期刊
MOLECULAR CANCER THERAPEUTICS
卷 20, 期 12, 页码 2519-2526出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0031
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- Chugai Pharmaceutical Co., Ltd.
- F. Hoffmann-La Roche, Ltd.
Our research found that using anti-PD-L1 and anti-PD-L2 antibodies exacerbated pneumonia in the IL pneumonia model, while the use of anti-VEGF antibodies was able to prevent the worsening of pneumonia caused by PD-1 signal blockade. PD-1 signal blockade led to interstitial T-cell infiltration in the lungs, but VEGF blockade did not affect this T-cell infiltration.
Immune-related pneumonitis is an important toxicity associated with checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1 antibodies, often necessitating discontinuation of treatment. Development of methods to mitigate checkpoint inhibitor-related pneumonitis is required. The contributions of PD-L1, PD-L2, and VEGF to the pathogenesis of pneumonitis were examined in an IL2- plus IL18-induced mouse pneumonitis model (IL pneumonitis model). Furthermore, the incidences of pneumonitis were retrospectively examined in patients with non-small cell lung cancer treated with the anti-PDLI mAb atezolizumab plus chemotherapy, with or without the anti-VEGF mAb bevacizumab, in the phase III IMpower150 trial. PD-1 signal blockade by anti-PD-L1 and anti-PD-L2 antibodies aggravated pneumonitis in the IL pneumonitis model. An anti-VEGF antibody prevented PD-1 signal blockade from aggravating pneumonitis in this model. PD-1 signal blockade induced interstitial T-cell infiltration in the lungs, but VEGF blockade did not affect this T-cell infiltration. The anti-VEGF antibody protected against vascular-to-alveolar leakage of protein and fluid due to PD-1 signal blockade in a murine model. In the IMpower150 trial, incidence rates of pneumonitis of any grade were 4.3% in the group without bevacizumab and 2.8% in the group with bevacizumab. In patients with pneumonitis, outcomes of Not recovered/Not resolved were reported for 29.4% in the group without bevacizumab compared with 9.1% in the group with bevacizumab. Our findings suggest that anti-VEGF antibodies in combination with checkpoint inhibitors may be a treatment method that can control checkpoint inhibitor-related pneumonitis.
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