title: The basic principles of chimeric antigen receptor design.
abstract: Chimeric antigen receptors (CAR) are recombinant receptors that provide both antigen-binding and T-cell-activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. Their biologic functions have dramatically changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. These have recently shown clinical benefit in patients treated with CD19-targeted autologous T cells. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors, or cytokines to further enhance T-cell potency, specificity, and safety. CARs represent a new class of drugs with exciting potential for cancer immunotherapy.
  
  
  CONCLUSIONS
  CARs are a new class of drugs with great potential for cancer immunotherapy. Upon their expression in T lymphocytes, CARs direct potent, targeted immune responses that have recently shown encouraging clinical outcomes in a subset of patients with B-cell malignancies. This review focuses on the design of CARs, including the requirements for optimal antigen recognition and different modalities to provide costimulatory support to targeted T cells, which include the use of second- and third generation CARs, costimulatory ligands, chimeric costimulatory receptors, and cytokines.
authors.affiliation: Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. m-sadelain@ski.mskcc.org
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Renier
authors.initials: R
authors.lastname: Brentjens
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rivière
mesh_terms: D000818:Animals; D006801:Humans; D016219:Immunotherapy, Adoptive; D009369:Neoplasms / Q000628:therapy; D011946:Receptors, Antigen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins
references.citation: Mol Ther. 2009 Aug;17(8):1453-64
references.pmid: 19384291
references.citation: Nat Med. 2003 Mar;9(3):279-86
references.pmid: 12579196
references.citation: Mol Ther. 2005 Nov;12(5):933-41
references.pmid: 15979412
references.citation: Cancer Res. 2011 Apr 15;71(8):2871-81
references.pmid: 21487038
references.citation: N Engl J Med. 2011 Nov 3;365(18):1673-83
references.pmid: 22047558
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5784-8
references.pmid: 19307587
references.citation: Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5426-35
references.pmid: 17855649
references.citation: Neoplasia. 2001 Nov-Dec;3(6):480-8
references.pmid: 11774030
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1457-62
references.pmid: 16432223
references.citation: Nat Rev Cancer. 2003 Jan;3(1):35-45
references.pmid: 12509765
references.citation: Immunology. 2009 Feb;126(2):165-76
references.pmid: 19125887
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8905-9
references.pmid: 1833767
references.citation: J Exp Med. 1993 Sep 1;178(3):951-60
references.pmid: 8350062
references.citation: Cell. 1991 Mar 8;64(5):1037-46
references.pmid: 1900456
references.citation: Blood. 2010 Feb 4;115(5):925-35
references.pmid: 19880495
references.citation: Autoimmun Rev. 2006 Apr;5(4):252-7
references.pmid: 16697965
references.citation: Nat Biotechnol. 2008 Apr;26(4):453-61
references.pmid: 18376399
references.citation: Cancer Res. 2006 Nov 15;66(22):10995-1004
references.pmid: 17108138
references.citation: Nat Med. 2007 Dec;13(12):1440-9
references.pmid: 18026115
references.citation: Blood. 2010 Nov 25;116(22):4532-41
references.pmid: 20702778
references.citation: Sci Transl Med. 2012 May 2;4(132):132ra53
references.pmid: 22553251
references.citation: Blood. 2012 Feb 2;119(5):1107-16
references.pmid: 22096239
references.citation: N Engl J Med. 2011 Aug 25;365(8):725-33
references.pmid: 21830940
references.citation: Blood. 1997 Aug 1;90(3):952-7
references.pmid: 9242523
references.citation: Mol Ther. 2010 Feb;18(2):413-20
references.pmid: 19773745
references.citation: Curr Opin Immunol. 2009 Apr;21(2):215-23
references.pmid: 19327974
references.citation: Gene Ther. 2013 Feb;20(2):177-86
references.pmid: 22378346
references.citation: Sci Transl Med. 2011 Aug 10;3(95):95ra73
references.pmid: 21832238
references.citation: Cancer Res. 2012 Apr 1;72(7):1844-52
references.pmid: 22315351
references.citation: Blood. 2012 Mar 22;119(12):2700-2
references.pmid: 22442331
references.citation: Mol Ther. 2011 Mar;19(3):432-8
references.pmid: 21358705
references.citation: Blood. 2011 Nov 3;118(18):4817-28
references.pmid: 21849486
references.citation: Curr Gene Ther. 2010 Apr;10(2):77-90
references.pmid: 20222863
references.citation: Immunity. 1996 Dec;5(6):527-35
references.pmid: 8986713
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7739-43
references.pmid: 7644487
references.citation: Biol Blood Marrow Transplant. 2010 Sep;16(9):1245-56
references.pmid: 20304086
references.citation: Nat Biotechnol. 2002 Jan;20(1):70-5
references.pmid: 11753365
references.citation: Immunol Res. 2011 May;50(1):39-48
