Review
. 2017 Nov; 191(2):133-148.
doi: 10.1111/cei.13081.

Immune checkpoint inhibitors: new strategies to checkmate cancer

R A M Wilson 1 T R J Evans 2 A R Fraser 1 R J B Nibbs 1 
Affiliations
  • PMID: 29139554
  •     141 References
  •     21 citations

Abstract

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or programmed cell death protein 1 (PD-1) receptors have demonstrated remarkable efficacy in subsets of patients with malignant disease. This emerging treatment modality holds great promise for future cancer treatment and has engaged pharmaceutical research interests in tumour immunology. While ICIs can induce rapid and durable responses in some patients, identifying predictive factors for effective clinical responses has proved challenging. This review summarizes the mechanisms of action of ICIs and outlines important preclinical work that contributed to their development. We explore clinical data that has led to disease-specific drug licensing, and highlight key clinical trials that have revealed ICI efficacy across a range of malignancies. We describe how ICIs have been used as part of combination therapies, and explore their future prospects in this area. We conclude by discussing the incorporation of these new immunotherapeutics into precision approaches to cancer therapy.

Keywords: T cell; antibodies; cancer; tumour immunology.

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Ronald J Buckanovich, Andrea Facciabene, +7 authors, George Coukos.
Nat Med, 2007 Dec 25; 14(1). PMID: 18157142
Highly Cited.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.
Louis Fehrenbacher, Alexander Spira, +16 authors, POPLAR Study Group.
Lancet, 2016 Mar 14; 387(10030). PMID: 26970723
Highly Cited.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Emanuela Romano, Monika Kusio-Kobialka, +7 authors, Daniel E Speiser.
Proc Natl Acad Sci U S A, 2015 Apr 29; 112(19). PMID: 25918390    Free PMC article.
Highly Cited.
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
Christina Twyman-Saint Victor, Andrew J Rech, +22 authors, Andy J Minn.
Nature, 2015 Mar 11; 520(7547). PMID: 25754329    Free PMC article.
Highly Cited.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2015 Jun 02; 373(1). PMID: 26027431    Free PMC article.
Highly Cited.
T-cell regulation by CD28 and CTLA-4.
M L Alegre, K A Frauwirth, C B Thompson.
Nat Rev Immunol, 2002 Mar 22; 1(3). PMID: 11905831
Highly Cited. Review.
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
Eugene D Kwon, Charles G Drake, +24 authors, CA184-043 Investigators.
Lancet Oncol, 2014 May 17; 15(7). PMID: 24831977    Free PMC article.
Highly Cited.
Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent.
Alice O Kamphorst, Andreas Wieland, +17 authors, Rafi Ahmed.
Science, 2017 Mar 11; 355(6332). PMID: 28280249    Free PMC article.
Highly Cited.
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
Sergio A Quezada, Karl S Peggs, Michael A Curran, James P Allison.
J Clin Invest, 2006 Jun 17; 116(7). PMID: 16778987    Free PMC article.
Highly Cited.
Nivolumab plus ipilimumab in advanced melanoma.
Jedd D Wolchok, Harriet Kluger, +21 authors, Mario Sznol.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724867    Free PMC article.
Highly Cited.
Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation.
Tadashi Yokosuka, Wakana Kobayashi, +6 authors, Takashi Saito.
Immunity, 2010 Sep 28; 33(3). PMID: 20870175
The future of cancer treatment: immunomodulation, CARs and combination immunotherapy.
Danny N Khalil, Eric L Smith, Renier J Brentjens, Jedd D Wolchok.
Nat Rev Clin Oncol, 2016 Mar 16; 13(5). PMID: 26977780    Free PMC article.
Highly Cited. Review.
Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.
Brian T Fife, Kristen E Pauken, +6 authors, Jeffrey A Bluestone.
Nat Immunol, 2009 Sep 29; 10(11). PMID: 19783989    Free PMC article.
Highly Cited.
Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma.
