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

¹ Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
² Cancer Research UK Beatson Institute, Glasgow, UK.

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.

Other Links

Free PMC article
Full text on Clinical and experimental immunology

References
Cited By

References
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. E A Tivol, F Borriello, +3 authors, A H Sharpe. less Immunity, 1995 Nov 01; 3(5). PMID: 7584144 Highly Cited.
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. Dung T Le, Jennifer N Uram, +32 authors, Luis A Diaz. less N Engl J Med, 2015 Jun 02; 372(26). PMID: 26028255 Free PMC article. Highly Cited.
PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Y Latchman, C R Wood, +18 authors, G J Freeman. less Nat Immunol, 2001 Feb 27; 2(3). PMID: 11224527 Highly Cited.
Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. H Nishimura, T Okazaki, +8 authors, T Honjo. less Science, 2001 Feb 24; 291(5502). PMID: 11209085 Highly Cited.
Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Jackson G Egen, James P Allison. Immunity, 2002 Feb 05; 16(1). PMID: 11825563 Highly Cited.
Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. Weijie Ma, Barbara M Gilligan, Jianda Yuan, Tianhong Li. J Hematol Oncol, 2016 May 29; 9(1). PMID: 27234522 Free PMC article. Highly Cited. Review.
Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Scott J Antonia, Augusto Villegas, +28 authors, PACIFIC Investigators. less N Engl J Med, 2017 Sep 09; 377(20). PMID: 28885881 Highly Cited.
Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Scott J Antonia, José A López-Martin, +21 authors, Emiliano Calvo. less Lancet Oncol, 2016 Jun 09; 17(7). PMID: 27269741 Highly Cited.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). E A Eisenhauer, P Therasse, +13 authors, J Verweij. less Eur J Cancer, 2008 Dec 23; 45(2). PMID: 19097774 Highly Cited.
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. Robert L Ferris, George Blumenschein, +20 authors, Maura L Gillison. less N Engl J Med, 2016 Oct 11; 375(19). PMID: 27718784 Free PMC article. Highly Cited.
Genetic basis for clinical response to CTLA-4 blockade in melanoma. Alexandra Snyder, Vladimir Makarov, +18 authors, Timothy A Chan. less N Engl J Med, 2014 Nov 20; 371(23). PMID: 25409260 Free PMC article. Highly Cited.
CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Colin W Steele, Saadia A Karim, +23 authors, Jennifer P Morton. less Cancer Cell, 2016 Jun 07; 29(6). PMID: 27265504 Free PMC article. Highly Cited.
Restoring function in exhausted CD8 T cells during chronic viral infection. Daniel L Barber, E John Wherry, +5 authors, Rafi Ahmed. less Nature, 2005 Dec 31; 439(7077). PMID: 16382236 Highly Cited.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. Robert J Motzer, Bernard Escudier, +25 authors, CheckMate 025 Investigators. less N Engl J Med, 2015 Sep 26; 373(19). PMID: 26406148 Free PMC article. Highly Cited.
Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Matthew D Hellmann, Naiyer A Rizvi, +14 authors, Scott J Antonia. less Lancet Oncol, 2016 Dec 10; 18(1). PMID: 27932067 Free PMC article. Highly Cited.
Immune escape of tumors: apoptosis resistance and tumor counterattack. Frederik H Igney, Peter H Krammer. J Leukoc Biol, 2002 Jun 07; 71(6). PMID: 12050175 Highly Cited. Review.
The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Lucy S K Walker, David M Sansom. Nat Rev Immunol, 2011 Nov 26; 11(12). PMID: 22116087 Highly Cited.
Role of radiation therapy as immune activator in the era of modern immunotherapy for metastatic malignant melanoma. Derick Okwan-Duodu, Brian P Pollack, David Lawson, Mohammad K Khan. Am J Clin Oncol, 2013 May 08; 38(1). PMID: 23648438 Review.
Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. A A Hurwitz, B A Foster, +5 authors, J P Allison. less Cancer Res, 2000 May 16; 60(9). PMID: 10811122 Highly Cited.
Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Kei Muro, Hyun Cheol Chung, +15 authors, Yung-Jue Bang. less Lancet Oncol, 2016 May 10; 17(6). PMID: 27157491 Highly Cited.
Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy. Anna Śledzińska, Laurie Menger, +2 authors, Katharina Bergerhoff, Karl S Peggs, Sergio A Quezada. less Mol Oncol, 2015 Nov 19; 9(10). PMID: 26578451 Free PMC article. Review.
PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. R Houston Thompson, Haidong Dong, +4 authors, Eugene D Kwon. less Clin Cancer Res, 2007 Mar 17; 13(6). PMID: 17363529 Highly Cited.
Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. Thomas J Lynch, Igor Bondarenko, +8 authors, Martin Reck. less J Clin Oncol, 2012 May 02; 30(17). PMID: 22547592 Highly Cited.
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Jonathan E Rosenberg, Jean Hoffman-Censits, +28 authors, Robert Dreicer. less Lancet, 2016 Mar 10; 387(10031). PMID: 26952546 Free PMC article. Highly Cited.
PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Christian Blank, Ian Brown, +4 authors, Thomas F Gajewski. less Cancer Res, 2004 Feb 12; 64(3). PMID: 14871849 Highly Cited.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Roy S Herbst, Paul Baas, +16 authors, Edward B Garon. less Lancet, 2015 Dec 30; 387(10027). PMID: 26712084 Highly Cited.
PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Feng Shi, Ming Shi, +6 authors, Fu-Sheng Wang. less Int J Cancer, 2010 May 18; 128(4). PMID: 20473887 Highly Cited.
Improved survival with ipilimumab in patients with metastatic melanoma. F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba. less N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992 Free PMC article. Highly Cited.
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman. less Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248 Highly Cited.
Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Yan Zhang, Shengdong Huang, +2 authors, Dejun Gong, Yanghua Qin, Qian Shen. less Cell Mol Immunol, 2010 Jun 02; 7(5). PMID: 20514052 Free PMC article. Highly Cited.
Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Y Agata, A Kawasaki, +4 authors, T Honjo. less Int Immunol, 1996 May 01; 8(5). PMID: 8671665 Highly Cited.
PD-1 and its ligands in tolerance and immunity. Mary E Keir, Manish J Butte, Gordon J Freeman, Arlene H Sharpe. Annu Rev Immunol, 2008 Jan 05; 26. PMID: 18173375 Highly Cited. Review.
Expression of programmed death 1 ligands by murine T cells and APC. Tomohide Yamazaki, Hisaya Akiba, +9 authors, Hideo Yagita. less J Immunol, 2002 Nov 08; 169(10). PMID: 12421930 Highly Cited.
Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Desirée Schubert, Claudia Bode, +37 authors, Bodo Grimbacher. less Nat Med, 2014 Oct 21; 20(12). PMID: 25329329 Free PMC article. Highly Cited.
Molecular mechanisms of T cell co-stimulation and co-inhibition. Lieping Chen, Dallas B Flies. Nat Rev Immunol, 2013 Mar 09; 13(4). PMID: 23470321 Free PMC article. Highly Cited. Review.
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. Jeffrey S Weber, Sandra P D'Angelo, +25 authors, James Larkin. less Lancet Oncol, 2015 Mar 22; 16(4). PMID: 25795410 Highly Cited.
Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Sebastian Zeissig, Britt-Sabina Petersen, +11 authors, Richard S Blumberg. less Gut, 2014 Nov 05; 64(12). PMID: 25367873 Free PMC article.
Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Yoshiko Iwai, Masayoshi Ishida, +3 authors, Nagahiro Minato. less Proc Natl Acad Sci U S A, 2002 Sep 10; 99(19). PMID: 12218188 Free PMC article. Highly Cited.
Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. Dirk Schadendorf, F Stephen Hodi, +7 authors, Jedd D Wolchok. less J Clin Oncol, 2015 Feb 11; 33(17). PMID: 25667295 Free PMC article. Highly Cited.
Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Mojgan Ahmadzadeh, Laura A Johnson, +4 authors, Steven A Rosenberg. less Blood, 2009 May 09; 114(8). PMID: 19423728 Free PMC article. Highly Cited.
T-regulatory cells: key players in tumor immune escape and angiogenesis. Andrea Facciabene, Gregory T Motz, George Coukos. Cancer Res, 2012 May 03; 72(9). PMID: 22549946 Free PMC article. Highly Cited. Review.
