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Identifying the factors modulating the efficacy of car-t cell therapy

  • A. Dolnikov
    Affiliations
    1Cord and marrow transplant laboratory, Sydney Children, Randwick, New South Wales, Australia

    2Faculty of medicine, UNSW, Randwick, New South Wales, Australia

    3Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia
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  • G. Klamer
    Affiliations
    2Faculty of medicine, UNSW, Randwick, New South Wales, Australia

    3Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia
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  • S. Shen
    Affiliations
    1Cord and marrow transplant laboratory, Sydney Children, Randwick, New South Wales, Australia

    3Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia
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  • A. Chitranjan
    Affiliations
    3Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia
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  • H. Carol
    Affiliations
    3Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia

    2Faculty of medicine, UNSW, Randwick, New South Wales, Australia
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  • R. Lock
    Affiliations
    2Faculty of medicine, UNSW, Randwick, New South Wales, Australia

    3Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia
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  • T. O'Brien
    Affiliations
    1Cord and marrow transplant laboratory, Sydney Children, Randwick, New South Wales, Australia

    2Faculty of medicine, UNSW, Randwick, New South Wales, Australia

    3Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia
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      T cells modified to express tumour-directed chimeric antigen receptors (CAR) have shown clinical efficacy in early phase clinical trials. The major hurdle in CAR-T cell therapy of cancer is inefficient expansion and rapid exhaustion of infused CAR-T cells. Here we identified the factors that modify CAR-T cell function using CARs targeting CD19+ B-cell leukaemia. CAR-T cell proliferation correlated with CD19 expression on target cells suggesting limited CAR-T cell expansion in “low” antigen-expressing tumours. Increasing CAR expression using epigenetic modification of CAR-T cells promoted anti-tumour activity of CAR-T cells. We speculate that up-regulation of CAR expression may promote antigen-specific activation of CAR-T cells and improve their activity in “low” antigen-expressing tumours. Effector to target ratio appears to be the strongest factor affecting CAR-T cell function. Low density of target cells promoted effector/target conjugation, cytokine secretion and target cell killing but reduced CAR-T expansion. This effect was also demonstrated in vivo using a ‘humanised’ hematochimeric mouse model where treatment of stem cell-derived CD19+ B cells with autologous CAR-T cells mimics B cell depletion observed in human patients. Single infusion of CAR-T cells used at high target cell ratio resulted in rapid and selective elimination of human B cells. B cell depletion, however, was not sustained and resulted in complete loss of CAR-T cells demonstrating that a large number of host target cells triggers CAR-T cell inactivation justifying the use of lymphodepleting conditioning prior to CAR-T cell infusion. CAR-T cells used at low target cell ratio resulted in sustained B cell depletion that did not required lymphodepletion prior to CAR-T cell infusion. Our data provide the information that may define novel strategies to enhance therapeutic efficacy of CAR-T cells.
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