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Factors promoting CD19-negative relapses following CAR19T cell therapy

  • Author Footnotes
    * Corresponding author.
    A. Dolnikov
    Footnotes
    * Corresponding author.
    Affiliations
    Kids Cancer Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia

    Children's Cancer Institute Sydeny Australia, Sydney, New South Wales, Australia

    Department of Medicine, UNSW, Sydney, New South Wales, Australia
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  • N. Xu
    Affiliations
    Kids Cancer Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia

    Children's Cancer Institute Sydeny Australia, Sydney, New South Wales, Australia

    Department of Medicine, UNSW, Sydney, New South Wales, Australia
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  • B. Tse
    Affiliations
    Children's Cancer Institute Sydeny Australia, Sydney, New South Wales, Australia

    Department of Medicine, UNSW, Sydney, New South Wales, Australia
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  • D. Bishop
    Affiliations
    Westmead Institute for Medical Research, Sydney, Westmead, New South Wales, Australia

    Haematology Department, Westmead Hospital, Sydney, New South Wales, Australia

    Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
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  • D. Gottlieb
    Affiliations
    Westmead Institute for Medical Research, Sydney, Westmead, New South Wales, Australia

    Haematology Department, Westmead Hospital, Sydney, New South Wales, Australia

    Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
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  • K. Micklethwaite
    Affiliations
    Westmead Institute for Medical Research, Sydney, Westmead, New South Wales, Australia

    Haematology Department, Westmead Hospital, Sydney, New South Wales, Australia

    Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
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  • T. O'Brien
    Affiliations
    Kids Cancer Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia

    Children's Cancer Institute Sydeny Australia, Sydney, New South Wales, Australia

    Department of Medicine, UNSW, Sydney, New South Wales, Australia
    Search for articles by this author
  • Author Footnotes
    * Corresponding author.
      Chimeric Antigen Receptor (CAR) T cell therapy employs patient's own T cells re-directed to target tumour cells. CAR T-cell therapy targeting CD19 (CAR19), induced remarkable responses in patients with B-cell leukaemia's and lymphomas. Recent trials have demonstrated that despite initial clearance of tumour, relapses with CD19-expressing leukaemia and with CD19 antigen loss can occur. Here we show that CD19-negative variants are present in patient derived B-cell Acute Lymphoblastic Leukaemia (B-ALL) samples. Flow cytometry analysis of leukaemia immunophenotype revealed heterogeneous proportions of CD19-negative and CD19-positive variants in the panel of paediatric B-ALLs (12–97%, MFI 1900–17000 range). Reduced CD34 and CD10 expression was registered in CD19-negative blasts compared to CD19-positive leukaemia cells. We further used patient derived B-ALLs xenografted to immunocompromised mice to analyse the factors promoting CD19-negative and CD19-positive leukaemia relapses. We have demonstrated that both CD19-positive and CD19-negative blasts efficiently engraft peripheral blood, bone marrow and spleen of mice, and expand in vivo generating “chimeric” leukaemias. Using this model we have shown that novel PiggyBac (PB) transposon–based CAR19T cell therapy promoted CD19+ leukaemia cell but not CD19-negative cell clearance in CAR19T-cell dose dependent manner. CAR19T cell persistence in mice infused with high doses of effector cells correlated with the CD19-negative relapses. Mice treated with high doses of CAR19T-cells remained CD19-positive leukaemia-free but exhibited CD19-negative leukaemia cell outgrowth. Additionally, we have demonstrated that CAR19T cells expressing co-stimulatory 41BB domain were more potent in CD19-positive leukaemia cell clearance, persisted longer and induced more CD19-negative relapses compared to CAR19T cells expressing CD28 co-stimulatory domain. Collectively, our data are suggesting that CAR19T cell dose escalation and increasing CAR19T cell in vivo persistence may represent a risk factor for CD19-negative relapses following CAR19T cell infusion.
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