Obajdin, J;
Larcombe-Young, D;
Glover, M;
Kausar, F;
Hull, CM;
Flaherty, KR;
Tan, G;
... Maher, J; + view all
(2024)
Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells.
Cell Reports Medicine
, 5
(11)
, Article 101827. 10.1016/j.xcrm.2024.101827.
Preview |
Text
main-3.pdf - Published Version Download (8MB) | Preview |
Abstract
NKG2D ligands (NKG2DLs) are broadly expressed in cancer. To target these, we describe an adaptor chimeric antigen receptor (CAR) termed NKG2D/Dap10-12. Herein, T cells are engineered to co-express NKG2D with a fusion protein that comprises Dap10 joined to a Dap12 endodomain. NKG2D/Dap10-12 T cells elicit compelling efficacy, eradicating or controlling NKG2DL-expressing tumors in several established xenograft models. Importantly, durable responses, long-term survival, and rejection of tumor re-challenge are reproducibly achieved. Efficacy is markedly superior to a clinical stage CAR analog, comprising an NKG2D-CD3ζ fusion. Structure-function analysis using an extended CAR panel demonstrates that potency is dependent on membrane proximity of signaling units, high NKG2D cell surface expression, adaptor structure, provision of exogenous Dap10, and inclusion of one rather than three immune tyrosine activation motifs per signaling unit. Potent therapeutic impact of NKG2D/Dap10-12 T cells is also underpinned by enhanced oxidative phosphorylation, reduced senescence, and transcriptomic re-programming for increased ribosomal biogenesis.
| Type: | Article |
|---|---|
| Title: | Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.xcrm.2024.101827 |
| Publisher version: | https://doi.org/10.1016/j.xcrm.2024.101827 |
| Language: | English |
| Additional information: | © 2024 The Author(s). Published by Elsevier Inc. 1 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Dap10, Dap12, NKG2D, adaptor, chimeric antigen receptor, NK Cell Lectin-Like Receptor Subfamily K, Humans, Animals, Mice, Receptors, Chimeric Antigen, Immunotherapy, Adoptive, T-Lymphocytes, Cell Line, Tumor, Neoplasms, Xenograft Model Antitumor Assays, Immunotherapy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10200987 |
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
