Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy

// Yasmin A. Lyons 1 , Sunila Pradeep 1 , Sherry Y. Wu 1 , Monika Haemmerle 1 , Jean M. Hansen 1 , Michael J. Wagner 1 , Alejandro Villar-Prados 1 , Archana S. Nagaraja 1 , Robert L. Dood 1 , Rebecca A. Previs 1 , Wei Hu 1 , Yang Zhao 4 , Duncan H. Mak, 7 Zhilan Xiao 5 , Brenda D. Melendez 5 , Gregory A. Lizee 5 , Imelda Mercado-Uribe 6 , Keith A. Baggerly 4 , Patrick Hwu 5 , Jinsong Liu 6 , Willem W. Overwijk 5 , Robert L. Coleman 1 and Anil K. Sood 1,2,3 1 Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Department of Pathology, Division of Pathology and Laboratory Medicine, Section of Gynecologic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Anil K. Sood, email: // Keywords : adaptive resistance, anti-VEGF therapy, tumor associated macrophages, tumor microenvironment, CSF1R inhibition Received : April 18, 2017 Accepted : July 20, 2017 Published : August 24, 2017 Abstract Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of in vivo experiments in both immune competent and nude mouse models. Given the pro-angiogenic properties of tumor-associated macrophages (TAMs) and the dominant role of CSF1R in macrophage function, we added CSF1R inhibitors following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with a CSF1R inhibitor (AC708) after anti-VEGF antibody resistance had little to no measurable tumor burden upon completion of the experiment while those that did not receive a CSF1R inhibitor still had abundant tumor. To mimic clinically used regimens, mice were also treated with anti-VEGF antibody and paclitaxel until resistance emerged, and then a CSF1R inhibitor was added. The addition of a CSF1R inhibitor restored response to anti-angiogenesis therapy, resulting in 83% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone. Collectively, our data demonstrate that the addition of a CSF1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects.