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Publication Detail
Avoidance of On-Target Off-Tumor Activation Using a Co-stimulation-Only Chimeric Antigen Receptor.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Fisher J, Abramowski P, Wisidagamage Don ND, Flutter B, Capsomidis A, Cheung GW-K, Gustafsson K, Anderson J
  • Publication date:
  • Journal:
    Molecular therapy : the journal of the American Society of Gene Therapy
  • Medium:
  • Print ISSN:
  • Language:
  • Addresses:
    Institute of Child Health, University College London, London WC1N 1EH, UK.
Chimeric antigen receptors (CARs) combine T cell activation with antibody-mediated tumor antigen specificity, bypassing the need for T cell receptor (TCR) ligation. A limitation of CAR technology is on-target off-tumor toxicity caused by target antigen expression on normal cells. Using GD2 as a model cancer antigen, we hypothesized that this could be minimized by using T cells expressing Vγ9Vδ2 TCR, which recognizes transformed cells in a major histocompatibility complex (MHC)-unrestricted manner, in combination with a co-stimulatory CAR that would function independently of the TCR. An anti-GD2 CAR containing a solitary endodomain derived from the NKG2D adaptor DAP10 was expressed in Vγ9Vδ2(+) T cells. Differential ligation of the CAR and/or TCR using antibody-coated beads showed that pro-inflammatory cytokine response depended on activation of both receptors. Moreover, in killing assays, GD2-expressing neuroblastoma cells that engaged the Vγ9Vδ2 TCR were efficiently lysed, whereas cells that expressed GD2 equivalently but did not engage the Vγ9Vδ2 TCR were untouched. Differentiation between X-on tumor and X-off tumor offers potential for safer immunotherapy and broader target selection.
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