title: CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity.
abstract: Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Elad
authors.initials: E
authors.lastname: Jacoby
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sang M
authors.initials: SM
authors.lastname: Nguyen
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fountaine
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Welp
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Berkley
authors.initials: B
authors.lastname: Gryder
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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, Maryland 20892, USA.
authors.forename: Yinmeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Christopher D
authors.identifier: 0000-0002-4871-5262
authors.initials: CD
authors.lastname: Chien
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, and Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Alix E
authors.initials: AE
authors.lastname: Seif
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Lei
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Young K
authors.initials: YK
authors.lastname: Song
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lee
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Hospital, and Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Gardner
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Hospital, and Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Shern
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019070:Cell Lineage; D000066670:Cell Plasticity; D002843:Chromatin / Q000378:metabolism; D002999:Clone Cells; D044127:Epigenesis, Genetic; D000072669:Gene Editing; D016678:Genome; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012008:Recurrence
chemical_list: C000605956:CD19-specific chimeric antigen receptor; D002843:Chromatin; D011948:Receptors, Antigen, T-Cell