CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

Elad Jacoby, Sang M. Nguyen, Thomas J. Fountaine, Kathryn Welp, Berkley Gryder, Haiying Qin, Yinmeng Yang, Christopher D. Chien, Alix E. Seif, Haiyan Lei, Young K. Song, Javed Khan, Daniel W. Lee, Crystal L. Mackall, Rebecca A. Gardner, Michael C. Jensen, Jack F. Shern and Terry J. Fry ()
Additional contact information
Elad Jacoby: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Sang M. Nguyen: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Thomas J. Fountaine: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Kathryn Welp: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Berkley Gryder: Genetics Branch, National Cancer Institute, National Institutes of Health
Haiying Qin: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Yinmeng Yang: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Christopher D. Chien: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Alix E. Seif: The Children’s Hospital of Philadelphia, Perelman School of Medicine of the University of Pennsylvania
Haiyan Lei: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Young K. Song: Genetics Branch, National Cancer Institute, National Institutes of Health
Javed Khan: Genetics Branch, National Cancer Institute, National Institutes of Health
Daniel W. Lee: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Crystal L. Mackall: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Rebecca A. Gardner: Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of Washington
Michael C. Jensen: Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of Washington
Jack F. Shern: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Terry J. Fry: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12320

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