Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade

Shergold, A. L., Millar, R. and Nibbs, R. J.B. (2019) Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade. Pharmacological research, 145, 104258. (doi: 10.1016/j.phrs.2019.104258) (PMID:31063806)

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Greater understanding of tumour immunobiology has led to a new era of cancer treatment in which immuno-oncology (IO) therapies are used to boost anti-cancer immune responses. Prominent among these therapies are immune checkpoint inhibitors (ICIs), antibody-based drugs that can unleash the power of tumour-specific CD8 + T-cells. ICIs targeting the Programmed cell death protein 1 (PD-1) cell surface receptor or its ligand PD-L1 are particularly effective, with clinical studies reporting powerful and durable therapeutic impact against many cancer types, including melanoma and non-small cell lung cancer. ICIs have the potential to transform the landscape of cancer treatment, and their development was recognised by the award of the 2018 Nobel Prize in Physiology or Medicine to James Allison and Tasuku Honjo. However, the proportion of patients responding to anti-PD-1/PD-L1 monotherapy can be low. The next major challenge involves understanding and overcoming the innate and acquired resistance that prevents most patients from responding to PD-1/PD-L1 blockade. In this review, we outline the physiological function of PD-1 and its exploitation by developing tumours. We give an overview of current FDA-approved drugs targeting PD-1 or PD-L1 and summarise clinical progress so far. We then discuss key mechanisms thought to underpin resistance to PD-1/PD-L1 blockade, describing biomarkers that could allow patient responses to be predicted before treatment, and tracked once treatment has started. We also present clinical and pre-clinical combination therapies that have been developed to overcome resistance and which have the potential to substantially extend the therapeutic reach of these revolutionary drugs.

Item Type:Articles
Additional Information:Work in RJBN’s lab is funded by the Wellcome Trust (grant number: 206284/Z/17/Z)
Glasgow Author(s) Enlighten ID:Shergold, Miss Amy and Nibbs, Professor Rob
Authors: Shergold, A. L., Millar, R., and Nibbs, R. J.B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Pharmacological research
ISSN (Online):1096-1186
Published Online:04 May 2019
Copyright Holders:Copyright © 2019 Elsevier
First Published:First published in Pharmacological research 145:104258
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
3014990Integrative Transport Phenomena in Chemokine Gradient EstablishmentRobert NibbsWellcome Trust (WELLCOTR)206284/Z/17/ZIII - Immunology