Low-Dose Apatinib Optimizes Tumor Microenvironment and Potentiates Antitumor Effect of PD-1/PD-L1 Blockade in Lung Cancer

• Published in: Cancer immunology research Vol. 7; no. 4; p. 630
• Main Authors: Zhao, Sha, Ren, Shengxiang, Jiang, Tao, Zhu, Bo, Li, Xuefei, Zhao, Chao, Jia, Yijun, Shi, Jinpeng, Zhang, Limin, Liu, Xiaozhen, Qiao, Meng, Chen, Xiaoxia, Su, Chunxia, Yu, Hui, Zhou, Caicun, Zhang, Jun, Camidge, D Ross, Hirsch, Fred R
• Format: Journal Article
• Language: English
• Published: United States 01.04.2019
• Subjects: Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Carcinoma, Lewis Lung - blood supply; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - metabolism; Cell Line, Tumor; Humans; Lung Neoplasms - blood supply; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Male; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; Tumor Microenvironment - drug effects
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-17-0640

The lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti-PD-1/PD-L1 monotherapy. Judicious dosing of antiangiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti-PD-1/PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance the therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8 T cells, reduced recruitment of tumor-associated macrophages in tumor and decreased TGFβ amounts in both tumor and serum. Combining low-dose apatinib with anti-PD-L1 significantly retarded tumor growth, reduced the number of metastases, and prolonged survival in mouse models. Anticancer activity was evident after coadministration of low-dose apatinib and anti-PD-1 in a small cohort of patients with pretreated advanced non-small cell lung cancer. Overall, our work shows the rationale for the treatment of lung cancer with a combination of PD-1/PD-L1 blockade and low-dose apatinib.