Anti-angiogenic Agents in Combination With Immune Checkpoint Inhibitors: A Promising Strategy for Cancer Treatment

Abstract

Advances in cancer immunity have promoted a major breakthrough in the field of cancer therapy. This is mainly associated with the successful development of immune checkpoint inhibitors (ICIs) for multiple types of human tumors. Blockade with different ICIs, including programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, may activate the immune system of the host against malignant cells. However, only a subgroup of patients with cancer would benefit from immune checkpoint blockade. Some patients experience primary resistance to initial immunotherapy, and a majority eventually develop acquired resistance to ICIs. However, the mechanisms involved in the development of drug resistance to immune checkpoint blockade remain unclear. Recent studies supported that combination of ICIs and anti-angiogenic agents could be a promising therapeutic strategy for overcoming the low efficacy of ICIs. Moreover, through their direct anti-cancer effect by inhibiting tumor growth and metastasis, anti-angiogenic drugs reprogram the tumor milieu from an immunosuppressive to an immune permissive microenvironment. Activated immunity by immune checkpoint blockade also facilitates anti-angiogenesis by downregulating the expression of vascular endothelial growth factor and alleviating hypoxia condition. Many clinical trials showed an improved anti-cancer efficacy and prolonged survival following the addition of anti-angiogenic agents to ICIs. This review summarizes the current understanding and clinical development of combination therapy with immune checkpoint blockade and anti-angiogenic strategy.

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

“…Indeed, VEGF and TGF-β signaling and abnormal vasculature, all belonging to the selected targets presented in this review has been implicated in fostering immunosuppression [ 398 ]. Their inhibition have been already shown to improved immunotherapies clinical outcomes in various cancer [ 399 ]. Although the impact of targeted therapies on iTME is still unclear, ongoing clinical trials combining bevacizumab or others targeted therapies to check-point inhibitors (for instance: NCT03743662, NCT03661723, NCT04704154) open new perspectives for GBM treatment.…”

Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer

“…Angiogenesis involves many signaling pathways, such as vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR), platelet derived growth factor (PDGF)-PDGF receptor (PDGFR) and fibroblast growth factor (FGF)-FGF receptor (FGFR). These signaling pathways influence multiple steps of the cancer immune response ( 31 , 32 ) ( Figure 1 ). VEGF is one of the most studied factors triggering angiogenesis.…”

“…Angiogenic molecules are capable to regulate the expression of different adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM1) to inhibit the transfer of immune cells to TME ( 28 ). Moreover, tumor endothelial cells could not only form a specific selective barrier to inhibit the penetration of certain immune cells ( 31 ), but also modulate the activity and variability of immune cells to regulate immunosuppression ( 32 ).…”

EPHA7 mutation as a predictive biomarker for immune checkpoint inhibitors in multiple cancers

“…As the largest family of receptor tyrosine kinases (RTKs), the erythropoietin-producing hepatocellular carcinoma (Eph) receptors are involved in a wide range of physiological activities, especially tumorigenesis, tumor immunity, and tumor angiogenesis [13][14][15]. Tumor angiogenesis is associated with immunosuppression [16]. Recent clinical trials showed that combination therapy of anti-angiogenesis and ICIs achieved more favorable outcomes than monotherapy in different cancers [17][18][19].…”