Purpose: Several clinical trials have combined antiangiogenic agents and radiation therapy (RT), but evidence of its clinical benefit is insufficient. In this study, we rationalized and investigated the combination of vascular endothelial growth factor-Grab (VEGF-Grab), an antiangiogenic drug that inhibits VEGF-A and placental growth factor (PIGF) and radiotherapy for anti-cancer therapy. Methods and Materials: To observe for changes in PIGF after radiation, HCT116, HCT15, SW480, BxPC3, and RAW264.7 cells and Lewis lung carcinoma (LLC) and BxPC3 tumors were given 10 Gy of radiation, and changes in the expression of PIGF were analyzed. Patients scheduled for RT for solid tumor mass were recruited, and their plasma VEGF-A and PIGF were analyzed at baseline and 2 and 4 weeks after the start of radiotherapy. To assess the effects of combining VEGF-Grab and radiotherapy, mice bearing LLC tumors were given 10 Gy of radiation once and 25 mg/ kg of VEGF-Grab every 2 days for 5 rounds. To show that VEGF-Grab is effective in human tumors, mice bearing BxPC3 xenografts were given 2 doses of 15 mg/kg of VEGF-Grab or VEGF-Trap. To assess the efficacy of combination therapy in BxPC3 xenografts, the same experiment used in the LLC model was performed. Results: We demonstrated that PIGF is increased as a direct consequence of irradiation in vitro and in vivo and in the plasma of patients being treated with radiation. Using a syngeneic tumor model, we showed that the combination of VEGF-Grab and RT most effectively inhibited tumor growth through antiangiogenesis, tumor vessel normalization, and tumor-associated macrophage polarization from protumorigenic M2-type to antitumorigenic M1 -type. Finally, we demonstrated similar enhanced antitumor effects using a human xenograft model. Conclusions: This study shows that PIGF is a potential target in patients being treated with RT and suggests VEGF-Grab as a viable therapeutic option in the context of inhibiting secondarily activated pathways responsible for tumor recurrence. (C) 2018 Elsevier Inc. All rights reserved.