Abstract
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.
©2019 American Association for Cancer Research.
Publication types
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Clinical Trial, Phase I
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology
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Antibodies, Monoclonal, Humanized / therapeutic use*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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B7-H1 Antigen / antagonists & inhibitors*
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B7-H1 Antigen / metabolism
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Carcinoma, Lewis Lung / blood supply
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Carcinoma, Lewis Lung / drug therapy*
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Carcinoma, Lewis Lung / immunology
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Carcinoma, Lewis Lung / metabolism
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Cell Line, Tumor
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Humans
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Lung Neoplasms / blood supply
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / immunology
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Lung Neoplasms / metabolism
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Lymphocytes, Tumor-Infiltrating / drug effects
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Lymphocytes, Tumor-Infiltrating / immunology
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Male
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Mice, Inbred C57BL
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Programmed Cell Death 1 Receptor / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Pyridines / pharmacology
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Pyridines / therapeutic use*
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Tumor Microenvironment / drug effects
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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B7-H1 Antigen
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Cd274 protein, mouse
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Protein Kinase Inhibitors
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Pyridines
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apatinib
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camrelizumab