Journal
MOLECULAR THERAPY
Volume 25, Issue 5, Pages 1234-1247Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.03.002
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Funding
- Wellcome Trust
- Sparks
- Dubois Children's Cancer Fund
- postdoctoral research fellowship of the Dr. Mildred Scheel Foundation for Cancer Research
- German Cancer Aid (Deutsche Krebshilfe)
- Erasmus+ traineeship exchange programme of the European Union
- University of Milan-Bicocca
- GOSH NIHR Biomedical Research Centre
- Great Ormond Street Hospital Children's Charity
- Wellcome Trust [110022/Z/15/Z] Funding Source: Wellcome Trust
- Action Medical Research [2400] Funding Source: researchfish
- Cancer Research UK [14779] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1360, V4015, V1243] Funding Source: researchfish
- Sparks Charity [12WTICH13 - DCCF] Funding Source: researchfish
- The Brain Tumour Charity [16/193] Funding Source: researchfish
- Wellcome Trust [110022/Z/15/Z] Funding Source: researchfish
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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 V gamma 9V delta 2 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 V gamma 9V delta 2(+) 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 V gamma 9V delta 2 TCR were efficiently lysed, whereas cells that expressed GD2 equivalently but did not engage the V gamma 9V delta 2 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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