title: CTLA-4 blockade in tumor models: an overview of preclinical and translational research.
abstract: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T cell activation. A complex integration of positive and negative co-stimulatory signals in the well-defined B7:CD28/CTLA-4 pathway modulates the generation and maintenance of immune responses. Inhibiting negative regulation through binding of CTLA-4 has been shown to promote stimulation of adaptive immunity and potentiation of T cell activation. CTLA-4-blocking antibodies have demonstrated efficacy in various murine malignancy models when administered as monotherapy; additionally, they have shown synergistic anti-tumor activity when utilized with other agents, such as vaccines, chemotherapy, and radiation. Preclinical studies have supported the rationale for current clinical development of anti-CTLA-4 antibodies, including ipilimumab and tremelimumab, as novel therapeutic strategies to augment anti-tumor immunity in cancer. Both ipilimumab and tremelimumab have been evaluated extensively in melanoma; notably, ipilimumab was recently approved as monotherapy for the treatment of advanced melanoma. Tremelimumab is currently undergoing evaluation in phase II trials as monotherapy in melanoma and malignant mesothelioma, while ipilimumab is under clinical investigation in phase II and III trials in various tumor types, including in melanoma, prostate, and lung cancers as monotherapy and with other therapeutic modalities, such as chemotherapy and radiation. In this review, we will provide a detailed overview of preclinical advances that have delineated many features of CTLA-4 and have helped define its role in T cell response. We will also highlight clinical application of anti-CTLA-4 therapy in cancer and describe knowledge gaps that future studies may address.
authors: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. joseph.grosso@bms.com
authors: Joseph F
authors: JF
authors: Grosso
authors: Maria N
authors: MN
authors: Jure-Kunkel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D057170:Translational Research, Biomedical
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen
keywords: CTLA-4; T cell; antibody; co-stimulation; preclinical
references: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19875-80
references: 19066215
references: Clin Cancer Res. 2009 Sep 1;15(17):5379-88
references: 19706802
references: N Engl J Med. 2011 Jun 30;364(26):2517-26
references: 21639810
references: J Exp Med. 1991 Sep 1;174(3):561-9
references: 1714933
references: J Immunol. 2003 Mar 15;170(6):3401-7
references: 12626601
references: Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8099-103
references: 9223321
references: Science. 2011 Mar 25;331(6024):1565-70
references: 21436444
references: Clin Cancer Res. 2011 Jul 15;17(14):4622-8
references: 21467163
references: Nat Immunol. 2009 Jan;10(1):29-37
references: 19043418
references: Nat Rev Immunol. 2011 Nov 25;11(12):852-63
references: 22116087
references: Cancer Immunol Immunother. 2001 May;50(3):125-33
references: 11419179
references: Cancer Res. 2000 May 1;60(9):2444-8
references: 10811122
references: Cancer Lett. 2006 Apr 28;235(2):229-38
references: 15927356
references: Blood. 2005 Nov 1;106(9):3127-33
references: 16037385
references: Immunity. 1995 Nov;3(5):541-7
references: 7584144
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: Scand J Immunol. 2010 Feb;71(2):70-82
references: 20384858
references: J Exp Med. 1999 Jan 18;189(2):435-40
references: 9892625
references: Nat Immunol. 2002 Nov;3(11):1097-101
references: 12368911
references: N Engl J Med. 2010 Aug 19;363(8):711-23
references: 20525992
references: J Exp Med. 1999 Aug 2;190(3):355-66
references: 10430624
references: J Clin Oncol. 2005 Dec 10;23(35):8968-77
references: 16204013
references: J Immunol. 2011 May 15;186(10):5580-9
references: 21478403
references: Immunol Rev. 2006 Aug;212:8-27
references: 16903903
references: Nature. 2001 Apr 26;410(6832):1107-11
references: 11323675
references: Clin Cancer Res. 2009 Jan 15;15(2):597-606
references: 19147765
references: Immunity. 1997 Dec;7(6):885-95
references: 9430233
references: Cytometry A. 2006 Dec 1;69(12):1162-73
references: 17089357
references: Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):728-34
references: 15701862
references: J Exp Med. 1995 Aug 1;182(2):289-92
references: 7543133
references: Immunity. 2001 Feb;14(2):145-55
references: 11239447
references: Leukemia. 2007 Jul;21(7):1451-9
references: 17508005
references: Nat Med. 2009 Oct;15(10):1170-8
references: 19767732
references: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4275-80
references: 20160101
references: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8603-8
references: 10411922
