Anti-angiogenic therapies in cancer: from endogenous inhibitors to bispecific VEGF x PD-(L)1 antibodies

Based on the hypothesis that neovascularization was required for tumor growth, the search for angiogenesis inhibitors attracted considerable attention, leading to the development of the monoclonal antibody bevacizumab against vascular endothelial growth factor (VEGF) which is currently standard treatment in several types of cancer. However, and despite encouraging preclinical data, clinical trials frequently failed to translate into benefits for patients due to limited efficacy, resistance and toxicity. Resistance mechanisms include triggering of alternative proangiogenic pathways, non-angiogenic vascularization, and the unforeseen heterogeneity of tumor endothelial cells. Early efforts to disrupt key interactions between extracellular matrix and endothelial cells via integrin or metalloproteinase inhibitors also had modest clinical outcomes, mainly due to poor selectivity and compensatory mechanisms. Similarly, the promise of endogenous angiogenesis inhibitors like endostatin and angiostatin did not led to durable clinical responses. Recent studies have shown that VEGF contributes to immune suppression, and therefore anti-VEGF therapy can not only normalize vasculature, improving immune infiltration, but also help to reshape tumor microenvironment. This has led to successful combinations of antiangiogenic agents and immune checkpoint inhibitors, now approved in several indications, including renal cell and hepatocellular carcinomas. Based on these results, bispecific antibodies targeting simultaneously VEGF and PD-(L)1 are emerging as promising therapeutic agents, with several worldwide phase 3 trials ongoing. Globally, around twenty bispecifics and trispecifics are in clinical development. In this review, we recapitulate previous successes and failures of anti-angiogenic strategies, and explore the potential of VEGF x PD-(L)1 antibodies as a new paradigm in cancer treatment.