title: Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.
abstract: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749.
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Joseph A
authors.identifier: http://orcid.org/0000-0001-7900-8993
authors.initials: JA
authors.lastname: Fraietta
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Beckwith
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Prachi R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Marco
authors.identifier: http://orcid.org/0000-0003-4301-5811
authors.initials: M
authors.lastname: Ruella
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: David M
authors.identifier: http://orcid.org/0000-0002-9407-6297
authors.initials: DM
authors.lastname: Barrett
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Simon F
authors.identifier: http://orcid.org/0000-0003-2882-1962
authors.initials: SF
authors.lastname: Lacey
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Jan Joseph
authors.identifier: http://orcid.org/0000-0001-7677-537X
authors.initials: JJ
authors.lastname: Melenhorst
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Shannon E
authors.initials: SE
authors.lastname: McGettigan
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Cook
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Changfeng
authors.identifier: http://orcid.org/0000-0002-2864-5551
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Priscilla
authors.initials: P
authors.lastname: Do
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Jessica
authors.initials: J
authors.lastname: Hulitt
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Sagar B
authors.initials: SB
authors.lastname: Kudchodkar
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Alexandria P
authors.initials: AP
authors.lastname: Cogdill
authors.affiliation: Center for Cellular Immunotherapies and Division of Hematology-Oncology, Department of Internal Medicine and.
authors.forename: Saar
authors.identifier: http://orcid.org/0000-0001-7946-7778
authors.initials: S
authors.lastname: Gill
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Division of Hematology-Oncology, Department of Internal Medicine and.
authors.forename: David L
authors.identifier: http://orcid.org/0000-0001-6333-9536
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Meixiao
authors.identifier: http://orcid.org/0000-0002-0820-5612
authors.initials: M
authors.lastname: Long
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; and.
authors.forename: Bruce L
authors.identifier: http://orcid.org/0000-0001-6971-8465
authors.initials: BL
authors.lastname: Levine
authors.affiliation: Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; and.
authors.forename: Carl H
authors.identifier: http://orcid.org/0000-0003-0241-3557
authors.initials: CH
authors.lastname: June
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Marcela V
authors.identifier: http://orcid.org/0000-0002-7578-0393
authors.initials: MV
authors.lastname: Maus
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000284:Administration, Oral; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003710:Demography; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D007165:Immunosuppression Therapy; D020014:K562 Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010880:Piperidines; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; C000598123:CTL019 chimeric antigen receptor; C105992:PDCD1 protein, human; D010880:Piperidines; D061026:Programmed Cell Death 1 Receptor; D011720:Pyrazoles; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C551803:ibrutinib; D000225:Adenine; C042739:antigens, CD200
references.citation: J Immunol. 2006 Jan 1;176(1):191-9
references.pmid: 16365410
references.citation: J Immunol. 2003 Jan 15;170(2):711-8
references.pmid: 12517932
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71
references.pmid: 11698646
references.citation: Leukemia. 2011 May;25(5):792-9
references.pmid: 21274000
references.citation: Br J Haematol. 2008 May;141(5):607-14
references.pmid: 18384436
references.citation: J Leukoc Biol. 2010 Aug;88(2):361-72
references.pmid: 20442224
references.citation: Blood. 2014 Mar 20;123(12):1957-60
references.pmid: 24652965
references.citation: N Engl J Med. 2014 Oct 16;371(16):1507-17
references.pmid: 25317870
references.citation: Sci Signal. 2012 Jun 26;5(230):ra46
references.pmid: 22740686
references.citation: Cell Cycle. 2012 Dec 1;11(23):4305-9
references.pmid: 23032366
references.citation: Cancer Discov. 2015 Dec;5(12):1282-95
references.pmid: 26516065
references.citation: Curr Protoc Immunol. 2009 Feb;Chapter 4:Unit4.9
references.pmid: 19235770
references.citation: Blood. 2011 Nov 3;118(18):4817-28
references.pmid: 21849486
references.citation: Sci Transl Med. 2014 Feb 19;6(224):224ra25
references.pmid: 24553386
references.citation: Am J Clin Pathol. 2010 Nov;134(5):726-33
references.pmid: 20959655
references.citation: Br J Haematol. 2015 Jun 18;:null
references.pmid: 26084925
references.citation: Blood. 2012 Aug 16;120(7):1412-21
references.pmid: 22547582
references.citation: PLoS Pathog. 2012;8(8):e1002840
references.pmid: 22916009
references.citation: Am J Clin Pathol. 2012 Jan;137(1):93-100
references.pmid: 22180482
references.citation: PLoS One. 2013;8(10):e76607
references.pmid: 24130782
references.citation: Leukemia. 2013 Jan;27(1):136-41
references.pmid: 22781591
references.citation: Cancer Res. 2010 Nov 15;70(22):9166-74
references.pmid: 20884631
references.citation: Mol Cell Biol. 2005 Nov;25(21):9543-53
references.pmid: 16227604
references.citation: J Immunol. 2007 May 1;178(9):5595-605
references.pmid: 17442942
references.citation: Blood. 2012 Mar 22;119(12):2709-20
references.pmid: 22160384
references.citation: Blood. 2015 Mar 26;125(13):2079-86
references.pmid: 25662332
references.citation: Br J Haematol. 2009 Jun;146(1):64-75
references.pmid: 19438485
references.citation: N Engl J Med. 2013 Apr 18;368(16):1509-18
references.pmid: 23527958
references.citation: Leuk Res. 2009 Mar;33(3):460-4
references.pmid: 18838168
references.citation: Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):E966-72
references.pmid: 25730880
references.citation: N Engl J Med. 2011 Aug 25;365(8):725-33
references.pmid: 21830940
references.citation: Blood. 2015 Jul 9;126(2):203-11
references.pmid: 25800048
references.citation: Blood. 2013 Feb 28;121(9):1612-21
references.pmid: 23247726
references.citation: J Immunol. 2005 Oct 1;175(7):4441-9
references.pmid: 16177086
references.citation: Sci Transl Med. 2015 Sep 2;7(303):303ra139
references.pmid: 26333935
references.citation: Leuk Res. 2011 Mar;35(3):363-8
references.pmid: 20880586
references.citation: Nature. 2011 Mar 17;471(7338):377-81
references.pmid: 21368758
references.citation: Eur J Immunol. 2001 Aug;31(8):2331-7
references.pmid: 11477545
references.citation: Mol Ther. 2009 Aug;17(8):1453-64
references.pmid: 19384291
references.citation: JAMA Oncol. 2015 Apr;1(1):80-7
references.pmid: 26182309
references.citation: J Immunol. 1999 Jan 15;162(2):774-81
references.pmid: 9916698
references.citation: Blood. 2012 Mar 15;119(11):2590-4
references.pmid: 22279054
references.citation: Blood. 2006 Feb 15;107(4):1325-31
references.pmid: 16269610
references.citation: Am J Hematol. 2012 Jun;87(6):628-31
references.pmid: 22460620
references.citation: Cancer. 1988 Jan 15;61(2):279-83
references.pmid: 2446736
references.citation: N Engl J Med. 2014 Jun 12;370(24):2286-94
references.pmid: 24869598
references.citation: Sci Transl Med. 2011 Aug 10;3(95):95ra73
references.pmid: 21832238
references.citation: J Immunol. 2004 Jul 15;173(2):945-54
references.pmid: 15240681
references.citation: Blood. 2013 Oct 10;122(15):2539-49
references.pmid: 23886836
references.citation: Cancer Res. 2012 Oct 1;72(19):4931-43
references.pmid: 22875025