title: Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology.
abstract: Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Synthetic-biology-based engineering of T lymphocytes to express high-affinity antigen receptors can overcome immune tolerance, which has been a major limitation of immunotherapy-based strategies. Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cell expansion have facilitated broader evaluation of this technology, moving adoptive transfer from a "boutique" application to the cusp of a mainstream technology. The major challenge currently facing the field is to increase the specificity of engineered T cells for tumors, because targeting shared antigens has the potential to lead to on-target off-tumor toxicities, as observed in recent trials. As the field of adoptive transfer technology matures, the major engineering challenge is the development of automated cell culture systems, so that the approach can extend beyond specialized academic centers and become widely available.
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5156, USA. michael.kalos@uphs.upenn.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D018929:Cell Culture Techniques / Q000379:methods / Q000639:trends; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods* / Q000639:trends; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D058615:Synthetic Biology / Q000379:methods / Q000639:trends; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D011948:Receptors, Antigen, T-Cell
references.citation: Cancer Gene Ther. 2009 Jun;16(6):489-97
references.pmid: 19096447
references.citation: Blood. 2011 Nov 3;118(18):4817-28
references.pmid: 21849486
references.citation: Clin Cancer Res. 2005 Jan 1;11(1):67-72
references.pmid: 15671529
references.citation: Sci Transl Med. 2012 Aug 29;4(149):149fs31
references.pmid: 22932219
references.citation: Mol Ther. 2007 Apr;15(4):825-33
references.pmid: 17299405
references.citation: J Clin Invest. 2011 Oct;121(10):3846-59
references.pmid: 21926464
references.citation: Nat Med. 2007 Jan;13(1):54-61
references.pmid: 17187072
references.citation: J Clin Invest. 2008 Sep;118(9):3132-42
references.pmid: 18688285
references.citation: Nat Biotechnol. 2005 Mar;23(3):349-54
references.pmid: 15723046
references.citation: Science. 2002 Oct 25;298(5594):850-4
references.pmid: 12242449
references.citation: Sci Transl Med. 2012 May 2;4(132):132ra53
references.pmid: 22553251
references.citation: N Engl J Med. 2011 Aug 25;365(8):725-33
references.pmid: 21830940
references.citation: Blood. 2000 Aug 1;96(3):785-93
references.pmid: 10910888
references.citation: Cancer Immunol Res. 2013 Jul;1(1):26-31
references.pmid: 24777247
references.citation: J Clin Invest. 2007 Aug;117(8):2083-6
references.pmid: 17671645
references.citation: Immunotherapy. 2011 Oct;3(10):1223-33
references.pmid: 21995573
references.citation: Genome Biol. 2012 Feb 20;13(2):240
references.pmid: 22348749
references.citation: Immunity. 2013 Jun 27;38(6):1250-60
references.pmid: 23746652
references.citation: Nat Med. 2008 Nov;14(11):1264-70
references.pmid: 18978797
references.citation: Sci Transl Med. 2013 Mar 13;5(176):176ra33
references.pmid: 23486779
references.citation: Immunol Rev. 1997 Jun;157:177-94
references.pmid: 9255630
references.citation: Mol Ther. 2011 Mar;19(3):620-6
references.pmid: 21157437
references.citation: Sci Transl Med. 2011 Aug 10;3(95):95ra73
references.pmid: 21832238
references.citation: Nat Immunol. 2004 Sep;5(9):927-33
references.pmid: 15300249
references.citation: Nat Med. 2005 Nov;11(11):1238-43
references.pmid: 16227988
references.citation: Nat Biotechnol. 2012 May;30(5):460-5
references.pmid: 22484455
