Synergism between anti-angiogenic and immune checkpoint inhibitor drugs: A hypothesis

Hepatocellular cancer (HCC) and renal cell cancer (RCC) are singularly resistant to conventional chemotherapy drugs but therapies targeting the supporting stroma have significantly altered their management. Two recent trials combining anti-angiogenic (AA) agents with immune checkpoint inhibitors (ICIs)- the IMbrave150 and IMmotion151 – have reported impressive progress over targeted agents. It has been suggested that bevacizumab, by improving tissue perfusion, changes the immune suppressive tumour microenvironment to an immune stimulatory one where the ICIs can be more effective. This hypothesis proposes an alternative explanation: That bevacizumab, by increasing tissue hypoxia, amplifies the mutational burden of the tumour by stress-induced mutagenesis, creating a hypermutator profile, which is more vulnerable to the ICI drug, atezolizumab. Additionally, ICIs are known to cause hyperprogression in some tumours, and bevacizumab could provide further benefit by starving these rapidly proliferative tumours of blood supply and nutrients.