title: Eradication of B-ALL using chimeric antigen receptor-expressing T cells targeting the TSLPR oncoprotein.
abstract: Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting the CD19 B cell-associated protein have demonstrated potent activity against relapsed/refractory B-lineage acute lymphoblastic leukemia (B-ALL). Not all patients respond, and CD19-negative relapses have been observed. Overexpression of the thymic stromal lymphopoietin receptor (TSLPR; encoded by CRLF2) occurs in a subset of adults and children with B-ALL and confers a high risk of relapse. Recent data suggest the TSLPR signaling axis is functionally important, suggesting that TSLPR would be an ideal immunotherapeutic target. We constructed short and long CARs targeting TSLPR and tested efficacy against CRLF2-overexpressing B-ALL. Both CARs demonstrated activity in vitro, but only short TSLPR CAR T cells mediated leukemia regression. In vivo activity of the short CAR was also associated with long-term persistence of CAR-expressing T cells. Short TSLPR CAR treatment of mice engrafted with a TSLPR-expressing ALL cell line induced leukemia cytotoxicity with efficacy comparable with that of CD19 CAR T cells. Short TSLPR CAR T cells also eradicated leukemia in 4 xenograft models of human CRLF2-overexpressing ALL. Finally, TSLPR has limited surface expression on normal tissues. TSLPR-targeted CAR T cells thus represent a potent oncoprotein-targeted immunotherapy for high-risk ALL.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Haiying
authors.initials: H
authors.lastname: Qin
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Monica
authors.initials: M
authors.lastname: Cho
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Waleed
authors.initials: W
authors.lastname: Haso
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada;
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Negri
authors.affiliation: iPSC Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD; and.
authors.forename: Yongshun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: iPSC Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD; and.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Zou
authors.affiliation: National Institutes of Health Stem Cell Unit, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Mallon
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: Shannon
authors.initials: S
authors.lastname: Maude
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Rimas J
authors.initials: RJ
authors.lastname: Orentas
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada;
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; C498762:CRLF2 protein, human; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins