title: Reversal of tumor immune inhibition using a chimeric cytokine receptor.
abstract: The success of adoptively transferred tumor-directed T cells requires them to survive and expand in vivo. Most tumors, however, employ immune evasion mechanisms, including the production of inhibitory cytokines that limit in vivo T-cell persistence and effector function. To protect tumor-directed T cells from such negative influences, we generated a chimeric cytokine receptor in which the interleukin (IL) 4 receptor exodomain was fused to the IL7 receptor endodomain. We thereby inverted the effects of tumor-derived IL4 so that the proliferation and activation of tumor directed cytotoxic T cells was enhanced rather than inhibited in the tumor microenvironment, resulting in superior antitumor activity. These transgenic T cells were only activated in the tumor environment since triggering required exposure to both tumor antigen (signal 1) and tumor-derived IL4 (signal 2). This selectivity supports future clinical adaptation.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA. Electronic address: amleen@txch.org.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Sujita
authors.initials: S
authors.lastname: Sukumaran
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Somala
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Keirnan
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Ryu
authors.initials: R
authors.lastname: Yanagisawa
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Usanarat
authors.initials: U
authors.lastname: Anurathapan
authors.affiliation: Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rendon
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Vera
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019076:Transgenes / Q000276:immunology; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D053662:Interleukin-4 Receptor alpha Subunit; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins
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: Sci Transl Med. 2011 Aug 10;3(95):95ra73
references.pmid: 21832238
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: Mol Ther. 2010 Apr;18(4):843-51
references.pmid: 20179677
references.citation: J Cell Biochem. 2012 May;113(5):1569-80
references.pmid: 22174091
references.citation: Mol Ther. 2009 May;17(5):880-8
references.pmid: 19259067
references.citation: N Engl J Med. 2003 Jan 16;348(3):255-6
references.pmid: 12529469
references.citation: Ann Oncol. 2013 Aug;24(8):2174-80
references.pmid: 23666915
references.citation: Oncogene. 2000 May 15;19(21):2577-84
references.pmid: 10851056
references.citation: J Clin Oncol. 2006 May 1;24(13):e20-2
references.pmid: 16648493
references.citation: Mol Ther. 2012 Feb;20(2):246-9
references.pmid: 22297819
references.citation: Annu Rev Immunol. 1999;17:701-38
references.pmid: 10358772
references.citation: Clin Exp Immunol. 2009 Jul;157(1):9-19
references.pmid: 19659765
references.citation: J Immunol. 2004 May 1;172(9):5467-77
references.pmid: 15100288
references.citation: J Immunother. 2010 Apr;33(3):305-15
references.pmid: 20445351
references.citation: Nat Med. 2008 Nov;14(11):1264-70
references.pmid: 18978797
references.citation: Mol Cell Biol. 2004 Jul;24(14):6501-13
references.pmid: 15226449
references.citation: Blood. 2001 Sep 1;98(5):1524-31
references.pmid: 11520803
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Annu Rev Immunol. 2007;25:243-65
references.pmid: 17129181
references.citation: Immunol Rev. 2014 Jan;257(1):56-71
references.pmid: 24329789
references.citation: Genes Dev. 1992 Jan;6(1):61-70
references.pmid: 1730410
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Diabetes. 2006 Feb;55(2):421-7
references.pmid: 16443776
references.citation: J Leukoc Biol. 2013 Jul;94(1):41-53
references.pmid: 23667165
references.citation: Am J Respir Cell Mol Biol. 2006 Feb;34(2):213-8
references.pmid: 16210693
references.citation: Leukemia. 2010 Dec;24(12):2080-9
references.pmid: 20944673
references.citation: Blood. 2002 May 1;99(9):3179-87
references.pmid: 11964281
references.citation: Curr Opin Rheumatol. 2001 Nov;13(6):505-11
references.pmid: 11698729
references.citation: Nat Biotechnol. 2013 Jan;31(1):71-5
references.pmid: 23242161
references.citation: Mol Ther. 2013 Apr;21(4):904-12
references.pmid: 23423337
references.citation: Cell Death Differ. 2008 Apr;15(4):762-72
references.pmid: 18202702
references.citation: J Clin Oncol. 2014 Mar 10;32(8):798-808
references.pmid: 24344220
references.citation: Blood. 2007 Oct 15;110(8):2838-45
references.pmid: 17609424
references.citation: Lancet Oncol. 2010 Feb;11(2):155-64
references.pmid: 20004617
references.citation: Mol Ther. 2014 Mar;22(3):623-633
references.pmid: 24213558
references.citation: Annu Rev Immunol. 2007;25:267-96
references.pmid: 17134371
references.citation: J Immunother. 2006 May-Jun;29(3):250-60
references.pmid: 16699368
references.citation: Immunol Rev. 2012 Nov;250(1):303-16
references.pmid: 23046137
references.citation: J Clin Immunol. 2012 Oct;32(5):1059-70
references.pmid: 22526592
references.citation: Lancet. 1995 Jan 7;345(8941):9-13
references.pmid: 7799740
references.citation: Mol Ther. 2014 Jan;22(1):132-9
references.pmid: 24297049
references.citation: Science. 2003 Oct 17;302(5644):415-9
references.pmid: 14564000
references.citation: Blood. 2005 Mar 1;105(5):1898-904
references.pmid: 15542583
references.citation: Clin Immunol. 2009 Aug;132(2):153-65
references.pmid: 19428306
references.citation: N Engl J Med. 2013 Apr 18;368(16):1509-1518
references.pmid: 23527958
references.citation: N Engl J Med. 2013 Jul 11;369(2):134-44
references.pmid: 23724846
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):389-402
references.pmid: 18371377