Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer: An in vivo validation study

BACKGROUND: Anti‐angiogenic therapy with bevacizumab (BEV), an anti‐VEGF antibody, plays a critical role in the treatment of ovarian cancer. However, despite an encouraging initial response, most tumors become resistant to BEV over time, and a new strategy that enables sustainable treatment using BEV is therefore needed. METHODS: To overcome the resistance to BEV in patients with ovarian cancer, we performed a validation study of combination therapy with BEV (10 mg/kg) and the CCR2 inhibitor BMS CCR2 22 (20 mg/kg) (BEV/CCR2i) using 3 consecutive patient‐derived xenografts (PDXs) of immunodeficient mice. RESULTS: BEV/CCR2i demonstrated a significant effect of growth suppression in the BEV‐resistant serous PDX and BEV‐sensitive serous PDX compared with BEV (30.4% after the second cycle and 15.5% after the first cycle, respectively), and treatment cessation did not attenuate this effect. Tissue clearing and immunohistochemistry with an anti‐α‐SMA antibody suggested that BEV/CCR2i suppressed angiogenesis from the host mice more than BEV. In addition, human CD31 immunohistochemistry revealed that BEV/CCR2i decreased microvessels originating from the patients to a significantly greater degree than BEV. Regarding the BEV‐resistant clear cell PDX, the effect of BEV/CCR2i was unclear during the first five cycles, but the following two cycles of increased‐dose BEV/CCR2i (CCR2i 40 mg/kg) significantly suppressed tumor growth compared with BEV (28.3%) by inhibiting the CCR2B‐MAPK pathway. CONCLUSIONS: BEV/CCR2i showed a sustained anticancer immunity‐independent effect in human ovarian cancer that was more significant in serous carcinoma than in clear cell carcinoma.