Combining Immune Checkpoint Inhibitors with Anti-Angiogenic Agents

Immunotherapy has recently emerged as a novel strategy for treating different types of solid tumors, with promising results. However, still a large fraction of patients do not primarily respond to such approaches, and even responders sooner or later develop resistance. Moreover, immunotherapy is a promising strategy for certain malignancies but not for others, with this discrepancy having been attributed to a more immunogenic microenvironment of some tumors. As abnormal and augmented tumor vessels often occur in cancerogenesis, anti-angiogenic drugs have already demonstrated their effectiveness both in preclinical and in clinical settings. By targeting abnormal formation of tumor vessels, anti-angiogenetic agents potentially result in an enhanced infiltration of immune effector cells. Moreover, crosstalks downstream of the immune checkpoint axis and vascular endothelial growth factor receptor (VEGFR) signaling may result in synergistic effects of combined treatment in tumor cells. In this review, we will describe and discuss the biological rationale of a combined therapy, underlying the modification in tumor microenvironment as well as in tumor cells after exposure to checkpoint inhibitors and anti-angiogenic drugs. Moreover, we will highlight this strategy as a possible way for overcoming drug resistance. By first discussing potential prognostic and predictive factors for combined treatment, we will then turn to clinical settings, focusing on clinical trials where this strategy is currently being investigated.