Mechanisms of resistance to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors ('targeted therapies'...

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Vydáno v:British journal of cancer Ročník 118; číslo 1; s. 9
Hlavní autoři: Jenkins, Russell W, Barbie, David A, Flaherty, Keith T
Médium: Journal Article
Jazyk:angličtina
Vydáno: England Nature Publishing Group 01.01.2018
Témata:
Animals
Biomarkers
Cancer
Chemotherapy
CTLA-4 protein
Cytotoxicity
Drug Resistance, Neoplasm
Humans
Immune checkpoint inhibitors
Immune response
Immunologic Factors - pharmacology
Immunologic Factors - therapeutic use
Immunotherapy
Lymphocytes T
Molecular Targeted Therapy
Neoplasms - drug therapy
Neoplasms - immunology
PD-1 protein
PD-L1 protein
Signal Transduction - drug effects
T-Lymphocytes - drug effects
Tumors
ISSN:0007-0920, 1532-1827, 1532-1827
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Popis
Shrnutí:Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors ('targeted therapies') largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data. Improved understanding of molecular and immunologic mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clinical and pre-clinical data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/bjc.2017.434