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Caroline Robert, Antoni Ribas, +22 authors, Adil Daud. less Lancet, 2014 Jul 19; 384(9948). PMID: 25034862 Highly Cited.
Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. R Houston Thompson, Michael D Gillett, +12 authors, Eugene D Kwon. less Proc Natl Acad Sci U S A, 2004 Dec 01; 101(49). PMID: 15569934 Free PMC article. Highly Cited.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol. less N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127 Free PMC article. Highly Cited.
Viral immune evasion due to persistence of activated T cells without effector function. A J Zajac, J N Blattman, +4 authors, R Ahmed. less J Exp Med, 1998 Dec 22; 188(12). PMID: 9858507 Free PMC article. Highly Cited.
Nivolumab in previously untreated melanoma without BRAF mutation. Caroline Robert, Georgina V Long, +25 authors, Paolo A Ascierto. less N Engl J Med, 2014 Nov 18; 372(4). PMID: 25399552 Highly Cited.
CTLA-4 can function as a negative regulator of T cell activation. T L Walunas, D J Lenschow, +5 authors, J A Bluestone. less Immunity, 1994 Aug 01; 1(5). PMID: 7882171 Highly Cited.
Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. Jonathan D Schoenfeld, Anand Mahadevan, +5 authors, Irving D Kaplan. less J Immunother Cancer, 2015 Dec 18; 3. PMID: 26672895 Free PMC article.
Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Y Ishida, Y Agata, K Shibahara, T Honjo. EMBO J, 1992 Nov 01; 11(11). PMID: 1396582 Free PMC article. Highly Cited.
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. G J Freeman, A J Long, +16 authors, T Honjo. less J Exp Med, 2000 Oct 04; 192(7). PMID: 11015443 Free PMC article. Highly Cited.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon. less J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982 Free PMC article. Highly Cited.
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Willy Hugo, Jesse M Zaretsky, +15 authors, Roger S Lo. less Cell, 2016 Mar 22; 165(1). PMID: 26997480 Free PMC article. Highly Cited.
CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. F A Harding, J G McArthur, +2 authors, J A Gross, D H Raulet, J P Allison. less Nature, 1992 Apr 16; 356(6370). PMID: 1313950 Highly Cited.
A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Jeffrey Weber, John A Thompson, +9 authors, Steven J O'Day. less Clin Cancer Res, 2009 Aug 13; 15(17). PMID: 19671877 Highly Cited.
Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. Suzanne L Topalian, Mario Sznol, +18 authors, F Stephen Hodi. less J Clin Oncol, 2014 Mar 05; 32(10). PMID: 24590637 Free PMC article. Highly Cited.
Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. H Nishimura, M Nose, +2 authors, H Hiai, N Minato, T Honjo. less Immunity, 1999 Sep 15; 11(2). PMID: 10485649 Highly Cited.
Suppression, subversion and escape: the role of regulatory T cells in cancer progression. K Oleinika, R J Nibbs, G J Graham, A R Fraser. Clin Exp Immunol, 2012 Dec 04; 171(1). PMID: 23199321 Free PMC article. Review.
Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. Caroline Bouzin, Agnès Brouet, +2 authors, Joelle De Vriese, Julie Dewever, Olivier Feron. less J Immunol, 2007 Jan 24; 178(3). PMID: 17237399
Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Padmanee Sharma, Margaret K Callahan, +15 authors, Jonathan E Rosenberg. less Lancet Oncol, 2016 Oct 14; 17(11). PMID: 27733243 Free PMC article. Highly Cited.
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. Martin Reck, Delvys Rodríguez-Abreu, +16 authors, KEYNOTE-024 Investigators. less N Engl J Med, 2016 Oct 11; 375(19). PMID: 27718847 Highly Cited.
Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Howard L Kaufman, Jeffery Russell, +15 authors, Paul Nghiem. less Lancet Oncol, 2016 Sep 07; 17(10). PMID: 27592805 Free PMC article. Highly Cited.
Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. S J O'Day, M Maio, +13 authors, J D Wolchok. less Ann Oncol, 2010 Feb 12; 21(8). PMID: 20147741 Highly Cited.
Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions. J L Greene, G M Leytze, +4 authors, P S Linsley. less J Biol Chem, 1996 Oct 25; 271(43). PMID: 8900156
Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. P Waterhouse, J M Penninger, +6 authors, T W Mak. less Science, 1995 Nov 10; 270(5238). PMID: 7481803 Highly Cited.
Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. F Stephen Hodi, Jason Chesney, +18 authors, Michael A Postow. less Lancet Oncol, 2016 Sep 14; 17(11). PMID: 27622997 Free PMC article. Highly Cited.
Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Tyler J Curiel, Shuang Wei, +19 authors, Weiping Zou. less Nat Med, 2003 Apr 22; 9(5). PMID: 12704383 Highly Cited.
T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Enfu Hui, Jeanne Cheung, +8 authors, Ronald D Vale. less Science, 2017 Mar 11; 355(6332). PMID: 28280247 Free PMC article. Highly Cited.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Achim Rittmeyer, Fabrice Barlesi, +23 authors, OAK Study Group. less Lancet, 2016 Dec 17; 389(10066). PMID: 27979383 Free PMC article. Highly Cited.
Inhibitory B7-family molecules in the tumour microenvironment. Weiping Zou, Lieping Chen. Nat Rev Immunol, 2008 May 27; 8(6). PMID: 18500231 Highly Cited. Review.
Pembrolizumab for the treatment of non-small-cell lung cancer. Edward B Garon, Naiyer A Rizvi, +25 authors, KEYNOTE-001 Investigators. less N Engl J Med, 2015 Apr 22; 372(21). PMID: 25891174 Highly Cited.
Reversal of the TCR stop signal by CTLA-4. Helga Schneider, Jos Downey, +7 authors, Christopher E Rudd. less Science, 2006 Aug 26; 313(5795). PMID: 16931720 Highly Cited.
Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Michael J Eppihimer, Jason Gunn, +4 authors, John P Leonard. less Microcirculation, 2002 Apr 05; 9(2). PMID: 11932780 Free PMC article. Highly Cited.
The immunobiology of cancer immunosurveillance and immunoediting. Gavin P Dunn, Lloyd J Old, Robert D Schreiber. Immunity, 2004 Aug 17; 21(2). PMID: 15308095 Highly Cited. Review.
OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy. Yannick Bulliard, Rose Jolicoeur, +3 authors, Jennifer L Brogdon. less Immunol Cell Biol, 2014 Apr 16; 92(6). PMID: 24732076 Highly Cited.
Immune escape as a fundamental trait of cancer: focus on IDO. G C Prendergast. Oncogene, 2008 Mar 05; 27(28). PMID: 18317452 Highly Cited. Review.
Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. Hossein Borghaei, Luis Paz-Ares, +25 authors, Julie R Brahmer. less N Engl J Med, 2015 Sep 29; 373(17). PMID: 26412456 Free PMC article. Highly Cited.
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. Michael A Postow, Jason Chesney, +18 authors, F Stephen Hodi. less N Engl J Med, 2015 Apr 22; 372(21). PMID: 25891304 Free PMC article. Highly Cited.
PD-1 as a potential target in cancer therapy. David F McDermott, Michael B Atkins. Cancer Med, 2014 Jan 10; 2(5). PMID: 24403232 Free PMC article. Highly Cited. Review.
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Scott Antonia, Sarah B Goldberg, +8 authors, Naiyer A Rizvi. less Lancet Oncol, 2016 Feb 10; 17(3). PMID: 26858122 Free PMC article. Highly Cited.
Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Manish J Butte, Mary E Keir, +2 authors, Theresa B Phamduy, Arlene H Sharpe, Gordon J Freeman. less Immunity, 2007 Jul 17; 27(1). PMID: 17629517 Free PMC article. Highly Cited.
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Frederick Arce Vargas, Andrew J S Furness, +29 authors, Sergio A Quezada. less Immunity, 2017 Apr 16; 46(4). PMID: 28410988 Free PMC article. Highly Cited.
Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. Dong-Ming Kuang, Qiyi Zhao, +4 authors, Limin Zheng. less J Exp Med, 2009 May 20; 206(6). PMID: 19451266 Free PMC article. Highly Cited.
CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. M F Krummel, J P Allison. J Exp Med, 1995 Aug 01; 182(2). PMID: 7543139 Free PMC article. Highly Cited.
Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. Robert J Motzer, Brian I Rini, +12 authors, Hans J Hammers. less J Clin Oncol, 2014 Dec 03; 33(13). PMID: 25452452 Free PMC article. Highly Cited.
Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Hye Sun Kuehn, Weiming Ouyang, +33 authors, Gulbu Uzel. less Science, 2014 Sep 13; 345(6204). PMID: 25213377 Free PMC article. Highly Cited.
Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. Ramaswamy Govindan, Aleksandra Szczesna, +19 authors, Martin Reck. less J Clin Oncol, 2017 Aug 31; 35(30). PMID: 28854067 Highly Cited.
CD28-mediated co-stimulation: a quantitative support for TCR signalling. Oreste Acuto, Frédérique Michel. Nat Rev Immunol, 2003 Dec 04; 3(12). PMID: 14647476 Highly Cited. Review.
Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Franz O Smith, Stephanie G Downey, +10 authors, Steven A Rosenberg. less Clin Cancer Res, 2008 Sep 04; 14(17). PMID: 18765555 Free PMC article.
Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Dongjun Peng, Ilona Kryczek, +15 authors, Weiping Zou. less Nature, 2015 Oct 28; 527(7577). PMID: 26503055 Free PMC article. Highly Cited.
Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. Laura Q M Chow, Robert Haddad, +19 authors, Tanguy Y Seiwert. less J Clin Oncol, 2016 Sep 21; 34(32). PMID: 27646946 Free PMC article. Highly Cited.
Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Jedd D Wolchok, Axel Hoos, +9 authors, F Stephen Hodi. less Clin Cancer Res, 2009 Nov 26; 15(23). PMID: 19934295 Highly Cited.
PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. Paul T Nghiem, Shailender Bhatia, +28 authors, Martin A Cheever. less N Engl J Med, 2016 Apr 20; 374(26). PMID: 27093365 Free PMC article. Highly Cited.
Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. A Gallimore, A Glithero, +5 authors, R Zinkernagel. less J Exp Med, 1998 Jun 06; 187(9). PMID: 9565631 Free PMC article. Highly Cited.
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Jedd D Wolchok, Bart Neyns, +14 authors, Celeste Lebbé. less Lancet Oncol, 2009 Dec 17; 11(2). PMID: 20004617 Highly Cited.
Immunologic correlates of the abscopal effect in a patient with melanoma. Michael A Postow, Margaret K Callahan, +18 authors, Jedd D Wolchok. less N Engl J Med, 2012 Mar 09; 366(10). PMID: 22397654 Free PMC article. Highly Cited.
Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. M Reck, I Bondarenko, +7 authors, T J Lynch. less Ann Oncol, 2012 Aug 04; 24(1). PMID: 22858559 Highly Cited.
New Strategies in Stereotactic Radiotherapy for Oligometastases. David A Palma, Alexander V Louie, George B Rodrigues. Clin Cancer Res, 2015 Dec 03; 21(23). PMID: 26626571 Review.
Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Haidong Dong, Scott E Strome, +10 authors, Lieping Chen. less Nat Med, 2002 Jul 02; 8(8). PMID: 12091876 Highly Cited.
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Jedd D Wolchok, Vanna Chiarion-Sileni, +30 authors, James Larkin. less N Engl J Med, 2017 Sep 12; 377(14). PMID: 28889792 Free PMC article. Highly Cited.
The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells. A J McAdam, A N Schweitzer, A H Sharpe. Immunol Rev, 1998 Dec 16; 165. PMID: 9850864 Review.
Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Ronald J Buckanovich, Andrea Facciabene, +7 authors, George Coukos. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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, Cynthia A Chambers, Alan J Korman, James P Allison. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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.

Citedby
Gut microbiome modulates efficacy of immune checkpoint inhibitors. Ming Yi, Shengnan Yu, +5 authors, Kongming Wu. less 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. less 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, V Sahai, T Baetz, J M Lakoff. less 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. less 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, Shuang Qin, Qian Chu, Suxia Luo, Kongming Wu. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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. less 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, Yukiko Kusama, Toshiaki Otsuki, Haruaki Kato. less J Med Case Rep, 2022 May 18; 16(1). PMID: 35581611 Free PMC article.

BioKDE: Biomedical Knowledge Discovery Engine

Abstract

Other Links