Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells.

Autor:	Obajdin J; King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, London SE1 9RT, UK., Larcombe-Young D; King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, London SE1 9RT, UK., Glover M; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Kausar F; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Hull CM; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Flaherty KR; King's College London, Department of Infectious Diseases, School of Immunology and Microbial Sciences, Guy's Hospital, London SE1 9RT, UK., Tan G; King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, London SE1 9RT, UK., Beatson RE; Department of Respiratory Medicine, Division of Medicinal Sciences, University College London, London, UK., Dunbar P; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Mazza R; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Bove C; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Taylor C; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Bille A; Department of Thoracic Surgery, Guy's and St. Thomas' NHS Trust Foundation, London SE1 9RT, UK., Spillane KM; Department of Physics, King's College London, London WC2R 2LS, UK., Cozzetto D; Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London W12 0NN, UK., Vigilante A; King's College London, Centre for Stem Cells and Regenerative Medicine & Institute for Liver Studies, Guy's Hospital, London SE1 9RT, UK., Schurich A; King's College London, Department of Infectious Diseases, School of Immunology and Microbial Sciences, Guy's Hospital, London SE1 9RT, UK., Davies DM; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK., Maher J; King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, London SE1 9RT, UK; Leucid Bio Ltd, Guy's Hospital, London SE1 9RT, UK; Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD, UK. Electronic address: john.maher@kcl.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Nov 19; Vol. 5 (11), pp. 101827.
DOI:	10.1016/j.xcrm.2024.101827
Abstrakt:	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. Competing Interests: Declaration of interests J.M. is CSO, scientific founder, and shareholder of Leucid Bio. M.G., F.K., C.M.H., R.M., C.B., C.T., and D.M.D. are employees of Leucid Bio while P.D. is a former Leucid Bio employee. D.L.-Y. is undertaking a PhD studentship funded by Leucid Bio and has acted as a consultant for Leucid Bio. J.M., D.M.D., D.L.-Y., and F.K. are co-inventors on patent filings in relation to adaptor CAR technology. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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