Targeting programmed cell death -1 (PD-1) and ligand (PD-L1): A new era in cancer active immunotherapy

Constantinidou, Anastasia; Alifieris, Constantinos; Trafalis, Dimitrios T.

doi:10.1016/j.pharmthera.2018.09.008

Cited by 369Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Targeting programmed cell death -1 (PD-1) and ligand (PD-L1): A new era in cancer active immunotherapy

Constantinidou, Anastasia, Alifieris, Constantinos, Trafalis, Dimitrios T.·2019·Pharmacology & Therapeutics

DOI 10.1016/j.pharmthera.2018.09.008

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Abstract

Improved understanding of the immune system and its role in cancer development and progression has led to impressive advances in the field of cancer immunotherapy over the last decade. Whilst the field is rapidly evolving and the list of drugs receiving regulatory approval for the treatment of various cancers is fast growing, the group of PD1- PDL-1 inhibitors is establishing a leading role amongst immunomodulatory agents. PD1- PDL-1 inhibitors act against pathways involved in adaptive immune suppression resulting in immune checkpoint blockade. Within the last four years two PD-1 and three PD-L1 inhibitors have been utilized in clinical practice against a variety of malignancies. Focus was initially placed on targeting cancers considered immunogenic such as melanoma, renal and lung cancers but subsequently the application expanded to include amongst others Hodgkin Lymphoma, urothelial as well as head and neck cancer. This article provides a comprehensive review of the early and late phase trials that led to the regulatory approval of all five PD1- PDL-1 inhibitors in the corresponding cancer types. It presents available data on the combinations of PD1- PDL-1 inhibitors with other therapies (immunotherapy, targeted therapy and chemotherapy), the toxicity profile of the PD1- PDL-1 inhibitors and ongoing trials testing the efficacy of these agents in cancer types beyond those that have been addressed already. Finally, current and future challenges in the application of PD-1 and PD-L1 inhibitors are discussed with emphasis on the role of predictive biomarkers.

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The PD-1/PD-L1 axis is hijacked by cancer cells to counteract immune activation, allowing tumor escape.
“The PD-1/ PD-L1 axis is hijacked by cancer cells to counteract immune activation, allowing the tumor to escape the immune response.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Constantinidou et al., 2019

