*2.2.2.1 Background & rationale*

Unregulated angiogenesis is one of the key characteristics of malignant tumors [35]. In addition to creating neovasculature, tumor angiogenesis plays a key role in creating an immunosuppressive tumor microenvironment by causing an accumulation of pro-tumor immune cells and a decrease in the abundance and function of anti-tumor immune cells. Anti-angiogenic cancer treatments have been shown to reverse this process, essentially 'reprogramming' the tumor microenvironment by converting it from an immunosuppressive to an immunogenic one. This has been accomplished by targeting and inhibiting vascular endothelial growth factor (VEGF), a well-known cell surface-signaling proangiogenic protein that becomes stimulated when bound to tyrosine kinase receptors. With the use of antiangiogenic small molecule tyrosine kinase inhibitors (TKIs), VEGF can be blocked from binding its receptor, stopping the tumor from being able to continue to create neovasculature [36]. However, cancer has been able to circumvent this blockade using multiple other pathways, suggesting the use of antiangiogenic therapies that inhibit more than one signaling pathway simultaneously.

The experimental drug, apatinib, is a highly selective VEGFR-2 TKI, administered orally, that has already been approved in China for ≥3rd-line treatment for advanced gastric cancer. The potential benefit of combining TKI and PD-1 therapies has been demonstrated in preclinical murine models, suggesting that

combining ICIs with antiangiogenesis therapy could have the synergistic antitumor effects needed to enhance the efficacy of the individual therapies [37]. This phase 1 single-center clinical trial beginning in 2018 evaluated the safety and tolerability of TKI, apatinib, and PD-1 inhibitor, nivolumab, in patients with unresectable or metastatic cancer.
