For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
17
views
74
references
 Top references
cited by
38
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      197
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies

      review-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The treatment landscape for patients with advanced non-small cell lung cancer has evolved greatly with the advent of immune checkpoint inhibitors. However, many patients do not derive benefit from checkpoint blockade, developing either primary or secondary resistance, highlighting a need for alternative approaches to modulate immune function. In this review, we highlight the absence of a common definition of primary and secondary resistance and summarize their frequency and clinical characteristics. Furthermore, we provide an overview of the biomarkers and mechanisms of resistance involving the tumor, the tumor microenvironment and the host, and suggest treatment strategies to overcome these mechanisms and improve clinical outcomes.

          Related collections

          Most cited references74

          • Record: found
          • Abstract: found
          • Article: not found

          The blockade of immune checkpoints in cancer immunotherapy.

          Drew M Pardoll (2012)
          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
          Article 0 comments Cited 5275 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

            Shohei Koyama, Esra A Akbay, Yvonne Y. Li … (2016)
            Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
            Article 0 comments Cited 688 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Mechanisms of resistance to immune checkpoint inhibitors

              Russell Jenkins, David Barbie, Keith Flaherty (2018)
              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.
              Article 0 comments Cited 567 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Robert J. Walsh
                Ross A. Soo
                Journal
                Journal ID (nlm-ta): Ther Adv Med Oncol
                Journal ID (iso-abbrev): Ther Adv Med Oncol
                Journal ID (publisher-id): TAM
                Journal ID (hwp): sptam
                Title: Therapeutic Advances in Medical Oncology
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 1758-8340
                ISSN (Electronic): 1758-8359
                Publication date (Electronic): 3 July 2020
                Publication date Collection: 2020
                Volume: 12
                Electronic Location Identifier: 1758835920937902
                Affiliations
                [1-1758835920937902]Department of Haematology–Oncology, National University Cancer Institute Singapore, Singapore
                [2-1758835920937902]Department of Haematology–Oncology, National University Cancer Institute Singapore, National University Health System, 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore, 119228, Singapore
                Author notes
                Article
                Publisher ID: 10.1177_1758835920937902
                DOI: 10.1177/1758835920937902
                PMC ID: 7339077
                PubMed ID: 32670423
                SO-VID: 635a58c5-a6f7-4c15-aef6-03d08e20499e
                Copyright © © The Author(s), 2020
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 16 October 2019
                Date accepted : 4 June 2020
                Categories
                Subject: Review
                Custom metadata
                cover-date January-December 2020
                typesetter ts1

                Keywords: acquired resistance,immune checkpoint inhibitors,pd-l1,primary resistance
                Data availability:
                Keywords: acquired resistance, immune checkpoint inhibitors, pd-l1, primary resistance

                Comments

                Comment on this article

                scite_

                Similar content197

                See all similar

                Cited by37

                See all cited by

                Most referenced authors4,181

                See all reference authors