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The foundations of immune checkpoint blockade and the ipilimumab approval decennial

An Author Correction to this article was published on 14 January 2022

This article has been updated

Abstract

Cancer immunity, and the potential for cancer immunotherapy, have been topics of scientific discussion and experimentation for over a hundred years. Several successful cancer immunotherapies — such as IL-2 and interferon-α (IFNα) — have appeared over the past 30 years. However, it is only in the past decade that immunotherapy has made a broad impact on patient survival in multiple high-incidence cancer indications. The emergence of immunotherapy as a new pillar of cancer treatment (adding to surgery, radiation, chemotherapy and targeted therapies) is due to the success of immune checkpoint blockade (ICB) drugs, the first of which — ipilimumab — was approved in 2011. ICB drugs block receptors and ligands involved in pathways that attenuate T cell activation — such as cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and its ligand, PDL1 — and prevent, or reverse, acquired peripheral tolerance to tumour antigens. In this Review we mark the tenth anniversary of the approval of ipilimumab and discuss the foundational scientific history of ICB, together with the history of the discovery, development and elucidation of the mechanism of action of the first generation of drugs targeting the CTLA4 and PD1 pathways.

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Fig. 1: Milestones in discovery and development of immunotherapeutics.
Fig. 2: Roles of Fcγ receptors in anti-CTLA4 function.
Fig. 3: Interactions of CTLA4 and PD1 with their ligands and antibodies.
Fig. 4: FDA approvals of ICB therapeutics.
Fig. 5: Combination therapy with CTLA4 and PD1 inhibitors.

Change history

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Acknowledgements

A.J.K. and N.L. thank the numerous colleagues that they worked with at Medarex and Bristol-Myers Squibb. The authors thank S. Lewin, S. Almo, G. Dranoff, S. Hodi and C. Bolger for discussions and critical review of the manuscript.

Competing interests

A.J.K. and N.L. are owners of BMS stock, the company that markets ipilimumab and nivolumab. S.C.G.-T. declares no competing interests.

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Korman, A.J., Garrett-Thomson, S.C. & Lonberg, N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov 21, 509–528 (2022). https://doi.org/10.1038/s41573-021-00345-8

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