Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma

Abstract

The management of advanced-stage renal cell carcinoma (RCC) has been transformed by the development of immune-checkpoint inhibitors (ICIs). Nonetheless, most patients do not derive durable clinical benefit from these agents. Importantly, unlike other immunotherapy-responsive solid tumours, most RCCs have only a moderate mutational burden, and paradoxically, high levels of tumour CD8+ T cell infiltration are associated with a worse prognosis in patients with this disease. Building on the successes of antibodies targeting the PD-1 and CTLA4 immune checkpoints, multiple innovative immunotherapies are now in clinical development for the treatment of patients with RCC, including ICIs with novel targets, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cell therapies and therapeutic vaccines. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a disease-specific framework that incorporates a deep understanding of RCC immunobiology. In this Review, using the structure provided by the well-described cancer–immunity cycle, we outline the key steps required for a successful antitumour immune response in the context of RCC, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyse the most encouraging targets of novel immune-based therapies within the RCC microenvironment, and review the landscape of emerging antigen-directed therapies for this disease.

Key points

  • The biology of renal cell carcinoma (RCC) differs substantially from that of other immunotherapy-responsive solid tumours; therefore, the successful development of novel immune treatments requires an understanding of disease-specific biology.

  • RCCs are highly infiltrated with CD8+ T cells and consequently many therapeutic approaches focus on reinvigorating T cells present in the tumour immune microenvironment.

  • Novel immune-checkpoint inhibitors, co-stimulatory pathway agonists, modified cytokine therapies and metabolic pathway modulators are all promising approaches that have the potential to remodel the RCC microenvironment and improve antitumour T cell responses.

  • Precision immunotherapies aim to target RCC-specific antigens, thereby ‘steering’ the immune response towards malignant cells.

  • Monoclonal antibodies, adoptive cell therapies and therapeutic vaccines are all promising approaches that act in an antigen-directed manner and might improve the efficacy of current immunotherapies in patients with RCC.

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Fig. 1: The renal cell carcinoma-specific cancer–immunity cycle.
Fig. 2: Targeting the RCC immune microenvironment.
Fig. 3: Precision immunotherapy strategies for the treatment of RCC.

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Acknowledgements

We acknowledge W. Kaelin for helpful discussion and comments. D.A.B. acknowledges support from the DF/HCC Kidney Cancer SPORE Career Enhancement Program (P50CA101942-15), the US Department of Defense (DOD) congressionally directed medical research programs (CDMRP) (KC170216 and KC190130) and the DOD Academy of Kidney Cancer Investigators (KC190128). L.H. is supported by the Fondation de France during her postdoctoral research fellowship at Dana-Farber Cancer Institute. E.M.V.A. acknowledges support from the US NIH (NCI-R01-CA227388 and U01-CA233100). C.J.W. is a Scholar of the Leukemia and Lymphoma Society, and is supported in part by the Parker Institute for Cancer Immunotherapy. C.J.W. acknowledges support from the US NIH (NCI-1RO1CA155010 and NIH/NCI U24 CA224331), and The G. Harold and Leila Y. Mathers Foundation. T.K.C. is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (P50CA101942) and Cancer Center Support Grant (P30CA006516), the Kohlberg Chair at Harvard Medical School, the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI, and various US National Cancer Institute (NCI), DOD, Research Foundations and industry grants.

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Correspondence to Toni K. Choueiri.

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D.A.B. has acted as a consultant of Adept Field Solutions, Blueprint Partnerships, Charles River Associates, Dedham Group, Defined Health, Insight Strategy, Octane Global, Slingshot Insights and Trinity Group, has received travel support from Bristol Myers Squibb and has received honoraria from LM Education/Exchange Services. Z.B. has received research support from Bristol Myers Squibb and Genentech. E.M.V.A. has served on the advisory boards of Enara Bio, Genome Medical, Manifold Bio, and Monte Rosa, has acted as a consultant of Invitae, Janssen and Tango Therapeutics, has received research funding from Bristol Myers Squibb-IION and Novartis, holds equity in Enara Bio, Genome Medical, Manifold Bio, Microsoft, Monte Rosa, Syapse and Tango Therapeutics, has received travel support from Roche/Genentech, and is listed on several institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation. C.J.W. holds equity in BioNtech. T.K.C. has acted as a consultant of AstraZeneca, Bristol Myers Squibb, Corvus, Eisai, Exelixis, Genentech, GlaxoSmithKline, Ipsen, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Surface Oncology, Tracon and Up-to-Date, and has received research funding from Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer and Tracon. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks J. Bedke, R. Figlin, and C. Porta for their contribution to the peer review of this work.

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Braun, D.A., Bakouny, Z., Hirsch, L. et al. Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma. Nat Rev Clin Oncol (2021). https://doi.org/10.1038/s41571-020-00455-z

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