Anti-VEGF antibody protects against alveolar exudate leakage caused by vascular hyperpermeability, resulting in mitigation of pneumonitis induced by immunotherapy.

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 IL-2- plus IL-18-induced mouse pneumonitis model (IL pneumonitis model). Furthermore, the incidences of pneumonitis were retrospectively examined in non-small-cell lung cancer patients treated with the anti-PD-L1 monoclonal antibody atezolizumab plus chemotherapy, with or without the anti-VEGF monoclonal antibody 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.