Programmed cell death-1/programmed cell death ligand-1 checkpoint inhibitors: differences in mechanism of action.

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors are widely used in many types of solid tumors, and are often considered to be in the same immunotherapy subclass. This review explores whether specific agents in these two categories exhibit differences in their mechanism of action, pharmacokinetics and pharmacodynamics, and clinical efficacy and safety. Due to the complicated functional pathways in the immune checkpoint system, the epitopes, interfaces and signal pathways between PD-1: PD-L1/PD-L2, PD-L1/CD28/CTLA-4: B7-1 axes often overlap and affect each other. Therefore, the mechanisms of action of PD-1 and PD-L1 inhibitors reflect the corresponding cross connectivity and their unique characteristics. Only head-to-head comparative studies can provide definitive information regarding clinical efficacy and safety differences between specific PD-1/PD-L1 inhibitors.

[1]  P. Hegde,et al.  Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  P. Medina,et al.  PD‐1 Pathway Inhibitors: Immuno‐Oncology Agents for Restoring Antitumor Immune Responses , 2016, Pharmacotherapy.

[3]  G. Linette,et al.  Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. , 2016, The Lancet. Oncology.

[4]  Keunchil Park,et al.  Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial , 2016, The Lancet.

[5]  M. Fujimoto,et al.  Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041) , 2017, Cancer Chemotherapy and Pharmacology.

[6]  Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells , 2015, Cancer Immunology Research.

[7]  K. Omura,et al.  Preferential contribution of B7‐H1 to programmed death‐1‐mediated regulation of hapten‐specific allergic inflammatory responses , 2003, European journal of immunology.

[8]  P. Aguiar,et al.  Comparative effectiveness of immune-checkpoint inhibitors for previously treated advanced non-small cell lung cancer - A systematic review and network meta-analysis of 3024 participants. , 2018, Lung cancer.

[9]  J. Schlom,et al.  Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. , 2017, The Lancet. Oncology.

[10]  S. Culine,et al.  Pembrolizumab as Second‐Line Therapy for Advanced Urothelial Carcinoma , 2017, The New England journal of medicine.

[11]  R. Bourgon,et al.  Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial , 2017, The Lancet.

[12]  K. Kelly,et al.  Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. , 2017, The Lancet. Oncology.

[13]  T. Okazaki,et al.  PD-1 and PD-1 ligands: from discovery to clinical application. , 2007, International immunology.

[14]  Ling-Long Tang,et al.  Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis , 2018, British Medical Journal.

[15]  Y. Doki,et al.  Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. , 2017, The Lancet. Oncology.

[16]  Yongliang Zhang,et al.  Regulation of T cell activation and tolerance by PDL2. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. Freeman,et al.  Blockade of Programmed Death-1 Ligands on Dendritic Cells Enhances T Cell Activation and Cytokine Production 1 , 2003, The Journal of Immunology.

[18]  J. Soria,et al.  Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[19]  K. Breckpot,et al.  PD1 signal transduction pathways in T cells , 2017, Oncotarget.

[20]  J. Salfeld,et al.  Isotype selection in antibody engineering , 2007, Nature Biotechnology.

[21]  H. Wakui,et al.  Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors , 2016, Investigational New Drugs.

[22]  Wei Zhou,et al.  Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. , 2015, The Lancet. Oncology.

[23]  Y. Shentu,et al.  Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. , 2016, The New England journal of medicine.

[24]  Carlos Barrios,et al.  Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial , 2017, The Lancet.

[25]  G. Gao,et al.  Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab , 2017, Protein & Cell.

[26]  G. Gao,et al.  Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies , 2016, Protein & Cell.

[27]  D. Schadendorf,et al.  Nivolumab in previously untreated melanoma without BRAF mutation. , 2015, The New England journal of medicine.

[28]  D. Jäger,et al.  Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. , 2016, The Lancet. Oncology.

[29]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[30]  T. Curiel,et al.  Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  G. Gao,et al.  An unexpected N-terminal loop in PD-1 dominates binding by nivolumab , 2017, Nature Communications.

