title: Role of T cell receptor affinity in the efficacy and specificity of adoptive T cell therapies.
abstract: Over the last several years, there has been considerable progress in the treatment of cancer using gene modified adoptive T cell therapies. Two approaches have been used, one involving the introduction of a conventional αβ T cell receptor (TCR) against a pepMHC cancer antigen, and the second involving introduction of a chimeric antigen receptor (CAR) consisting of a single-chain antibody as an Fv fragment linked to transmembrane and signaling domains. In this review, we focus on one aspect of TCR-mediated adoptive T cell therapies, the impact of the affinity of the αβ TCR for the pepMHC cancer antigen on both efficacy and specificity. We discuss the advantages of higher-affinity TCRs in mediating potent activity of CD4 T cells. This is balanced with the potential disadvantage of higher-affinity TCRs in mediating greater self-reactivity against a wider range of structurally similar antigenic peptides, especially in synergy with the CD8 co-receptor. Both TCR affinity and target selection will influence potential safety issues. We suggest pre-clinical strategies that might be used to examine each TCR for possible on-target and off-target side effects due to self-reactivities, and to adjust TCR affinities accordingly.
authors: Department of Biochemistry, University of Illinois , Urbana, IL , USA.
authors: Jennifer D
authors: JD
authors: Stone
authors: David M
authors: DM
authors: Kranz
keywords: T cell cross-reactivity; T cell sensitivity; TCR affinity; adoptive T cell therapy; tumor-associated epitopes
references: Nature. 1996 Dec 12;384(6609):577-81
references: 8955273
references: J Immunol. 2009 Dec 15;183(12):7639-43
references: 19923452
references: Proc Natl Acad Sci U S A. 2005 May 31;102(22):7934-9
references: 15908507
references: J Immunol. 2007 Dec 15;179(12):8243-51
references: 18056368
references: J Exp Med. 1995 Jun 1;181(6):2097-108
references: 7539039
references: Nat Med. 2004 Mar;10(3):294-8
references: 14981514
references: Cancer Res. 2005 Feb 15;65(4):1570-6
references: 15735047
references: Cancer Res. 2010 Nov 1;70(21):8368-77
references: 20940398
references: J Exp Med. 1996 Sep 1;184(3):1017-26
references: 9064319
references: Immunology. 2009 Feb;126(2):165-76
references: 19125887
references: Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4580-5
references: 22403068
references: Mol Immunol. 2012 Oct;52(3-4):155-64
references: 22683645
references: Immunity. 2000 Jun;12(6):677-86
references: 10894167
references: Immunity. 1998 May;8(5):553-62
references: 9620676
references: J Immunol. 2008 Sep 15;181(6):4363-70
references: 18768895
references: Nat Biotechnol. 2005 Mar;23(3):349-54
references: 15723046
references: Gene Ther. 2005 Jan;12(2):140-6
references: 15496961
references: Cell. 2007 Apr 6;129(1):135-46
references: 17418792
references: Blood. 2000 Aug 15;96(4):1480-9
references: 10942395
references: J Mol Recognit. 2010 Mar-Apr;23(2):142-52
references: 20151417
references: J Immunol. 2011 Jan 15;186(2):685-96
references: 21149604
references: Annu Rev Immunol. 2009;27:287-312
references: 19302042
references: Blood. 2000 Apr 1;95(7):2198-203
references: 10733485
references: Nat Med. 2012 Jun;18(6):980-7
references: 22561687
references: J Biol Chem. 2012 Jan 6;287(2):1168-77
references: 22102287
references: N Engl J Med. 2012 Jun 28;366(26):2455-65
references: 22658128
references: J Exp Med. 1994 Jul 1;180(1):347-52
references: 7516411
references: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5387-92
references: 10779548
references: J Exp Med. 2007 Oct 29;204(11):2553-9
references: 17938233
references: J Clin Oncol. 2011 Mar 1;29(7):917-24
references: 21282551
references: Nature. 2012 Feb 08;482(7385):400-4
references: 22318521
references: Immunity. 2003 Feb;18(2):255-64
references: 12594952
references: Nat Rev Immunol. 2005 Oct;5(10):772-82
references: 16200080
references: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13838-43
references: 9391114
references: N Engl J Med. 2010 Aug 19;363(8):711-23
references: 20525992
references: Nature. 2010 Feb 18;463(7283):963-7
references: 20164930
references: J Immunol. 2008 Nov 1;181(9):6255-64
references: 18941216
references: J Biol Chem. 2004 May 28;279(22):23438-46
references: 15004033
references: Biomol Eng. 2007 Oct;24(4):361-73
references: 17409021
references: Blood. 2013 Feb 14;121(7):1112-23
references: 23255554
references: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16846-51
references: 17077145
references: Annu Rev Immunol. 2001;19:1-21