Ryosuke Hino, Kenji Kabashima, +5 authors, Yoshiki Tokura.
Cancer, 2010 Feb 10; 116(7). PMID: 20143437
Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
The blockade of immune checkpoints in cancer immunotherapy.
Drew M Pardoll.
Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437870    Free PMC article.
Highly Cited. Review.
Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial.
Jeffrey S Weber, Geoff Gibney, +14 authors, F Stephen Hodi.
Lancet Oncol, 2016 Jun 09; 17(7). PMID: 27269740    Free PMC article.
Highly Cited.
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies.
Karl S Peggs, Sergio A Quezada, +2 authors, James P Allison.
J Exp Med, 2009 Jul 08; 206(8). PMID: 19581407    Free PMC article.
Highly Cited.
Merkel cell polyomavirus infection and Merkel cell carcinoma.
Wei Liu, Margo MacDonald, Jianxin You.
Curr Opin Virol, 2016 Aug 16; 20. PMID: 27521569    Free PMC article.
Review.
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.
Julie Brahmer, Karen L Reckamp, +22 authors, David R Spigel.
N Engl J Med, 2015 Jun 02; 373(2). PMID: 26028407    Free PMC article.
Highly Cited.
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Caroline Robert, Jacob Schachter, +20 authors, KEYNOTE-006 investigators.
N Engl J Med, 2015 Apr 22; 372(26). PMID: 25891173
Highly Cited.
Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up.
R Houston Thompson, Susan M Kuntz, +11 authors, Eugene D Kwon.
Cancer Res, 2006 Apr 06; 66(7). PMID: 16585157
Highly Cited.
Immune surveillance of tumors.
Jeremy B Swann, Mark J Smyth.
J Clin Invest, 2007 May 04; 117(5). PMID: 17476343    Free PMC article.
Highly Cited. Review.
Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.
Martin Reck, Alexander Luft, +17 authors, David Spigel.
J Clin Oncol, 2016 Jul 28; 34(31). PMID: 27458307
Highly Cited.
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells.
Loise M Francisco, Victor H Salinas, +4 authors, Arlene H Sharpe.
J Exp Med, 2009 Dec 17; 206(13). PMID: 20008522    Free PMC article.
Highly Cited.
First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.
David P Carbone, Martin Reck, +27 authors, CheckMate 026 Investigators.
N Engl J Med, 2017 Jun 22; 376(25). PMID: 28636851    Free PMC article.
Highly Cited.
Immunity, inflammation, and cancer.
Sergei I Grivennikov, Florian R Greten, Michael Karin.
Cell, 2010 Mar 23; 140(6). PMID: 20303878    Free PMC article.
Highly Cited. Review.
Confusing signals: recent progress in CTLA-4 biology.
Lucy S K Walker, David M Sansom.
Trends Immunol, 2015 Jan 15; 36(2). PMID: 25582039    Free PMC article.
Highly Cited. Review.
Innate and adaptive immune cells in the tumor microenvironment.
Thomas F Gajewski, Hans Schreiber, Yang-Xin Fu.
Nat Immunol, 2013 Sep 21; 14(10). PMID: 24048123    Free PMC article.
Highly Cited. Review.
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Omar S Qureshi, Yong Zheng, +12 authors, David M Sansom.
Science, 2011 Apr 09; 332(6029). PMID: 21474713    Free PMC article.
Highly Cited.
Immune-checkpoint inhibition in first-line treatment of advanced non-small cell lung cancer patients: Current status and future approaches.
J Remon, N Pardo, +4 authors, E Felip.
Lung Cancer, 2017 Mar 14; 106. PMID: 28285697
Review.
Regulatory circuits of T cell function in cancer.
Daniel E Speiser, Ping-Chih Ho, Grégory Verdeil.
Nat Rev Immunol, 2016 Aug 17; 16(10). PMID: 27526640
Highly Cited. Review.
Molecular basis of T cell inactivation by CTLA-4.
