Sunitinib reverses tumor-mediated immune suppression from human MDSCs (8)

Sunitinib reverses tumor-mediated immune suppression from human MDSCs (8). hematopoiesis, monocytes, tumor immunology Introduction While stereotactic body radiotherapy (SBRT) can effectively eradicate oligometastases, the majority of patients with distant metastases ultimately succumb to distant metastases (1). There is growing enthusiasm for combining SBRT with brokers that enhance antitumor immunity as an approach to reducing the probability of subsequent distant metastases (2,3). Ongoing studies are investigating the combination of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors with radiation, particularly in melanoma (4). Prior to the clinical development of CTLA-4 and PD-1 inhibitors, sunitinib was demonstrated to modulate the tumor microenvironment and reverse the immune suppressive function of myeloid-derived suppressor cells (MDSCs) (5). Compared with other GJ-103 free acid tyrosine kinases approved for human use, sunitinib is a relatively broad spectrum tyrosine kinase inhibitor (6). Sunitinib is usually a selective inhibitor of multiple protein tyrosine kinases, including vascular endothelial growth factor (VEGF) receptor types 1C3, GJ-103 free acid platelet-derived growth factor receptor and , c-kit, Fms-like tyrosine kinase 3, RET and colony-stimulating factor 1 receptor (7). Sunitinib reverses tumor-mediated immune suppression from human MDSCs (8). Preclinical data suggests a supra-additive antitumor effect when combining sunitinib with radiotherapy compared to either treatment independently (9). Based on these promising data, our group conducted a clinical trial administering sunitinib followed by combined sunitinib and radiation for patients with limited metastatic cancer (10,11). With long-term follow-up, this regimen achieved a 4-year progression-free survival rate of 34% (12). As part of this clinical study, an increased incidence of grades 3 and 4 myelosuppression was observed with sunitinib and radiation compared to historical controls treated with sunitinib alone (11). Comprehensive flow cytometric analysis exhibited that sunitinib reduced the population of CD33+CD14+CD16+ monocytic MDSCs in patients receiving sunitinib and radiotherapy (13). To complement these studies, the current analysis was undertaken to characterize the effects of combined sunitinib and radiation therapy on hematopoiesis. Materials and methods Experimental therapy The GJ-103 free acid study population consisted of 21 patients with oligometastatic cancer (1C5 sites of metastatic cancer measuring 6 cm) from various primary tumors enrolled on a phase I/II trial of sunitinib and radiotherapy between May 2007 and September 2010 with clinical follow-up through July 2012 (“type”:”clinical-trial”,”attrs”:”text”:”NCT00463060″,”term_id”:”NCT00463060″NCT00463060). The institutional review board of Mount Sinai School of Medicine (New York, NY, USA) approved this study and all participants provided written informed consent. For all those patients, chemotherapy was discontinued 21 days prior to initiating protocol therapy. Sunitinib (25C50 mg qd) was administered on days 1C28. Radiotherapy was delivered to all clinically apparent sites of disease with a margin of 5C10 mm using an image-guided technique described elsewhere (10). The radiation doses were 40 or 50 Gy in 10 fractions from days 8C19. Further systemic therapy consisting of either maintenance sunitinib or chemotherapy was administered starting on day 42 at the discretion of the treating medical oncologist. Stratifying for the location and volume of bone GJ-103 free acid marrow irradiated, a matched-pair cohort analysis was performed on a contemporary cohort of 21 patients with metastatic cancer who were treated with radiation alone. These patients underwent complete blood counts immediately prior to the start and following the completion of radiotherapy. Baseline patient and treatment characteristics for the two groups are described in Table I. Table I. Baseline characteristics of the study population (n=21). thead th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Variable /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ Radiotherapy alone /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ Radiotherapy + sunitinib /th th align=”center” valign=”bottom” CFD1 GJ-103 free acid rowspan=”1″ colspan=”1″ P-value /th /thead Age, years??Median (range)66 (28C90)65 (47C82)0.33?? 40, n??2??0??40C69, n1213??70, n??7??8Performance status, n0.10??0C11116??2C310??5Bone metastases, n0.58??Yes1311??No??810Volume of bone marrow irradiated, cm3; median (range)??Volume receiving 10 Gy59 (3C220)??35 (1C149)0.66??Volume receiving 15 Gy52 (3C201)??29 (1C114)0.16??Volume receiving 20 Gy40.