references: 11244028
references: BMC Bioinformatics. 2005 May 31;6:132
references: 15927070
references: Protein Sci. 2003 May;12(5):1007-17
references: 12717023
references: Cancer Res. 2012 Oct 15;72(20):5209-18
references: 22915761
references: Immunity. 2002 Dec;17(6):737-47
references: 12479820
references: PLoS One. 2011;6(5):e20057
references: 21629697
references: Nat Rev Immunol. 2012 Mar 22;12(4):269-81
references: 22437939
references: Cancer Immun. 2005 Jun 06;5:8
references: 15934727
references: J Transl Med. 2012 Mar 15;10:48
references: 22420641
references: PLoS One. 2012;7(8):e41466
references: 22870225
references: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5201-6
references: 18362335
references: J Immunol. 2006 Nov 15;177(10):6911-9
references: 17082606
references: Cancer Immunol Immunother. 2013 Feb;62(2):359-69
references: 22926060
references: Blood. 2011 Jul 14;118(2):319-29
references: 21606483
references: Blood. 2007 Jun 15;109(12):5346-54
references: 17327412
references: J Biol Chem. 2007 Aug 17;282(33):23799-810
references: 17540778
references: N Engl J Med. 2012 Jun 28;366(26):2443-54
references: 22658127
references: J Immunol. 2000 Jul 15;165(2):948-55
references: 10878370
references: Gene Ther. 2013 Jun;20(6):634-44
references: 23052828
references: Nature. 2012 Feb 08;482(7385):405-9
references: 22318517
references: Blood. 2005 Nov 1;106(9):3062-7
references: 16020516
references: J Immunol. 2007 Nov 1;179(9):5845-54
references: 17947658
references: Eur J Immunol. 2012 Dec;42(12):3174-9
references: 22949370
references: Leukemia. 2003 Jul;17(7):1301-12
references: 12835718
references: Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6973-8
references: 23576742
references: Clin Cancer Res. 2009 Sep 1;15(17):5323-37
references: 19723653
references: Proc Natl Acad Sci U S A. 1984 Jan;81(2):573-7
references: 6607474
references: J Immunol. 2000 Jan 15;164(2):562-5
references: 10623795
references: J Leukoc Biol. 2013 Jul;94(1):41-53
references: 23667165
references: Nat Immunol. 2001 Mar;2(3):229-34
references: 11224522
references: J Immunol. 2008 Jul 15;181(2):1063-70
references: 18606658
references: Blood. 2011 Aug 11;118(6):1495-503
references: 21673345
references: J Immunol. 2007 Sep 1;179(5):2952-60
references: 17709510
references: Nat Rev Immunol. 2003 May;3(5):383-91
references: 12766760
references: J Exp Med. 1998 Jan 19;187(2):265-70
references: 9432985
references: Immunity. 2001 Jul;15(1):59-70
references: 11485738
references: Oncologist. 2012;17(2):250-9
references: 22291091
references: Blood. 2009 Jul 16;114(3):535-46
references: 19451549
references: Immunity. 1996 Jun;4(6):565-71
references: 8673703
references: Immunity. 1998 Dec;9(6):817-26
references: 9881972
references: J Exp Med. 2001 Oct 15;194(8):1043-52
references: 11602635
references: Immunity. 2010 Feb 26;32(2):163-74
references: 20137987
references: Nature. 2010 May 20;465(7296):350-4
references: 20445539
references: Nat Methods. 2011 Jun 26;8(8):659-61
references: 21706014
references: Annu Rev Immunol. 1999;17:51-88
references: 10358753
references: Immunology. 2012 Jan;135(1):9-18
references: 22044041
references: J Immunol. 2010 May 1;184(9):4936-46
references: 20351194
references: Protein Eng. 2003 Sep;16(9):707-11
references: 14560057
references: Proc Natl Acad Sci U S A. 1995 May 23;92(11):5042-6
references: 7761445
references: Immunity. 1999 Feb;10(2):219-25
references: 10072074
references: Immunology. 2012 Oct;137(2):139-48
references: 22804746
references: Nature. 2009 Nov 26;462(7272):510-3
references: 19898495
references: Science. 1998 Feb 20;279(5354):1166-72
references: 9469799
references: J Exp Med. 2010 Mar 15;207(3):651-67
references: 20156973
references: J Immunol. 2011 May 1;186(9):5193-200
references: 21451107
references: Hum Gene Ther Methods. 2012 Dec;23(6):376-86
references: 23186165
references: Viral Immunol. 2006 Summer;19(3):458-67
references: 16987064
references: Science. 1991 Dec 13;254(5038):1643-7
references: 1840703
references: Methods Enzymol. 2012;503:189-222
references: 22230570
references: Mol Ther. 2012 Mar;20(3):652-60
references: 22233579
references: Immunol Rev. 2011 May;241(1):164-79
references: 21488897
references: Trends Immunol. 2002 Aug;23(8):408-13
references: 12133804
references: Immunogenetics. 1999 Nov;50(3-4):213-9
references: 10602881
references: Immunogenetics. 2000 Feb;51(2):99-107
references: 10663572
references: Cancer Immunol Immunother. 2013 Apr;62(4):773-85
references: 23263452
references: Immunity. 2002 Aug;17(2):131-42
references: 12196285
references: J Immunol. 2009 Jul 15;183(2):1166-78