K M Lee, E Chuang, +7 authors, J A Bluestone.
Science, 1998 Dec 18; 282(5397). PMID: 9856951
Highly Cited.
Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure.
Philippe Armand, Margaret A Shipp, +8 authors, Craig H Moskowitz.
J Clin Oncol, 2016 Jun 30; 34(31). PMID: 27354476    Free PMC article.
Highly Cited.
Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.
Naiyer A Rizvi, Julien Mazières, +27 authors, Suresh S Ramalingam.
Lancet Oncol, 2015 Feb 24; 16(3). PMID: 25704439    Free PMC article.
Highly Cited.
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
Jesse M Zaretsky, Angel Garcia-Diaz, +26 authors, Antoni Ribas.
N Engl J Med, 2016 Jul 20; 375(9). PMID: 27433843    Free PMC article.
Highly Cited.
Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.
S A Rosenberg, J C Yang, +13 authors, D E White.
Nat Med, 1998 Mar 21; 4(3). PMID: 9500606    Free PMC article.
Highly Cited.
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.
Stephen M Ansell, Alexander M Lesokhin, +16 authors, Philippe Armand.
N Engl J Med, 2014 Dec 09; 372(4). PMID: 25482239    Free PMC article.
Highly Cited.
Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies.
Charles B Simone, Stuart H Burri, John H Heinzerling.
Transl Lung Cancer Res, 2015 Dec 03; 4(5). PMID: 26629423    Free PMC article.
Review.
The future of immune checkpoint therapy.
Padmanee Sharma, James P Allison.
Science, 2015 Apr 04; 348(6230). PMID: 25838373
Highly Cited. Review.
Enhancement of antitumor immunity by CTLA-4 blockade.
D R Leach, M F Krummel, J P Allison.
Science, 1996 Mar 22; 271(5256). PMID: 8596936
Highly Cited.
Gut microbiome modulates efficacy of immune checkpoint inhibitors.
Ming Yi, Shengnan Yu, +5 authors, Kongming Wu.
J Hematol Oncol, 2018 Mar 28; 11(1). PMID: 29580257    Free PMC article.
Highly Cited. Review.
Oncolytic Virus Combination Therapy: Killing One Bird with Two Stones.
Nikolas Tim Martin, John Cameron Bell.
Mol Ther, 2018 Apr 29; 26(6). PMID: 29703699    Free PMC article.
Review.
Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma.
Naofumi Mukaida, Yasunari Nakamoto.
World J Gastroenterol, 2018 May 10; 24(17). PMID: 29740200    Free PMC article.
Review.
Targeting adenosine for cancer immunotherapy.
Robert D Leone, Leisha A Emens.
J Immunother Cancer, 2018 Jun 20; 6(1). PMID: 29914571    Free PMC article.
Highly Cited. Review.
Nivolumab-Induced Autoimmune Encephalitis in Two Patients with Lung Adenocarcinoma.
Suma Shah, Anastasie Dunn-Pirio, +3 authors, Christopher Eckstein.
Case Rep Neurol Med, 2018 Aug 04; 2018. PMID: 30073101    Free PMC article.
Predictors of immunotherapy-induced immune-related adverse events.
A Kartolo, J Sattar, +2 authors, J M Lakoff.
Curr Oncol, 2018 Nov 23; 25(5). PMID: 30464691    Free PMC article.
CD8+ T cells modulate autosomal dominant polycystic kidney disease progression.
Emily K Kleczko, Kenneth H Marsh, +11 authors, Katharina Hopp.
Kidney Int, 2018 Sep 27; 94(6). PMID: 30249452    Free PMC article.
Prospects for combining immune checkpoint blockade with PARP inhibition.
Anping Li, Ming Yi, +3 authors, Kongming Wu.
J Hematol Oncol, 2019 Sep 16; 12(1). PMID: 31521196    Free PMC article.
Review.
Identification of the immune checkpoint signature of multiple myeloma using mass cytometry-based single-cell analysis.