references: Immunity. 1994 Aug;1(5):405-13
references: 7882171
references: Oncologist. 2008;13 Suppl 4:16-25
references: 19001147
references: J Immunother. 2010 Apr;33(3):225-35
references: 20445343
references: Cancer Res. 2004 Aug 1;64(15):5407-14
references: 15289349
references: J Exp Med. 2001 Sep 17;194(6):823-32
references: 11560997
references: Int J Cancer. 2007 Jul 1;121(1):95-105
references: 17315190
references: Nat Immunol. 2007 May;8(5):457-62
references: 17440451
references: J Immunol. 2010 May 15;184(10):5493-501
references: 20400706
references: Science. 1995 Nov 10;270(5238):985-8
references: 7481803
references: Immunity. 2000 Sep;13(3):313-22
references: 11021529
references: Nat Rev Immunol. 2009 May;9(5):353-63
references: 19365408
references: Eur J Immunol. 1998 Oct;28(10):3137-43
references: 9808182
references: Science. 2008 Oct 10;322(5899):271-5
references: 18845758
references: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15074-9
references: 10611340
references: Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):266-71
references: 21173239
references: Clin Cancer Res. 2007 Apr 1;13(7):2158-67
references: 17404100
references: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10067-71
references: 9707601
references: Science. 2006 Sep 29;313(5795):1972-5
references: 16931720
references: Nat Rev Cancer. 2004 Apr;4(4):314-22
references: 15057291
references: J Immunol. 2000 May 15;164(10):5015-8
references: 10799854
references: Cancer Res. 2006 Jul 15;66(14):7276-84
references: 16849577
references: Cancer Res. 1998 Dec 1;58(23):5301-4
references: 9850053
references: J Immunol. 1996 Dec 1;157(11):4762-70
references: 8943377
references: Cancer Res. 2003 Jun 15;63(12):3281-8
references: 12810660
references: Immunity. 2002 Aug;17(2):201-10
references: 12196291
references: Nat Med. 2006 May;12(5):574-9
references: 16604087
references: Immunol Rev. 2009 May;229(1):67-87
references: 19426215
references: Eur J Immunol. 2002 Feb;32(2):366-73
references: 11807776
references: Nat Rev Immunol. 2003 Dec;3(12):939-51
references: 14647476
references: Cancer Res. 1997 Sep 15;57(18):4036-41
references: 9307290
references: Nat Immunol. 2004 Nov;5(11):1134-42
references: 15467723
references: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12861-6
references: 16126897
references: Nat Med. 2007 Sep;13(9):1050-9
references: 17704786
references: Clin Cancer Res. 2009 Dec 1;15(23):7412-20
references: 19934295
references: Cancer Lett. 2006 Jan 18;231(2):247-56
references: 16399226
references: Vaccine. 2010 Sep 24;28(41):6757-64
references: 20682365
references: Immunity. 2004 May;20(5):563-75
references: 15142525
references: Nat Immunol. 2002 Jul;3(7):611-8
references: 12087419
references: Mol Cell Biol. 2005 Nov;25(21):9543-53
references: 16227604
references: Cancer Immunol Immunother. 2012 Jul;61(7):1019-31
references: 22146893
references: Semin Oncol. 2010 Oct;37(5):473-84
references: 21074063
references: Oncologist. 2008;13 Suppl 4:10-5
references: 19001146
references: J Exp Med. 1998 Nov 16;188(10):1849-57
references: 9815262
references: Cancer Res. 2012 Jan 15;72(2):430-9
references: 22108823
references: J Immunol. 2005 Jul 1;175(1):177-81
references: 15972645
references: Onco Targets Ther. 2010 Jun 24;3:15-25
references: 20616954
references: J Exp Med. 1999 May 3;189(9):1363-72
references: 10224276
references: Immunity. 2010 Sep 24;33(3):326-39
references: 20870175
references: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16723-8
references: 21933959
references: J Immunol. 2009 Jun 1;182(11):6659-69
references: 19454660
references: Cancer J. 2010 Jul-Aug;16(4):311-7
references: 20693841
references: Int Immunol. 2004 Oct;16(10):1391-401
references: 15351783
references: J Exp Med. 2009 Aug 3;206(8):1717-25
references: 19581407
references: J Exp Med. 1997 Feb 3;185(3):393-403
references: 9053440
references: J Transl Med. 2008 May 01;6:22
references: 18452610
references: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14987-92
references: 18818309
references: Immunity. 1999 Oct;11(4):483-93
references: 10549630
references: J Immunol. 2000 May 15;164(10):5319-27
references: 10799894
references: Science. 2011 Apr 29;332(6029):600-3
references: 21474713
references: Immunity. 1997 Apr;6(4):411-7
references: 9133420
references: Nat Immunol. 2003 Dec;4(12):1206-12
references: 14578884
references: J Transl Med. 2011 Nov 28;9:204
references: 22123319
references: Science. 1996 May 24;272(5265):1170-3
references: 8638161
references: Immunity. 1997 Oct;7(4):445-50
references: 9354465
references: J Clin Invest. 2011 Jul;121(7):2750-67
references: 21633166
references: Science. 1996 Mar 22;271(5256):1734-6
references: 8596936
references: J Immunol. 2009 Oct 15;183(8):5146-57
references: 19783679