[32]  J. Elassaiss-Schaap,et al.  Translational Pharmacokinetic/Pharmacodynamic Modeling of Tumor Growth Inhibition Supports Dose‐Range Selection of the Anti–PD‐1 Antibody Pembrolizumab , 2016, CPT: pharmacometrics & systems pharmacology.

[33]  E. Buchbinder,et al.  CTLA-4 and PD-1 Pathways , 2016, American journal of clinical oncology.

[34]  F. Nestle,et al.  IgG4 Characteristics and Functions in Cancer Immunity , 2016, Current Allergy and Asthma Reports.

[35]  K. Sheppard,et al.  PD‐1 inhibits T‐cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ , 2004 .

[36]  T. Anagnostou,et al.  The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation , 2016, Front. Immunol..

[37]  Ju Yeon Lee,et al.  Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab , 2017, Scientific Reports.

[38]  Matteo Brunelli,et al.  Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers , 2015, PloS one.

[39]  G. Linette,et al.  Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. , 2015, The Lancet. Oncology.

[40]  M. Aldarouish,et al.  Trends and advances in tumor immunology and lung cancer immunotherapy , 2016, Journal of Experimental & Clinical Cancer Research.

[41]  Su-Jin Shin,et al.  Clinicopathologic Analysis of PD-L1 and PD-L2 Expression in Renal Cell Carcinoma: Association with Oncogenic Proteins Status , 2016, Annals of Surgical Oncology.

[42]  A. Bello,et al.  Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors , 2017, Journal of clinical pharmacology.

[43]  J. Lunceford,et al.  PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer , 2017, Clinical Cancer Research.

[44]  C. Shao,et al.  Lessons learned from the blockade of immune checkpoints in cancer immunotherapy , 2018, Journal of Hematology & Oncology.

[45]  A. Iyer,et al.  PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome , 2017, Front. Pharmacol..

[46]  C. Langer,et al.  PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. , 2015, Clinical advances in hematology & oncology : H&O.

[47]  S. Ryu,et al.  Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy , 2016, Nature Communications.

[48]  T. Seiwert,et al.  Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  Loise M. Francisco,et al.  RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance , 2014, The Journal of experimental medicine.

[50]  H. Hamm,et al.  Mechanism of action of monoclonal antibodies that block the light activation of the guanyl nucleotide-binding protein, transducin. , 1987, The Journal of biological chemistry.

[51]  G. Scapin,et al.  Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab , 2015, Nature Structural &Molecular Biology.

[52]  G. Freeman,et al.  Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. , 2007, Immunity.

[53]  G. Gao,et al.  Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy , 2016, Cell Research.

[54]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[55]  P. Sharma,et al.  Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, phase 1/2 trial , 2016, The Lancet. Oncology.

[56]  J. Lunceford,et al.  Pembrolizumab for the treatment of non-small-cell lung cancer. , 2015, The New England journal of medicine.

[57]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[58]  S. Gettinger,et al.  Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  J. Larkin,et al.  Pembrolizumab versus Ipilimumab in Advanced Melanoma. , 2015, The New England journal of medicine.

[60]  K. Savage,et al.  Nivolumab for classical Hodgkin lymphoma after autologous stem-cell transplantation and brentuximab vedotin failure: a prospective phase 2 multi-cohort study , 2016, The Lancet. Oncology.

[61]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[62]  B. Rath,et al.  Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity , 2017, Expert opinion on biological therapy.

[63]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[64]  K. Harrington,et al.  Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. , 2016, The New England journal of medicine.

[65]  E. Plimack,et al.  Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. , 2017, The Lancet. Oncology.

[66]  R. Stewart,et al.  PD-L1 blockade for cancer treatment: MEDI4736. , 2015, Seminars in oncology.

[67]  A. Korman,et al.  In Vitro Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and In Vivo Toxicology in Non-Human Primates , 2014, Cancer Immunology Research.