Jinheng Wang, Yongjiang Zheng, +4 authors, Jinbao Liu.
Clin Transl Immunology, 2020 May 02; 9(5). PMID: 32355560    Free PMC article.
Targeting CD47 in Anaplastic Thyroid Carcinoma Enhances Tumor Phagocytosis by Macrophages and Is a Promising Therapeutic Strategy.
Christian M Schürch, Matthias A Roelli, +11 authors, Matthias S Dettmer.
Thyroid, 2019 Apr 03; 29(7). PMID: 30938231    Free PMC article.
Exploration of the personalized immune checkpoint atlas of plasma cell dyscrasias patients using high‑dimensional single‑cell analysis.
Chenggong Tu, Yongjiang Zheng, Hui Zhang, Jinheng Wang.
Oncol Rep, 2020 Apr 23; 44(1). PMID: 32319658    Free PMC article.
Inhibition of Programmed Death Receptor-1/Programmed Death Ligand-1 Interactions by Ginsenoside Metabolites.
Nam-Hui Yim, Young Soo Kim, Hwan-Suck Chung.
Molecules, 2020 May 06; 25(9). PMID: 32365500    Free PMC article.
Combined immune checkpoint blockade increases CD8+CD28+PD-1+ effector T cells and provides a therapeutic strategy for patients with neuroblastoma.
Soheila Shirinbak, Randall Y Chan, +11 authors, Shahab Asgharzadeh.
Oncoimmunology, 2021 Jan 26; 10(1). PMID: 33489468    Free PMC article.
Revisiting the role of CD4+ T cells in cancer immunotherapy-new insights into old paradigms.
Rong En Tay, Emma K Richardson, Han Chong Toh.
Cancer Gene Ther, 2020 May 28; 28(1-2). PMID: 32457487    Free PMC article.
Review.
Cancer-on-a-Chip for Modeling Immune Checkpoint Inhibitor and Tumor Interactions.
Xing Jiang, Li Ren, +18 authors, Ali Khademhosseini.
Small, 2021 Jan 28; 17(7). PMID: 33502118    Free PMC article.
Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma.
Luuk van Hooren, Alessandra Vaccaro, +16 authors, Anna Dimberg.
Nat Commun, 2021 Jul 07; 12(1). PMID: 34226552    Free PMC article.
Efficacy of the mRNA-Based BNT162b2 COVID-19 Vaccine in Patients with Solid Malignancies Treated with Anti-Neoplastic Drugs.
Abed Agbarya, Ina Sarel, +14 authors, Ronen Brenner.
Cancers (Basel), 2021 Aug 28; 13(16). PMID: 34439346    Free PMC article.
Co-Stimulatory Bispecific Antibodies Induce Enhanced T Cell Activation and Tumor Cell Killing in Breast Cancer Models.
Karsten M Warwas, Marten Meyer, +9 authors, Frank Momburg.
Front Immunol, 2021 Sep 07; 12. PMID: 34484225    Free PMC article.
Rheumatic Manifestations and Diseases From Immune Checkpoint Inhibitors in Cancer Immunotherapy.
Pan Shen, Xuan Deng, +9 authors, Shenghao Tu.
Front Med (Lausanne), 2021 Nov 23; 8. PMID: 34805229    Free PMC article.
Review.
From 3D printing to 3D bioprinting: the material properties of polymeric material and its derived bioink for achieving tissue specific architectures.
Nihal Engin Vrana, Sharda Gupta, +12 authors, Arindam Bit.
Cell Tissue Bank, 2022 Jan 10;. PMID: 35000046
Review.
Complete response to combination therapy using nivolumab and ipilimumab for metastatic, sarcomatoid collecting duct carcinoma presenting with high expression of programmed death-ligand 1: a case report.
Takayoshi Fuu, Kazuyoshi Iijima, +2 authors, Haruaki Kato.
J Med Case Rep, 2022 May 18; 16(1). PMID: 35581611    Free PMC article.