López Cabrera, Ernesto;
(2024)
Metabolic transport blockade enhances chimeric antigen receptors T cell therapy against B cell lymphoma.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Chimeric antigen receptor (CAR) T cells have shown remarkable results against B cell malignancies, but only a minority of patients have long-term remission. The metabolic requirements of both tumour cells and activated T cells result in production of lactate and depletion of key nutrients fundamental for T cell function, like glucose and glutamine. Here, we studied the combination of CD19-specific CAR T cell therapy with pharmacological blockade of metabolic transporters against B cell lymphoma. The export of lactate is facilitated by expression of monocarboxylate transporters (MCTs). CAR T cells express high levels of MCT-1 and MCT-4 upon activation, while certain tumours predominantly express MCT-1. MCT-1 inhibition with the small molecules AZD3965 or AR-C155858 induced CAR T cell metabolic rewiring, but their effector function and phenotype remained unchanged, suggesting CAR T cells are insensitive to MCT-1 inhibition. Moreover, improved cytotoxicity in vitro and antitumoral control on mouse models was found with the combination of CAR T cells and MCT-1 blockade. Tumour and CAR T cells express high levels of the glutamine transporter ASCT-2 to sustain energy and biomass production. Pharmacological inhibition of ASCT-2 with V-9302 severely suppressed CAR T cell functions and expression of surrogate glutamine transporters like ATB0+, partially restored CAR T cell proliferation. However, glutamine-neutralizing antibodies against ASCT-2 showed limited efficacy against tumour and CAR T cells. This work highlights the potential of selective targeting metabolism via inhibition of metabolic transporters in combination with CAR T cells therapies against B cell malignancies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Metabolic transport blockade enhances chimeric antigen receptors T cell therapy against B cell lymphoma |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | 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 > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10185729 |
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