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Medline ® Abstract for Reference 140

of 'Principles of cancer immunotherapy'

Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy.
Mok S, Koya RC, Tsui C, Xu J, Robert L, Wu L, Graeber TG, West BL, Bollag G, Ribas A
Cancer Res. 2014 Jan;74(1):153-61. Epub 2013 Nov 18.
Colony stimulating factor 1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIM) that suppress tumor immunity, including M2 macrophages and myeloid-derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAF(V600E)-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive cell therapy (ACT). In this model, we found that combined treatment produced superior antitumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCII(low) to MHCII(hi) macrophages were observed. Furthermore, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TIL) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immunosuppressive macrophages.
Authors' Affiliations: Department of Molecular and Medical Pharmacology; Jonsson Comprehensive Cancer Center; Surgery, Division of Surgical Oncology; Institute for Molecular Medicine; Departments of Urology and Pediatrics; Crump Institute for Molecular Imaging; Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, Los Angeles; Plexxikon Inc., Berkeley, California; and Roswell Park Cancer Institute, Buffalo, New York.