references.pmid: 21365321
references.citation: Nat Rev Cancer. 2008 Apr;8(4):299-308
references.pmid: 18354418
references.citation: Clin Dev Immunol. 2012;2012:124187
references.pmid: 22778760
references.citation: Gene Ther. 2011 Sep;18(9):849-56
references.pmid: 21451576
references.citation: Blood. 2007 Oct 15;110(8):2793-802
references.pmid: 17638856
references.citation: Cell. 1991 Mar 8;64(5):891-901
references.pmid: 1705867
references.citation: Methods Mol Biol. 2009;506:115-26
references.pmid: 19110623
references.citation: J Exp Med. 1995 May 1;181(5):1653-9
references.pmid: 7722445
references.citation: Mol Ther. 2010 Apr;18(4):843-51
references.pmid: 20179677
references.citation: Curr Opin Immunol. 2012 Oct;24(5):598-608
references.pmid: 22995202
references.citation: Blood. 1994 Apr 1;83(7):1988-97
references.pmid: 8142665
references.citation: Neoplasia. 1999 Jun;1(2):123-7
references.pmid: 10933046
references.citation: J Biol Chem. 2005 Jan 28;280(4):2972-80
references.pmid: 15537658
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3360-5
references.pmid: 19211796
references.citation: Clin Cancer Res. 2012 Mar 15;18(6):1672-83
references.pmid: 22291136
references.citation: Blood. 2013 Jan 24;121(4):573-84
references.pmid: 23160470
references.citation: Blood. 2012 Apr 26;119(17):3940-50
references.pmid: 22308288
references.citation: Cancer Res. 2009 Dec 1;69(23):9003-11
references.pmid: 19903853
references.citation: Nat Rev Cancer. 2011 Dec 01;12(1):51-8
references.pmid: 22129804
references.citation: Cancer Res. 1995 Aug 1;55(15):3369-73
references.pmid: 7614473
references.citation: J Exp Med. 1998 Aug 17;188(4):619-26
references.pmid: 9705944
references.citation: Blood. 2008 Sep 15;112(6):2278-86
references.pmid: 18566328
references.citation: Cancer Res. 2010 Sep 1;70(17):6725-34
references.pmid: 20647327
references.citation: Cell. 1992 Mar 6;68(5):889-97
references.pmid: 1547489
references.citation: Blood. 2012 May 3;119(18):4133-41
references.pmid: 22354001
references.citation: J Immunol. 1998 Sep 15;161(6):2791-7
references.pmid: 9743337
references.citation: Blood. 2011 Dec 1;118(23):6050-6
references.pmid: 21984804
references.citation: Nat Biotechnol. 2013 Jan;31(1):71-5
references.pmid: 23242161
references.citation: Gene Ther. 2009 May;16(5):596-604
references.pmid: 19158846
references.citation: N Engl J Med. 2011 Nov 3;365(18):1735-7
references.pmid: 22047566
references.citation: Blood. 2007 Jun 15;109(12):5168-77
references.pmid: 17353346
references.citation: J Immunol. 2005 Dec 1;175(11):7226-34
references.pmid: 16301627
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: Nat Med. 2010 May;16(5):565-70, 1p following 570
references.pmid: 20400962
references.citation: Hum Gene Ther. 2007 Aug;18(8):712-25
references.pmid: 17685852
references.citation: J Clin Invest. 2011 May;121(5):1822-6
references.pmid: 21540550
references.citation: Mol Ther. 2006 Jan;13(1):151-9
references.pmid: 16140584
references.citation: Clin Cancer Res. 1997 Jan;3(1):81-5
references.pmid: 9815541
references.citation: Oncoimmunology. 2012 Dec 1;1(9):1577-1583
references.pmid: 23264903
references.citation: Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):720-4
references.pmid: 8421711
references.citation: Hum Gene Ther. 2010 Jan;21(1):75-86
references.pmid: 19719389
references.citation: Nat Rev Immunol. 2011 Sep 09;11(10):672-84
references.pmid: 21904389
references.citation: Eur J Immunol. 2011 May;41(5):1288-97
references.pmid: 21469084
references.citation: J Clin Invest. 2011 Dec;121(12):4746-57
references.pmid: 22056381
references.citation: Blood. 2003 Feb 15;101(4):1637-44
references.pmid: 12393484
references.citation: Cancer Cell. 2003 May;3(5):431-7
references.pmid: 12781360
references.citation: J Immunother. 2009 Sep;32(7):726-36
references.pmid: 19561536
references.citation: J Clin Oncol. 2006 May 1;24(13):e20-2
references.pmid: 16648493
references.citation: Blood. 2010 Nov 18;116(20):4099-102
references.pmid: 20668228
references.citation: J Clin Immunol. 2012 Oct;32(5):1059-70
references.pmid: 22526592
references.citation: Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6106-15
references.pmid: 17062687
references.citation: J Immunother. 2007 Jul-Aug;30(5):506-16
references.pmid: 17589291
references.citation: Otolaryngol Head Neck Surg. 2012 Oct;147(4):744-9
references.pmid: 22597578
references.citation: Mol Ther. 2009 Sep;17(9):1537-47
references.pmid: 19532134
references.citation: Nat Biotechnol. 2013 Jan;31(1):33-4
references.pmid: 23302931
references.citation: Immunotherapy. 2011 Jan;3(1):33-48
references.pmid: 21174556
references.citation: Hum Gene Ther. 2010 Mar;21(3):241-50
references.pmid: 20121594
references.citation: Blood. 2010 Apr 29;115(17):3508-19
references.pmid: 20190192
references.citation: J Immunol. 2008 Jun 1;180(11):7736-46
references.pmid: 18490778