558P - Capecitabine recovers anti-angiogenic effect of bevacizumab in bevacizumab beyond progression through inhibition of myeloid-derived suppressor cell...

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Translational Research
Presenter Toshiki Iwai
Citation Annals of Oncology (2014) 25 (suppl_4): iv167-iv209. 10.1093/annonc/mdu333
Authors T. Iwai1, Y. Harada2, Y. Maehara3, Y. Yonemitsu2
  • 1Surgery And Science, kyushu University, 8128582 - Fukuoka/JP
  • 2R&d Laboratory For Innovative Biotherapeutics, Kyushu University, Fukuoka/JP
  • 3Surgery And Science, kyushu University, Fukuoka/JP

Abstract

Aim

Bevacizumab (Bev) is a humanized anti-human VEGF monoclonal antibody (Ab), and maintaining VEGF inhibition with Bev plus chemotherapy beyond progression (BBP) has had clinical benefits in patients with metastatic colorectal cancer. However the mechanism of BBP is still unknown and, although some chemotherapeutic agents have been shown to modulate the host immune response against malignancies, the role of chemotherapy in BBP is also unknown. In this study, we examined the mechanism of BBP.

Methods

Murine Lewis lung carcinoma (LLC) was s.c. inoculated into C57BL/6 or CCR2-/- knockout (KO) mice. Mice were randomly allocated to control and treatment groups after tumor formation. Anti-VEGF Ab (5 mg/kg, weekly) and anti-G-CSF Ab (10 µg/day, daily) were i.p. administered, and capecitabine (Cape) (718 mg/kg, daily) was p.o. administered for 18 days. Cytokine levels were analyzed by ELISA and cytometric bead array. Myeloid-derived suppressor cells (MDSC) were identified as CD11b +/Gr1 high by flow cytometry. Microvessel density (MVD) was determined by CD31-immunostaining.

Results

The LLC model showed resistance to anti-VEGF Ab as previously reported [1]. In this model, anti-VEGF Ab increased the intratumor infiltration by MDSC expressing PD-L1. In addition, a significant increase in G-CSF and CCL2 was observed in the tumors. Although anti-G-CSF Ab did not affect tumor growth, anti-G-CSF combined with anti-VEGF significantly reduced tumor growth compared with anti-VEGF alone. The number of intratumor MDSC was significantly decreased in the combination group compared with the anti-VEGF group. However, no difference in the number of intratumor MDSC induced by anti-VEGF was observed in CCR2 KO mice compared with wild type mice. Adding Cape to anti-VEGF abolished both MDSC and the intratumor G-CSF level, and significantly reduced tumor growth compared with either monotherapy. MVD in the combination group was significantly reduced compared with the anti-VEGF group.

Conclusions

Add-on Cape abolished MDSC by decreasing intratumor G-CSF, suggesting that the mechanism of BBP may be that chemotherapy recovers the anti-angiogenic effect of Bev. [1] Nature Biotechnology 25, 911-20 (2007).

Disclosure

T. Iwai: COI Disclosure: Research funding from Chugai Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.