Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer

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Abstract

The immune checkpoints are regulatory molecules that maintain immune homeostasis in physiological conditions. By sending T cells a series of co-stimulatory or co-inhibitory signals via receptors, immune checkpoints can both protect healthy tissues from adaptive immune response and activate lymphocytes to remove pathogens effectively. However, due to their mode of action, suppressive immune checkpoints may serve as unwanted protection for cancer cells. To restore the functioning of the immune system and make the patient’s immune cells able to recognize and destroy tumors, monoclonal antibodies are broadly used in cancer immunotherapy to block the suppressive or to stimulate the positive immune checkpoints. In this review, we aim to present the current state of application of monoclonal antibodies in clinics, used either as single agents or in a combined treatment. We discuss the limitations of these therapies and possible problem-solving with combined treatment approaches involving both non-biological and biological agents. We also highlight the most promising strategies based on the use of monoclonal or bispecific antibodies targeted on immune checkpoints other than currently implemented in clinics.

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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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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.

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Combination of CTLA-4 and PD-1 blockers for treatment of cancer

Anand Rotte (2019)

Targeting checkpoints of immune cell activation has been demonstrated to be the most effective approach for activation of anti-tumor immune responses. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), both inhibitory checkpoints commonly seen on activated T-cells have been found to be the most reliable targets for the treatment of cancer. Six drugs targeting PD-1 or its ligand PD-L1 and one drug targeting CTLA-4 have been approved for treatment of different types of cancers and several others are in advanced stages of development. The drugs when administered as monotherapy had dramatic increase in durable response rates and had manageable safety profile, but more than 50% of patients failed to respond to treatment. Combination of CTLA-4 and PD-1 blockers was then evaluated to increase the response rates in patients, and ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) combination was shown to significantly enhance efficacy in metastatic melanoma patients. Subsequently, ipilimumab plus nivolumab was approved for treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancer with MMR/MSI-H aberrations. The success of combination encouraged multiple clinical studies in other cancer types. Efficacy of the combination has been shown in a number of published studies and is under evaluation in multiple ongoing studies. This review aims to support future research in combination immunotherapy by discussing the basic details of CTLA-4 and PD-1 pathways and the results from clinical studies that evaluated combination of CTLA-4 and PD-1/PD-L1 blockers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1259-z) contains supplementary material, which is available to authorized users.

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 08 November 2019

Publication date Collection: November 2019

Volume: 11

Issue: 11

Electronic Location Identifier: 1756

Affiliations

[1 ]Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59 Street, 02-006 Warsaw, Poland; k.marhelava@ 123456gmail.com (K.M.); malgorzata.bajor@ 123456wum.edu.pl (M.B.)

[2 ]Postgraduate School of Molecular Medicine, Medical University of Warsaw, Trojdena 2a Street, 02-091 Warsaw, Poland

[3 ]Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; zofia.pilch@ 123456gmail.com (Z.P.); agnieszka.graczyk-jarzynka@ 123456wum.edu.pl (A.G.-J.)

[4 ]Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59 Street, 02-006 Warsaw, Poland

[5 ]Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A Street, 02-106 Warsaw, Poland

Author notes

[* ]Correspondence: radoslaw.zagozdzon@ 123456wum.edu.pl ; Tel.: +48-(22)-502-14-72; Fax: +48-(22)-502-21-59

Author information

Malgorzata Bajor https://orcid.org/0000-0001-5778-0165

Agnieszka Graczyk-Jarzynka https://orcid.org/0000-0001-7980-0542

Radoslaw Zagozdzon https://orcid.org/0000-0002-7957-2372

Article

Publisher ID: cancers-11-01756

DOI: 10.3390/cancers11111756

PMC ID: 6895894

PubMed ID: 31717326

SO-VID: 9ff05596-5822-4305-ae32-bdad38e9eaad

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer

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Most cited references 76

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

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

Combination of CTLA-4 and PD-1 blockers for treatment of cancer

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