Development and clinical applications of cancer immunotherapy against PD-1 signaling pathway

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Abstract

Dramatic advances in immune therapy have emerged as a promising strategy in cancer therapeutics. In addition to chemotherapy and radiotherapy, inhibitors targeting immune-checkpoint molecules such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death receptor-1 (PD-1) and its ligand (PD-L1) demonstrate impressive clinical benefits in clinical trials. In this review, we present background information about therapies involving PD-1/PD-L1 blockade and provide an overview of current clinical trials. Furthermore, we present recent advances involving predictive biomarkers associated with positive therapeutic outcomes in cancer immunotherapy.

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Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Y Iwai, M. Ishida, Y. Tanaka … (2002)

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

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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.

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Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy

Paolo Ascierto, Georgina V Long, Caroline Robert … (2018)

This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors.

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Author and article information

Contributors

Grace Wakabayashi: gwakabayashi@nyu.edu

Yu-Ching Lee: ycl@tmu.edu.tw

Frank Luh: frankluh@sacfamerica.org

Chun-Nan Kuo: rencouter@gmail.com

Wei-Chao Chang: wcchang@tmu.edu.tw

Yun Yen:

ORCID: http://orcid.org/0000-0003-0815-412X

yyen@tmu.edu.tw

Journal

Journal ID (nlm-ta): J Biomed Sci

Journal ID (iso-abbrev): J. Biomed. Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central (London )

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date (Electronic): 5 December 2019

Publication date PMC-release: 5 December 2019

Publication date Collection: 2019

Volume: 26

Electronic Location Identifier: 96

Affiliations

[1 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Taipei Medical University, ; 250 Wu-Hsing Street, Taipei, Taiwan 110

[2 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Center for Cancer Transnational Research, , Taipei Medical University, ; 250 Wu-Hsing Street, Taipei, Taiwan 110

[3 ]Sino-American Cancer Foundation, 668 Arrow Grand Circle, Suite 101, Covina, California, 91722 USA

[4 ]Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University; Department of Pharmacy, Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital; Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan 110

[5 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, PhD Program for Cancer Biology and Drug Discovery, , Taipei Medical University, ; 250 Wu-Hsing Street, Taipei, Taiwan 110

Author information

Yun Yen http://orcid.org/0000-0003-0815-412X

Article

Publisher ID: 588

DOI: 10.1186/s12929-019-0588-8

PMC ID: 6894306

PubMed ID: 31801525

SO-VID: f4a4ff35-8307-4278-8164-d9b869677575

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 October 2019

Date accepted : 13 November 2019

Funding

Funded by: TMU Research Center of Cancer Translational Medicine

Award ID: Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan

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ScienceOpen disciplines: Molecular medicine

Keywords: checkpoint inhibitor,cancer immunotherapy,pd-1 pd-l1 signaling

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ScienceOpen disciplines: Molecular medicine

Keywords: checkpoint inhibitor, cancer immunotherapy, pd-1 pd-l1 signaling

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Most cited references 34

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Mechanisms of resistance to immune checkpoint inhibitors

Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy

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