Abstract LB-194: Targeting tumor associated myeloid cells with CCR2 inhibitor PF-04136309 enhances gemcitabine/paclitaxel and doxorubicin anti-tumor activity
Authors: Farina Sasha , Yang Hsunhui , Tu Guang Huan , Gamelin Erick C. , Lin John C. , Wang Changyu , Feldman Reid , Panowski Siler , Oderup Cecilia 
Published: July 2017

Abstract
Purpose: MDSCs and macrophages have been reported to be increased in the tumor microenvironment by chemotherapy treatment. These cells may limit the beneficial effects of chemotherapy by limiting drug access or by suppressing the tumor targeted immune response evoked by the chemotherapy. The purpose of the current study was to investigate the ability of chemokine receptor CCR2 inhibitor, PF-04136309, to block tumor MDSC and macrophage accumulation and to investigate the combination of this treatment with standard of care chemotherapies. Experimental design: The ability of CCR2 inhibitor, PF-04136309, to reduce tumor growth in mice was evaluated using orthotopically or SC injected syngeneic colon, pancreatic and ovarian tumor cell lines. PF-04136309 was evaluated as single agent, in combination with doxorubicin, or in the combination of gemcitabine and paclitaxel. Results: In a model of ovarian carcinomatosis (ID8), where tumor progression is driven by MDSCs and macrophages, single agent PF-04136309 reduced peritoneal tumor load as well as the total volume and rate of ascites fluid production. Even delayed treatment of established tumors, at 6 weeks post tumor inoculation, was effective. Ascites volume correlated with overall tumor load in treated mice. The treatment of ovarian tumor bearing mice with PF-04136309 in combination with doxorubicin, resulted in significant reduction in tumor load and ascites formation, beyond that produced by doxorubicin alone. To evaluate the addition of PF-04136309 to the chemotherapy combination, gemcitabine/paclitaxel, we selected models of pancreatic (Pan02) and colon (MC38) carcinoma, where PF-04136309 did not show single agent efficacy. The addition of PF-04136309 resulted in significantly decreased tumor burden compared to mice treated with chemotherapy alone. To investigate the mechanism of action of PF-04136309 we selected the MC38 model. PF-04136309 treatment of MC38 tumor bearing mice resulted in a substantial reduction, as a proportion of CD45+ cells, of MDSCs (CD11b+MHCII-Ly6C+) in the circulation (80%), and of MDSCs (60%) and macrophages (CD11b+F4/80+MHCII+Ly6C/G-) (70%) in the tumor, respectively. Conclusion: PF-04136309 significantly improved the response to several chemotherapeutics, providing strong rationale for CCR2 antagonism as an addition to standard of care chemotherapies. PF-04136309 is currently being evaluated in combination with gemcitabine/nab-paclitaxel in metastatic pancreatic cancer patients. The observed inhibitory effect of PF-04136309 on ID8 ascites formation, the synergy with doxorubicin, and the known intervention of MDSC and macrophages in human ovarian peritoneal carcinomatosis, suggests potential clinical efficacy with reduction of ascites volume and synergy in combination with pegylated doxorubicin in platinum resistant ovarian cancer patients.
Citation Format: Sasha Farina, Hsunhui Yang, Guang Huan Tu, Erick C. Gamelin, John C. Lin, Changyu Wang, Reid Feldman, Siler Panowski, Cecilia Oderup. Targeting tumor associated myeloid cells with CCR2 inhibitor PF-04136309 enhances gemcitabine/paclitaxel and doxorubicin anti-tumor activity [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 LB-194. doi:10.1158/1538-7445.AM2017-LB-194