Revisiting Antiangiogenic Multikinase Inhibitors in the Era of Immune Checkpoint Blockade: The Case of Sorafenib

Abstract

The successful development of multikinase inhibitors over the last two decades has revolutionized the management of many malignant cancers. Agents such as the antiangiogenic kinase inhibitor sorafenib have certain advantages such as a broad spectrum of activity against cancer cells, vascular endothelial cells, and pericytes, and are the mainstay of treatment in diseases such as advanced renal or liver cancer. The more recent emergence of immunotherapy-using immune checkpoint blockade-in some of the same diseases has raised important questions about the treatment interaction with antiangiogenic drugs, seven such combinations have been approved for lung, liver, kidney, and endometrial cancers, and multiple combination therapies are being aggressively pursued in the clinic. Thus, revealing mechanisms of action of antiangiogenic kinase inhibitors in combination with immune checkpoint blockade is critical to improving the treatment outcome further. This Landmark commentary on sorafenib in cancer therapy highlights these important questions. See related article by Wilhelm et al., Cancer Res 2004;64:7099-109.

Figure 1.

Anti-VEGFR treatment-induced vascular normalization can reprogram the immunosuppressive tumor microenvironment into an immunosupportive one. Tumors develop an abnormal tumor vasculature, which leads to tissue hypoxia and acidosis. These microenvironmental characteristics impede T effector cell infiltration into the tumor via multiple mechanisms, including PD-L1 upregulation on myeloid-derived suppressor cells (MDSC), dendritic cells, and cancer cells; increased regulatory T cells (Treg) and M2-like macrophage infiltration; production of immunosuppressive factors (e.g., VEGF and TGFβ); and impaired effector T-cell function. When delivered at an appropriate dose/schedule, antiangiogenic treatment using anti-VEGFR drugs such as sorafenib can promote vascular normalization by reprogramming the microenvironment and alleviating immunosuppression. Conversely, excessive dosing or duration of anti-VEGFR therapy could aggravate immunosuppression by reducing perfusion and further increasing hypoxia. Adapted and updated from ref. . Reprinted from Cancer Cell, Volume 26, Issue 5, Jain RK, Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia, Pages 605–622, Copyright 2014, with permission from Elsevier.