references: 19553539
references: Sci Transl Med. 2013 Feb 27;5(174):174ra27
references: 23447018
references: Microbes Infect. 2003 Mar;5(3):233-40
references: 12681413
references: Mol Immunol. 2008 May;45(9):2700-9
references: 18243322
references: Clin Cancer Res. 2008 May 15;14(10):3044-51
references: 18483370
references: J Exp Med. 2001 Dec 3;194(11):1549-59
references: 11733570
references: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16916-21
references: 20837541
references: J Immunol. 2011 Sep 1;187(5):2824-33
references: 21821799
references: Proteins. 2009 Mar;74(4):948-60
references: 18767161
references: Blood. 2007 Jun 1;109(11):4865-76
references: 17284532
references: Hum Gene Ther. 2005 Apr;16(4):457-72
references: 15871677
references: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19033-8
references: 16365315
references: Nature. 2010 Apr 8;464(7290):932-6
references: 20357766
references: Transplantation. 2003 May 15;75(9):1429-36
references: 12792492
references: J Exp Med. 2010 Mar 15;207(3):637-50
references: 20156971
references: Blood. 2013 Jul 18;122(3):348-56
references: 23673862
references: J Immunol. 2005 May 1;174(9):5593-601
references: 15843558
references: Cancer Cell. 2013 Apr 15;23(4):516-26
references: 23597565
references: Mol Immunol. 2013 Mar;53(3):283-94
references: 22982754
references: Leukemia. 2006 Nov;20(11):2025-33
references: 16990779
references: Nat Immunol. 2004 May;5(5):524-30
references: 15048111
references: Immunity. 1994 Apr;1(1):15-22
references: 7889394
references: J Exp Med. 1994 Mar 1;179(3):921-30
references: 8113684
references: Annu Rev Immunol. 2008;26:171-203
references: 18304006
references: J Immunol. 2006 Nov 1;177(9):6548-59
references: 17056587
references: Nat Rev Cancer. 2012 Mar 22;12(4):252-64
references: 22437870
references: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):623-8
references: 18182487
references: Mol Immunol. 2009 Sep;46(15):3000-8
references: 19595460
references: Clin Cancer Res. 2001 Mar;7(3 Suppl):766s-772s
references: 11300471
references: Leuk Lymphoma. 2009 Feb;50(2):260-9
references: 19197722
references: Genome Res. 2004 Oct;14(10B):2128-35
references: 15489335
references: J Immunother. 2013 Feb;36(2):133-51
references: 23377668
references: Science. 2006 Oct 6;314(5796):126-9
references: 16946036
references: J Immunother. 2001 Jan-Feb;24(1):1-9
references: 11211143
references: Mol Immunol. 2010 Sep;47(15):2519-24
references: 20619457
references: J Immunol. 2006 Jul 15;177(2):976-82
references: 16818753
references: Blood. 2013 Aug 8;122(6):863-71
references: 23770775
references: Nature. 2005 Oct 20;437(7062):1173-8
references: 16189514
references: Nature. 1988 Nov 3;336(6194):73-6
references: 3263574
references: Immunity. 2000 Mar;12(3):251-61
references: 10755612
references: Adv Cancer Res. 2006;95:1-30
references: 16860654
references: Eur J Immunol. 2009 Mar;39(3):717-22
references: 19224639
references: Blood. 2005 Jul 15;106(2):470-6
references: 15790789
references: Protein Sci. 2006 Apr;15(4):710-21
references: 16600963
references: J Biol Chem. 2009 Nov 20;284(47):32551-61
references: 19755422
references: Nat Med. 2012 May;18(5):807-815
references: 22466705
references: J Immunol. 2008 May 1;180(9):6116-31
references: 18424733
references: Gene. 2001 Aug 8;273(2):141-61
references: 11595161
references: Clin Immunol. 2010 Sep;136(3):338-47
references: 20547105
references: Nat Immunol. 2003 Jan;4(1):55-62
references: 12469116
references: Science. 1996 Oct 11;274(5285):209-19
references: 8824178
references: J Immunother. 2004 Nov-Dec;27(6):472-7
references: 15534491
references: Haematologica. 2010 Jan;95(1):126-34
references: 19679884
references: Nature. 1995 May 11;375(6527):148-51
references: 7753171
references: Blood. 2000 Jan 1;95(1):286-93
references: 10607714
references: J Exp Med. 2005 Apr 18;201(8):1243-55
references: 15837811
references: Cancer Sci. 2009 Nov;100(11):2014-21
references: 19719775
references: J Immunol. 2011 Sep 1;187(5):2453-63
references: 21795600
references: N Engl J Med. 2013 Jul 11;369(2):134-44
references: 23724846
references: Science. 1991 May 31;252(5010):1308-10
references: 1833816
references: Immunity. 2005 Jan;22(1):117-29
references: 15664164
references: J Exp Med. 1995 Jan 1;181(1):363-8
references: 7807017
references: Curr Opin Pharmacol. 2005 Aug;5(4):438-43
references: 15939669
references: J Immunol. 1998 Jan 15;160(2):802-9
references: 9551915
references: N Engl J Med. 2008 Jun 19;358(25):2698-703
references: 18565862
references: Cancer Cell. 2011 Jan 18;19(1):72-85
references: 21251614