High dose apatinib in the reversal of immunosuppressive tumor microenvironment for irradiation therapy in lung carcinoma.

Abstract

e14503 Background: The purpose of this study was to investigate the potential systemic anti-tumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma. Methods: Lewis lung cancer cells were injected into C57BL/6 mice in the right hindlimb (primary tumor; irradiated) and in the left flank (secondary tumor; nonirradiated). When both tumors grew to palpable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 100 mg/kg, 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy to the primary tumor or no radiotherapy. Further tumor growth/regression of mice was followed and observed. Results: For the single 15 Gy modality, delays in tumor growth could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growths could be observed, indicating that an abscopal effect had been induced. Mechanism analysis suggested that programmed death ligand-1 expression increased with SABR and was counteracted by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor-antigen-specific immune responses, and the mice were resistant to subsequent tumor rechallenge. Ultimately, long-term survival was improved. Conclusions: Our results suggested that the tumor microenvironment could be managed with high-dose of apatinib, which was effective in eliciting an abscopal effect induced by SABR.