Angiogenic inhibitor pre‐administration improves the therapeutic effects of immunotherapy

In lung cancer, immune checkpoint inhibitors (ICIs) are often inadequate for tumor growth inhibition. Angiogenic inhibitors (AIs) are required to normalize tumor vasculature for improved immune cell infiltration. However, in clinical practice, ICIs and cytotoxic antineoplastic agents are simultaneously administered with an AI when tumor vessels are abnormal. Therefore, we examined the effects of pre‐administering an AI for lung cancer immunotherapy in a mouse lung cancer model. Using DC101, an anti‐vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, a murine subcutaneous Lewis lung cancer (LLC) model was used to determine the timing of vascular normalization. Microvessel density (MVD), pericyte coverage, tissue hypoxia, and CD8‐positive cell infiltration were analyzed. The effects of an ICI and paclitaxel after DC101 pre‐administration were investigated. On Day 3, increased pericyte coverage and alleviated tumor hypoxia represented the highest vascular normalization. CD8+ T‐cell infiltration was also highest on Day 3. When combined with an ICI, DC101 pre‐administration significantly reduced PD‐L1 expression. When combined with an ICI and paclitaxel, only DC101 pre‐administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre‐administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration. A pre‐angiogenesis inhibitor strategy improves immune checkpoint inhibitor effects by improving CD8 infiltration and drug delivery.The current clinical protocol of administering AI and ICI on the same day results in ICI acting when vascular normalization is insufficient to mobilize CTL in the tumor tissue. In contrast, the anti‐tumor effect is enhanced when AI is administered several days before ICI, as ICI is given after vascular normalization and the number of immune cells infiltrating into the tissue has increased.