Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications

The dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence and for improving their cytotoxic potency in case of treatment failure. Here we...

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Bibliographic Details
Published in:Theranostics 2023-01, Vol.13 (15), p.5469-5482
Main Authors: Kurtz, Keifer, Eibler, Laura, Dacek, Megan M, Carter, Lukas M, Veach, Darren R, Lovibond, Samantha, Reynaud, Emma, Qureshy, Sarah, McDevitt, Michael R, Bourne, Christopher, Monette, Sebastien, Punzalan, Blesida, Khayat, Shireen, Verma, Svena, Kesner, Adam L, Cheung, Nai-Kong V, Schöder, Heiko, Gajecki, Leah, Cheal, Sarah M, Larson, Steven M, Scheinberg, David A, Krebs, Simone
Format: Article
Language:English
Subjects:
Antineoplastic Agents - metabolism
Immunotherapy, Adoptive - methods
Positron Emission Tomography Computed Tomography
Radioimmunotherapy
Radioisotopes - metabolism
Research Paper
T-Lymphocytes - metabolism
Tissue Distribution
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Summary:The dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence and for improving their cytotoxic potency in case of treatment failure. Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer using Thor-cells in lymphoma models. We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies.
ISSN:1838-7640
1838-7640
DOI:10.7150/thno.87489