Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2024-11-19
Date Acceptance
2024-10-21
Citation
Cell Reports Medicine, 2024, 5 (11)
ISSN
2666-3791
Publisher
Elsevier
Journal / Book Title
Cell Reports Medicine
Volume
5
Issue
11
Copyright Statement
© 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39566469
PII: S2666-3791(24)00598-6
Subjects
Cell Biology
CHIMERIC ANTIGEN RECEPTOR
EXPRESSION
Life Sciences & Biomedicine
LIGANDS
Medicine, Research & Experimental
NKG2D
OVARIAN-CANCER
PROLIFERATION
Research & Experimental Medicine
Science & Technology
Publication Status
Published
Coverage Spatial
United States
Article Number
101827
Date Publish Online
2024-11-19