we demonstrated that AXL expressing tumors induced a pro-tumorigenic immune environment, and treatment with RXDX-106 resulted in complete tumor regression and re-polarization of macrophages towards an M1, anti-tumor phenotype. Conclusion: RXDX-106 has the potential to restore and enhance immune function in macrophages and T cells, resulting in repolarization of the immune response towards an anti-tumor microenvironment. The unique mechanism of activating both innate and adaptive immunity, plus regulating cross-talk between immune cells and tumor cells by RXDX-106 supports clinical development of RXDX-106 to potentially treat a wide variety of cancers. Citation Format: Yumi Yokoyama, Erin D. Lew, Colin Walsh, Jack Lee, Joanne Oh, Elizabeth A. Tindall, Robin Nevarez, Amy Diliberto, Heather Ely, Ruth Seelige, Amanda Albert, Jack Bui, Gary Li. Immuno-oncological efficacy of RXDX-106, a novel TAM (TYRO3, AXL, MER) family small-molecule kinase inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A37.