Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways

The discovery and clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1 and PD-L1 has revolutionized the treatment of cancer, as recognized by the 2018 Nobel Prize for Medicine and Physiology. This groundbreaking new approach has improved the outcomes of patients with...

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Bibliographic Details
Published in:Nature reviews. Clinical oncology Vol. 19; no. 1; pp. 37 - 50
Main Authors: Kraehenbuehl, Lukas, Weng, Chien-Huan, Eghbali, Shabnam, Wolchok, Jedd D, Merghoub, Taha
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.01.2022
Subjects:
Adenosine
BTLA protein
Cancer
Clinical trials
CTLA-4 protein
Glucose metabolism
Humans
Immune checkpoint
Immune checkpoint inhibitors
Immune Checkpoint Inhibitors - pharmacology
Immune Checkpoint Inhibitors - therapeutic use
Immunologic Factors - metabolism
Immunomodulation
Immunomodulators
Immunotherapy
Immunotherapy - methods
Lymphocytes
Lymphocytes T
Metabolism
Neoplasms - therapy
Patients
PD-1 protein
PD-L1 protein
Receptor mechanisms
Signal transduction
T cell receptors
Tumor necrosis factor
Tumors
ISSN:1759-4774, 1759-4782, 1759-4782
Online Access:Get full text
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Summary:The discovery and clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1 and PD-L1 has revolutionized the treatment of cancer, as recognized by the 2018 Nobel Prize for Medicine and Physiology. This groundbreaking new approach has improved the outcomes of patients with various forms of advanced-stage cancer; however, the majority of patients receiving these therapies, even in combination, do not derive clinical benefit. Further development of agents targeting additional immune checkpoints, co-stimulatory receptors and/or co-inhibitory receptors that control T cell function is therefore critical. In this Review, we discuss the translational potential and clinical development of agents targeting both co-stimulatory and co-inhibitory T cell receptors. Specifically, we describe their mechanisms of action, and provide an overview of ongoing clinical trials involving novel ICIs including those targeting LAG3, TIM3, TIGIT and BTLA as well as agonists of the co-stimulatory receptors GITR, OX40, 41BB and ICOS. We also discuss several additional approaches, such as harnessing T cell metabolism, in particular via adenosine signalling, inhibition of IDO1, and targeting changes in glucose and fatty acid metabolism. We conclude that further efforts are needed to optimize the timing of combination ICI approaches and, most importantly, to individualize immunotherapy based on both patient-specific and tumour-specific characteristics.
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ISSN:1759-4774
1759-4782
1759-4782
DOI:10.1038/s41571-021-00552-7