Checkpoint inhibitor immunotherapy in kidney cancer

Abstract

Kidney cancer has unique features that make this malignancy attractive for therapeutic approaches that target components of the immune system. Immune checkpoint inhibition is a well-established part of kidney cancer treatment, and rapid advances continue to be made in this field. Initial preclinical studies that elucidated the biology of the programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) immune checkpoints led to a series of clinical trials that resulted in regulatory approval of nivolumab and the combination of ipilimumab plus nivolumab for the treatment of advanced renal cell carcinoma. Subsequent data led to approvals of combination strategies of immune checkpoint inhibition plus agents that target the vascular endothelial growth factor receptor and a shift in the current standard of renal cell carcinoma care. However, controversies remain regarding the optimal therapy selection and treatment strategy for individual patients, which might be eventually overcome by current intensive efforts in biomarker research. That work includes evaluation of tumour cell PD-L1 expression, gene expression signatures, CD8+ T cell density and others. In the future, further advances in the understanding of immune checkpoint biology might reveal new therapeutic targets beyond PD-1, PD-L1 and CTLA-4, as well as new combination approaches.

Key points

  • Renal cell carcinoma (RCC) has unique characteristics that potentially increase its susceptibility to treatments that target components of the immune system, including immune checkpoint inhibition (ICI).

  • Preclinical and clinical studies have provided a rationale for the treatment of RCC with programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade.

  • Combination regimens that include ICI are the current standard of care in advanced RCC, but controversies remain and a thoughtful and systematic approach to the selection of first-line therapy is needed.

  • Research into useful biomarkers for patient selection is ongoing and includes the evaluation of tumour cell PD-L1 expression, gene expression signatures, CD8+ T cell density and others.

  • Further developments in ICI in RCC will be driven by an improved understanding of the immunobiology of their efficacy and emerging biomarkers, which is also informed by findings in other malignancies.

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Fig. 1: Immune checkpoint inhibition of PD-1, PD-L1 and CTLA-4 in RCC.
Fig. 2: Selected clinical trials of ICI in renal cell carcinoma.

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W.X. researched data for the article. All authors made substantial contributions to discussion of the article content, and wrote and reviewed and/or edited the manuscript before submission.

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Correspondence to David F. McDermott.

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M.B.A. serves on the advisory boards of Bristol-Myers Squibb (BMS), Merck, Novartis, Arrowhead, Pfizer, Galactone, Werewolf and Fathom. He serves as a consultant to BMS, Merck, Novartis, Pfizer, Genentech-Roche, Exelixis, Eisai, Aveo, Array, Ideera, Aduro, ImmunoCore, Boehringer-Ingelheim, Iovance, Newlink, Surface, Alexion, Acceleron, Pyxis, Cota and Amgen. He receives research support from BMS (to his institution) and owns stock options in Werewolf and Pyxis. D.F.M. receives consulting honoraria from BMS, Pfizer, Merck, Novartis, Exelixis, Array BioPharm, Genentech, Alkermes, Jounce Therapeutics, X4 Pharmaceuticals, Peloton, EMD Serono and Eli Lilly. He receives research support from BMS, Prometheus Laboratories, Merck, Genentech, Pfizer, Exelixis, Novartis, X4 Pharmaceuticals, Alkermes and Peloton. W.X. declares no competing interests.

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Xu, W., Atkins, M.B. & McDermott, D.F. Checkpoint inhibitor immunotherapy in kidney cancer. Nat Rev Urol 17, 137–150 (2020). https://doi.org/10.1038/s41585-020-0282-3

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