Novel Oral Small Molecule Cxcr4 Inhibitor Improves Activity Of Immune Checkpoint Blockade In Ovarian Cancer Mouse Model

Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patients presenting with advanced stage disease. Immune check point blockade showed modest clinical response in patient with recurrent ovarian cancer, thus additional therapeutic strategies for combination therapy are needed. As chemokines and their receptors drive both immune cell migration and tumor growth, angiogenesis and metastasis formation, they are an attractive target for combinatorial cancer therapy. CXCR4 is the most highly expressed chemokine receptor in advanced stage high grade serous ovarian cancer, thus the objective of this study was to evaluate the efficacy of a novel oral small molecule CXCR4 inhibitor (X4-136) alone and in combination with immune checkpoint inhibition and the anti-angiogenic agent bevacizumab, and characterize the changes in circulating immune cells during treatment in murine ovarian cancer model. The ID8 cell line was used in C57BL/6J mice to establish an immune competent murine model and to compare single agent and combination therapy with oral X4-136 CXCR4 inhibitor, bevacizumab, and anti-PD1. During treatment blood sampling was performed and immune cells were analyzed by flow cytometry. Our results demonstrated that single agent therapies alone with either drug had no significant effect on tumor progression or survival. Combination therapy with the CXCR4 inhibitor and anti-PD1 improved survival compared to control animals and the other combination therapy groups. The addition of bevacizumab to the dual combination did not further prolong survival. Analysis of circulating immune cells revealed elevations in CD11b+Ly6C+ and the ratio of CD11b+Ly6C+ to CD11b+Ly6G+ in groups treated with the CXCR4 inhibitor, indicating an increase in circulating myeloid cells. Bevacizumab had no activity in this mouse model as a single agent, and did not have synergistic effect in combination therapy. For the first time we demonstrated that novel CXCR4 inhibitor X4-136 in combination therapy with anti-PD1 showed improved survival in murine ovarian cancer model. CXCR4 blockade increased the proportion of circulating myeloid cells during active treatment, thus further investigation into this novel therapeutic approach is warranted. Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 956. doi:10.1158/1538-7445.AM2017-956