title: T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia.
abstract: Induction treatments for acute myeloid leukemia (AML) have remained largely unchanged for nearly 50 years, and AML remains a disease of poor prognosis. Allogeneic hematopoietic cell transplantation can achieve cures in select patients and highlights the susceptibility of AML to donor-derived immunotherapy. The interleukin-3 receptor α chain (CD123) has been identified as a potential immunotherapeutic target because it is overexpressed in AML compared with normal hematopoietic stem cells. Therefore, we developed 2 chimeric antigen receptors (CARs) containing a CD123-specific single-chain variable fragment, in combination with a CD28 costimulatory domain and CD3-ζ signaling domain, targeting different epitopes on CD123. CD123-CAR-redirected T cells mediated potent effector activity against CD123+ cell lines as well as primary AML patient samples. CD123 CAR T cells did not eliminate granulocyte/macrophage and erythroid colony formation in vitro. Additionally, T cells obtained from patients with active AML can be modified to express CD123 CARs and are able to lyse autologous AML blasts in vitro. Finally, CD123 CAR T cells exhibited antileukemic activity in vivo against a xenogeneic model of disseminated AML. These results suggest that CD123 CAR T cells are a promising immunotherapy for the treatment of high-risk AML.
authors.affiliation: Hematology and Hematopoietic Cell Transplantation and.
authors.forename: Armen
authors.initials: A
authors.lastname: Mardiros
authors.forename: Cedric
authors.initials: C
authors.lastname: Dos Santos
authors.forename: Tinisha
authors.initials: T
authors.lastname: McDonald
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.forename: L Elizabeth
authors.initials: LE
authors.lastname: Budde
authors.forename: Lauren
authors.initials: L
authors.lastname: Hoffman
authors.forename: Brenda
authors.initials: B
authors.lastname: Aguilar
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chang
authors.forename: William
authors.initials: W
authors.lastname: Bretzlaff
authors.forename: Brenda
authors.initials: B
authors.lastname: Chang
authors.forename: Mahesh
authors.initials: M
authors.lastname: Jonnalagadda
authors.forename: Renate
authors.initials: R
authors.lastname: Starr
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ostberg
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D053650:Interleukin-3 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; D011946:Receptors, Antigen; D057127:Single-Chain Antibodies
references.citation: Leukemia. 2000 Oct;14(10):1777-84
references.pmid: 11021753
references.citation: Cancer Res. 2004 Dec 15;64(24):9160-6
references.pmid: 15604287
references.citation: Cancer Gene Ther. 2009 Jun;16(6):489-97
references.pmid: 19096447
references.citation: Sci Transl Med. 2013 Mar 20;5(177):177ra38
references.pmid: 23515080
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11872-7
references.pmid: 12193648
references.citation: Cancer Res. 2001 Sep 15;61(18):6846-50
references.pmid: 11559560
references.citation: Cell Stem Cell. 2009 Jul 2;5(1):31-42
references.pmid: 19570512
references.citation: J Clin Invest. 2008 Jan;118(1):294-305
references.pmid: 18060041
references.citation: Haematologica. 2001 Dec;86(12):1261-9
references.pmid: 11726317
references.citation: Cell. 2009 Jul 23;138(2):286-99
references.pmid: 19632179
references.citation: J Immunother. 2009 Sep;32(7):689-702
references.pmid: 19561539
references.citation: Blood. 1993 Aug 1;82(3):752-61
references.pmid: 7687890
references.citation: Blood. 2009 Oct 29;114(18):3909-16
references.pmid: 19710498
references.citation: Leukemia. 2013 Apr;27(5):1107-15
references.pmid: 23178753
references.citation: Blood. 2011 Aug 4;118(5):1255-63
references.pmid: 21653320
references.citation: Br J Haematol. 2013 May;161(3):389-401
references.pmid: 23432359
references.citation: Mol Ther. 2009 Aug;17(8):1453-64
references.pmid: 19384291
references.citation: Clin Dev Immunol. 2011;2011:104926
references.pmid: 22028726
references.citation: Sci Transl Med. 2011 Aug 10;3(95):95ra73
references.pmid: 21832238
references.citation: Mol Ther. 2013 Mar;21(3):638-47
references.pmid: 23295945
references.citation: N Engl J Med. 2010 Jun 17;362(24):2326-7
references.pmid: 20554989
references.citation: Blood. 2011 Apr 21;117(16):4243-52
references.pmid: 21330473
references.citation: J Virol. 2009 Sep;83(18):9122-30
references.pmid: 19587053
references.citation: Blood. 2011 Nov 3;118(18):4817-28
references.pmid: 21849486
references.citation: Blood. 2010 Jan 21;115(3):453-74
references.pmid: 19880497
references.citation: Blood. 2012 Jun 28;119(26):6198-208
references.pmid: 22286199
references.citation: Nat Rev Immunol. 2008 Apr;8(4):247-58
references.pmid: 18323851
references.citation: Br J Haematol. 2006 Feb;132(4):398-409
references.pmid: 16412015
references.citation: J Immunother. 2007 Sep;30(6):607-13
references.pmid: 17667524
references.citation: Cancer Res. 2007 Dec 1;67(23):11428-37
references.pmid: 18056471
references.citation: J Clin Oncol. 2001 Jul 1;19(13):3244-54
references.pmid: 11432892
references.citation: Adv Hematol. 2012;2012:683065
references.pmid: 22272203
references.citation: Cancer Res. 2006 Jun 1;66(11):5875-82
references.pmid: 16740727
references.citation: Blood. 2005 Jun 1;105(11):4247-54
references.pmid: 15728125
references.citation: Blood. 2012 Apr 26;119(17):3940-50
references.pmid: 22308288
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: Oncogene. 2011 Mar 3;30(9):1009-19
references.pmid: 21076471
references.citation: Br J Haematol. 2003 Feb;120(3):442-51
references.pmid: 12580958
references.citation: J Clin Invest. 2011 May;121(5):1822-6
references.pmid: 21540550
references.citation: Gene Ther. 2010 May;17(5):678-86
references.pmid: 20200563
references.citation: Nat Med. 2008 Jun;14(6):623-8
references.pmid: 18535580
references.citation: Blood. 2003 Feb 15;101(4):1637-44
references.pmid: 12393484
references.citation: J Leukoc Biol. 2006 Jan;79(1):46-58
references.pmid: 16380601
references.citation: Blood. 2010 Aug 19;116(7):1035-44
references.pmid: 20439624
references.citation: Blood. 2005 Dec 15;106(13):4086-92
references.pmid: 16131573
references.citation: Blood. 1995 Jun 15;85(12):3636-45
references.pmid: 7780147
references.citation: Clin Cancer Res. 2013 Jun 15;19(12):3153-64
references.pmid: 23620405
references.citation: Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5426-35
references.pmid: 17855649
references.citation: Cell Stem Cell. 2010 Dec 3;7(6):708-17
references.pmid: 21112565