references.citation: Hum Gene Ther. 2008 May;19(5):511-21
references.pmid: 18471037
references.citation: Trends Immunol. 2005 Feb;26(2):111-7
references.pmid: 15668127
references.citation: Blood. 2001 Aug 1;98(3):597-603
references.pmid: 11468156
references.citation: Cancer Res. 2009 Apr 1;69(7):3077-85
references.pmid: 19293190
references.citation: Nat Rev Immunol. 2012 Mar 22;12(4):269-81
references.pmid: 22437939
references.citation: Cancer Res. 2001 May 1;61(9):3689-97
references.pmid: 11325840
references.citation: Curr Opin Immunol. 2011 Apr;23(2):299-305
references.pmid: 21237630
references.citation: Nat Biotechnol. 2008 Jul;26(7):808-16
references.pmid: 18587387
references.citation: Sci Transl Med. 2013 Mar 20;5(177):177ra38
references.pmid: 23515080
references.citation: Biol Blood Marrow Transplant. 2010 Sep;16(9):1245-56
references.pmid: 20304086
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(24):10024-8
references.pmid: 2513569
references.citation: Nat Clin Pract Oncol. 2006 Dec;3(12):668-81
references.pmid: 17139318
references.citation: Blood. 2005 Jun 15;105(12):4677-84
references.pmid: 15713795
references.citation: J Immunol. 2007 Nov 1;179(9):5845-54
references.pmid: 17947658
references.citation: Clin Cancer Res. 2010 Dec 1;16(23):5852-61
references.pmid: 21138872
references.citation: Eur J Immunol. 2012 Dec;42(12):3174-9
references.pmid: 22949370
references.citation: Regen Med. 2010 May;5(3):307-13
references.pmid: 20455641
references.citation: Mol Ther. 2010 Apr;18(4):843-51
references.pmid: 20179677
references.citation: N Engl J Med. 2003 Feb 6;348(6):567-8
references.pmid: 12571271
references.citation: Regen Med. 2012 Jan;7(1):7-13
references.pmid: 22168489
references.citation: J Clin Invest. 2011 Jun;121(6):2350-60
references.pmid: 21555851
references.citation: Sci Rep. 2012;2:249
references.pmid: 22355761
references.citation: J Allergy Clin Immunol. 1989 May;83(5):871-5
references.pmid: 2654255
references.citation: Blood. 2009 Jul 16;114(3):535-46
references.pmid: 19451549
references.citation: Clin Cancer Res. 2011 Jul 15;17(14):4719-30
references.pmid: 21610146
references.citation: Nat Rev Immunol. 2009 Oct;9(10):704-16
references.pmid: 19859065
references.citation: Science. 2000 Apr 28;288(5466):675-8
references.pmid: 10784451
references.citation: Br J Haematol. 2008 Oct;143(1):84-91
references.pmid: 18673367
references.citation: Science. 1996 Apr 12;272(5259):263-7
references.pmid: 8602510
references.citation: J Exp Med. 1998 Aug 17;188(4):619-26
references.pmid: 9705944
references.citation: Science. 2009 May 29;324(5931):1199-202
references.pmid: 19478183
references.citation: J Clin Invest. 2011 Jun;121(6):2264-77
references.pmid: 21576823
references.citation: J Immunother. 2012 Nov-Dec;35(9):689-701
references.pmid: 23090078
references.citation: Sci Transl Med. 2010 Oct 27;2(55):55ra78
references.pmid: 20980695
references.citation: Blood. 2002 May 1;99(9):3179-87
references.pmid: 11964281
references.citation: Hum Gene Ther. 1999 Aug 10;10(12):1941-51
references.pmid: 10466628
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
references.pmid: 12427970
references.citation: Blood. 2012 May 3;119(18):4133-41
references.pmid: 22354001
references.citation: J Clin Invest. 2008 Jan;118(1):294-305
references.pmid: 18060041
references.citation: Nat Med. 2005 Nov;11(11):1230-7
references.pmid: 16227990
references.citation: Mol Ther. 2013 Apr;21(4):904-12
references.pmid: 23423337
references.citation: Mol Ther. 2008 Apr;16(4):635-6
references.pmid: 18362918
references.citation: Annu Rev Immunol. 2006;24:657-79
references.pmid: 16551262
references.citation: Adv Immunol. 1991;49:281-355