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Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma
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A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC).
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OA13.01 A Phase II Study of Nivolumab in Malignant Pleural Mesothelioma (NivoMes): with Translational Research (TR) Biopies
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Cell death and thymic tolerance
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Clinical activity, safety and biomarker results from a phase Ia study of atezolizumab (atezo) in advanced/recurrent endometrial cancer (rEC).
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Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial.
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Letrozole and palbociclib versus 3rd generation chemotherapy as neoadjuvant treatment of minal breast cancer. Results of the UNICANCER-eoPAL study
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Pembrolizumab in patients (pts) with PD-L1–positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028.
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Pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma: Phase 1 KEYNOTE-022 study.
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Multicenter phase II study of pembrolizumab (P) in advanced soft tissue (STS) and bone sarcomas (BS): Final results of SARC028 and biomarker analyses.
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Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC).
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A phase I study of cabozantinib plus nivolumab (CaboNivo) and ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors.
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First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial.
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Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer.
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KEYNOTE-059 Update: Efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal (G/GEJ) cancer
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Programmed death-1 blockade in mismatch repair deficient cancer independent of tumor histology.
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OA13.02 Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis
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Safety and Response With Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) Plus Erlotinib in Patients (Pts) With Epidermal Growth Factor Receptor Mutant (EGFR MT) Advanced Non-Small Cell Lung Cancer (NSCLC)
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Adaptive immune contexture at the tumour site and downmodulation of circulating myeloid-derived suppressor cells in the response of solitary fibrous tumour patients to anti-angiogenic therapy
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REGN2810: A fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC)—Initial safety and efficacy from expansion cohorts (ECs) of phase I study.
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Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts).
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KEYNOTE-059 cohort 3: safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients (pts) with PD-L1-positive advanced gastric/gastroesophageal (G/GEJ) cancer
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Cuproptosis: mechanisms and links with cancers
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Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial
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Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment
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The Role Of PD-1/PD-L1 Axis In Treg Development And Function: Implications For Cancer Immunotherapy
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PD-1/PD-L1 Inhibitors in Cervical Cancer
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Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells.
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Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy
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Metformin Liposome-Mediated PD-L1 Downregulation for Amplifying the Photodynamic Immunotherapy Efficacy
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Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model
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Monoclonal Antibodies: Past, Present and Future
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Nanotransferrin-Based Programmable Catalysis Mediates Three-Pronged Induction of Oxidative Stress to Enhance Cancer Immunotherapy
Bai, S., Lu, Z., Jiang, Y., Shi, X., Xu, D., Shi, Y., Lin, G., Liu, C., Zhang, Y., & Liu, G. (2021) · ACS Nano · doi:10.1021/acsnano.1c08619 · Cited by 104 · see citing works
Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy
Luo, X., He, X., Zhang, X., Zhao, X., Zhang, Y., Shi, Y., & Hua, S. (2024) · MedComm · doi:10.1002/mco2.474 · Cited by 111 · see citing works
Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano‐immunotherapy in Breast Cancer Lung Metastasis
Mpekris, F., Panagi, M., Voutouri, C., Martin, J. D., Samuel, R., Takahashi, S., Gotohda, N., Suzuki, T., Papageorgis, P., Demetriou, P., et al. (2020) · Advanced Science · doi:10.1002/advs.202001917 · Cited by 103 · see citing works
Regulation of PD-L1 expression on cancer cells with ROS-modulating drugs
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Increased expression of PD-1 and PD-L1 in oral lesions progressing to oral squamous cell carcinoma: a pilot study
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Longitudinal immune characterization of syngeneic tumor models to enable model selection for immune oncology drug discovery
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Head and Neck Squamous Cell Carcinoma: Risk Factors, Molecular Alterations, Immunology and Peptide Vaccines
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The Emerging Role of YAP/TAZ in Tumor Immunity
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Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects
Makaremi, S., Asadzadeh, Z., Hemmat, N., Baghbanzadeh, A., Sgambato, A., Ghorbaninezhad, F., Safarpour, H., Argentiero, A., Brunetti, O., Bernardini, R., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9091075 · Cited by 97 · see citing works
Triple negative breast cancer: Immunogenicity, tumor microenvironment, and immunotherapy
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Clinical Relevance of Immune Checkpoints on Circulating Tumor Cells in Breast Cancer
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Anticytokine Immune Therapy and Atherothrombotic Cardiovascular Risk
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Oncolytic Herpes Simplex Virus Encoding IL12 Controls Triple-Negative Breast Cancer Growth and Metastasis
Ghouse, S. M., Nguyen, H.-M., Bommareddy, P. K., Guz-Montgomery, K., & Saha, D. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00384 · Cited by 78 · see citing works
Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer
Yang, H., Zhang, X., Lao, M., Sun, K., He, L., Xu, J., Duan, Y., Chen, Y., Ying, H., Li, M., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01102-z · Cited by 78 · see citing works
Oncolytic Virus Engineering and Utilizations: Cancer Immunotherapy Perspective
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Immunotherapy for colorectal cancer: Rational strategies and novel therapeutic progress
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Ginsenoside Rk1 induces apoptosis and downregulates the expression of PD-L1 by targeting the NF-κB pathway in lung adenocarcinoma
Hu, M., Yang, J. F., Qu, L., Deng, X., Duan, Z., Fu, R., Liang, L., & Fan, D. (2019) · Food & Function · doi:10.1039/c9fo02166c · Cited by 77 · see citing works
The Biogenesis, Biology, and Clinical Significance of Exosomal PD-L1 in Cancer
Tang, Y., Zhang, P., Wang, Y., Wang, J., Su, M., Wang, Y., Zhou, L., Zhou, J., Xiong, W., Zeng, Z., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00604 · Cited by 77 · see citing works
MRTF-A-NF-κB/p65 axis-mediated PDL1 transcription and expression contributes to immune evasion of non-small-cell lung cancer via TGF-β
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Icaritin inhibits PD‐L1 expression by Targeting Protein IκB Kinase α
Mo, D., Zhu, H., Wang, J., Hao, H., Guo, Y., Wang, J., Han, X., Zou, L., Li, Z., Yao, H., et al. (2020) · European Journal of Immunology · doi:10.1002/eji.202048905 · Cited by 72 · see citing works
Adjuvant Effect of Toll-Like Receptor 9 Activation on Cancer Immunotherapy Using Checkpoint Blockade
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Discovery of 4-Arylindolines Containing a Thiazole Moiety as Potential Antitumor Agents Inhibiting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction
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Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity
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Immuno-PET imaging of 68Ga-labeled nanobody Nb109 for dynamic monitoring the PD-L1 expression in cancers
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Small molecules targeting protein–protein interactions for cancer therapy
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Immunotherapy-Based Targeting and Elimination of Leukemic Stem Cells in AML and CML
Valent, P., Sadovnik, I., Eisenwort, G., Bauer, K., Herrmann, H., Gleixner, K. V., Schulenburg, A., Rabitsch, W., Sperr, W. R., & Wolf, D. G. F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174233 · Cited by 60 · see citing works
PD-L1 expression on circulating tumor cells and platelets in patients with metastatic breast cancer
Darga, E. P., Dolce, E. M., Fang, F., Kidwell, K., Gersch, C. L., Kregel, S., Thomas, D. G., Gill, A., Brown, M. E., Gross, S. C., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0260124 · Cited by 59 · see citing works
Discovery of the programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing an indoline scaffold
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New insights into checkpoint inhibitor immunotherapy and its combined therapies in hepatocellular carcinoma: from mechanisms to clinical trials
Jin, H., Qin, S., He, J., Xiao, J., Li, Q., Mao, Y., & Zhao, L. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.70691 · Cited by 58 · see citing works
A Dual Role of Type I Interferons in Antitumor Immunity
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Overview of PD-1 and PD-L1 Inhibitors
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Authors: Constantinidou, A., Alifieris, C., & Trafalis, D. T.
Affiliations: University of Cyprus (CY)
National and Kapodistrian University of Athens (GR)
Corresponding author: Trafalis, Dimitrios T.
ORCID: Constantinidou, Anastasia
Alifieris, Constantinos
Trafalis, Dimitrios T.
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 2019-02
Volume: 194
Pages: 84-106
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/j.pharmthera.2018.09.008
OpenAlex: W2894101188
Cited by: 342
References: 230
Citations by year: 2026: 13 · 2025: 16 · 2024: 43 · 2023: 51 · 2022: 58 · 2021: 72 · 2020: 53 · 2019: 35
FWCI: 4.31
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: PD-1 inhibitors, PD-L1 inhibitors, immune checkpoint blockade, cancer immunotherapy, melanoma, renal cell carcinoma, lung cancer, Hodgkin's disease, urothelial carcinoma, head and neck cancer, combination therapy, toxicity profile, predictive biomarkers, regulatory approval
MeSH terms: Antineoplastic Agents, Immunological, Animals, Humans, Immunotherapy, Neoplasms, B7-H1 Antigen, Programmed Cell Death 1 Receptor

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Targeting programmed cell death -1 (PD-1) and ligand (PD-L1): A new era in cancer active immunotherapy

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