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Theranostics 2023; 13(15):5469-5482. doi:10.7150/thno.87489 This issue Cite

Research Paper

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

Keifer Kurtz1,2#, Laura Eibler3#, Megan M. Dacek1,2, Lukas M. Carter4, Darren R. Veach5,6, Samantha Lovibond3, Emma Reynaud3, Sarah Qureshy1, Michael R. McDevitt5,6, Christopher Bourne1,7, Sebastien Monette8, Blesida Punzalan1, Shireen Khayat1,2, Svena Verma2, Adam L. Kesner4, Nai-Kong V. Cheung9, Heiko Schöder3,6, Leah Gajecki3, Sarah M. Cheal1,6, Steven M. Larson1,3,6##, David A. Scheinberg1,2##, Simone Krebs3,5,6##,✉

1. Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2. Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
3. Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5. Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6. Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA.
7. Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, New York, NY 10065, USA.
8. Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY 10065, USA.
9. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
##Contributed equally as senior authors.
#Contributed equally as first authors.

✉ Corresponding author: Simone Krebs, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 77, New York, NY 10065; Email: krebssorg, Phone: 212-639-7373, Fax: 212-717-3263.

Citation:
Kurtz K, Eibler L, Dacek MM, Carter LM, Veach DR, Lovibond S, Reynaud E, Qureshy S, McDevitt MR, Bourne C, Monette S, Punzalan B, Khayat S, Verma S, Kesner AL, Cheung NKV, Schöder H, Gajecki L, Cheal SM, Larson SM, Scheinberg DA, Krebs S. Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications. Theranostics 2023; 13(15):5469-5482. doi:10.7150/thno.87489. https://www.thno.org/v13p5469.htm
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Abstract

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Rationale: The in vivo 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 in vivo and for improving their cytotoxic potency in case of treatment failure.

Methods: 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 in vivo using Thor-cells in lymphoma models.

Results: 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.

Conclusion: 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.

Keywords: CAR-T cells, reporter gene, T cell tracking, theranostic, alpha-particles

Citation styles

APA
Kurtz, K., Eibler, L., Dacek, M.M., Carter, L.M., Veach, D.R., Lovibond, S., Reynaud, E., Qureshy, S., McDevitt, M.R., Bourne, C., Monette, S., Punzalan, B., Khayat, S., Verma, S., Kesner, A.L., Cheung, N.K.V., Schöder, H., Gajecki, L., Cheal, S.M., Larson, S.M., Scheinberg, D.A., Krebs, S. (2023). Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications. Theranostics, 13(15), 5469-5482. https://doi.org/10.7150/thno.87489.

ACS
Kurtz, K.; Eibler, L.; Dacek, M.M.; Carter, L.M.; Veach, D.R.; Lovibond, S.; Reynaud, E.; Qureshy, S.; McDevitt, M.R.; Bourne, C.; Monette, S.; Punzalan, B.; Khayat, S.; Verma, S.; Kesner, A.L.; Cheung, N.K.V.; Schöder, H.; Gajecki, L.; Cheal, S.M.; Larson, S.M.; Scheinberg, D.A.; Krebs, S. Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications. Theranostics 2023, 13 (15), 5469-5482. DOI: 10.7150/thno.87489.

NLM
Kurtz K, Eibler L, Dacek MM, Carter LM, Veach DR, Lovibond S, Reynaud E, Qureshy S, McDevitt MR, Bourne C, Monette S, Punzalan B, Khayat S, Verma S, Kesner AL, Cheung NKV, Schöder H, Gajecki L, Cheal SM, Larson SM, Scheinberg DA, Krebs S. Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications. Theranostics 2023; 13(15):5469-5482. doi:10.7150/thno.87489. https://www.thno.org/v13p5469.htm

CSE
Kurtz K, Eibler L, Dacek MM, Carter LM, Veach DR, Lovibond S, Reynaud E, Qureshy S, McDevitt MR, Bourne C, Monette S, Punzalan B, Khayat S, Verma S, Kesner AL, Cheung NKV, Schöder H, Gajecki L, Cheal SM, Larson SM, Scheinberg DA, Krebs S. 2023. Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications. Theranostics. 13(15):5469-5482.

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