references.pmid: 1853786
references.citation: Clin Cancer Res. 2009 Jul 1;15(13):4499-507
references.pmid: 19509133
references.citation: Curr Opin Immunol. 2005 Apr;17(2):195-201
references.pmid: 15766681
references.citation: Blood. 2008 Jul 15;112(2):362-73
references.pmid: 18354038
references.citation: Blood. 2007 Jun 15;109(12):5168-77
references.pmid: 17353346
references.citation: Nat Med. 2011 Sep 18;17(10):1290-7
references.pmid: 21926977
references.citation: Blood. 2012 Mar 22;119(12):2709-20
references.pmid: 22160384
references.citation: Blood. 2009 Sep 17;114(12):2417-26
references.pmid: 19605850
references.citation: Science. 2003 Apr 11;300(5617):339-42
references.pmid: 12690202
references.citation: Nat Med. 2010 May;16(5):565-70, 1p following 570
references.pmid: 20400962
references.citation: Eur J Immunol. 2009 Feb;39(2):491-506
references.pmid: 19180469
references.citation: Nat Med. 2011 May;17(5):519
references.pmid: 21546948
references.citation: Blood. 2003 Apr 1;101(7):2563-9
references.pmid: 12456496
references.citation: Blood. 2006 Mar 15;107(6):2294-302
references.pmid: 16282341
references.citation: N Engl J Med. 2011 Nov 3;365(18):1673-83
references.pmid: 22047558
references.citation: J Exp Med. 2010 Mar 15;207(3):637-50
references.pmid: 20156971
references.citation: Blood. 2004 Feb 15;103(4):1548-56
references.pmid: 14576063
references.citation: Blood. 2005 Apr 15;105(8):3051-7
references.pmid: 15632206
references.citation: Cancer Res. 2005 Mar 1;65(5):2001-8
references.pmid: 15753400
references.citation: Mol Ther. 2009 May;17(5):844-50
references.pmid: 19259065
references.citation: J Immunother. 2013 Feb;36(2):133-51
references.pmid: 23377668
references.citation: J Clin Invest. 2011 Dec;121(12):4746-57
references.pmid: 22056381
references.citation: Blood. 2013 Aug 8;122(6):863-71
references.pmid: 23770775
references.citation: J Clin Oncol. 2008 Nov 10;26(32):5233-9
references.pmid: 18809613
references.citation: Cancer Discov. 2013 Apr;3(4):388-98
references.pmid: 23550147
references.citation: J Immunol Methods. 2008 Dec 31;339(2):175-84
references.pmid: 18854190
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17469-74
references.pmid: 19805141
references.citation: Mol Ther. 2010 Apr;18(4):674-83
references.pmid: 20104209
references.citation: Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6106-15
references.pmid: 17062687
references.citation: Immunity. 2007 Dec;27(6):985-97
references.pmid: 18082432
references.citation: Gene Ther. 2002 Apr;9(8):527-35
references.pmid: 11948378
references.citation: J Immunol. 2007 May 1;178(9):5727-34
references.pmid: 17442956
references.citation: Cancer Res. 2010 Nov 15;70(22):9053-61
references.pmid: 20926399
references.citation: Blood. 2011 Jan 6;117(1):72-82
references.pmid: 20889925
references.citation: J Exp Med. 1955 Aug 1;102(2):157-77
references.pmid: 13242741
references.citation: N Engl J Med. 2013 Apr 18;368(16):1509-1518
references.pmid: 23527958
references.citation: Blood. 2003 Sep 15;102(6):2004-13
references.pmid: 12763934
references.citation: Blood. 2003 Feb 15;101(4):1290-8
references.pmid: 12393508
references.citation: Clin Cancer Res. 2012 Dec 15;18(24):6732-41
references.pmid: 23092876
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3001-6
references.pmid: 11867736
references.citation: J Exp Med. 2003 Sep 15;198(6):947-55
references.pmid: 12963692
references.citation: Immunol Invest. 2006;35(3-4):251-77
references.pmid: 16916754
references.citation: Cancer Res. 2003 Oct 15;63(20):6838-46
references.pmid: 14583481
references.citation: J Exp Med. 2009 Feb 16;206(2):463-75
references.pmid: 19171765