Angiogenesis Inhibitors and Immunomodulation in Renal Cell Cancers: The Past, Present, and Future

Abstract

Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due to therapeutic resistance mechanisms, and there remains a need to develop novel therapeutic strategies. This article will review the synergistic mechanisms behind angiogenesis and immunomodulation in the tumor microenvironment and discuss the pre-clinical and clinical evidence for both clear-cell and non-clear-cell RCC, exploring opportunities for future growth in this exciting area of drug development.

Keywords: angiogenesis inhibitor; drug resistance; immunotherapy; renal cell carcinoma; targeted therapy; tumor microenvironment.

Figure 1

Timeline of US Food and Drug Administration drug approvals for advanced-stage renal cell carcinoma. Initial clinical success was seen with targeted therapies affecting angiogenesis and PI3K pathways in 2005, until 2015 when the first immune checkpoint inhibitor was approved for use. Within the last five years, more successes have been experienced with combination therapies, suggesting therapeutic synergy. Belzutifan is only approved for von Hippel–Lindau-related clear-cell renal cell carcinomas. Abbreviations: IFN-α = interferon alpha; TKI = tyrosine kinase inhibitor; mTOR = mammalian target of rapamycin; VEGF = vascular endothelial growth factor; HIF-2α = hypoxia-inducible factor-2α.

Figure 2

Schematic diagram of tumor environment in renal cell carcinoma with currently available therapeutic drug targets. Created with Biorender.com. (a) Intratumoral cell hypoxia leads to PI3K pathway pVHL activation, leading to HIF accumulation and altered cellular transcription, with downstream effects including angiogenesis factor production. (b) Various receptors and pro-angiogenic factors that interact with endothelial cells. (c) Immune checkpoints on regulatory T cells such as PD-1 and CTLA-4 are integral to the anti-tumor response, and their inhibition allows T cells to activate and cause cell death.