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

Authors: 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.
Article Title: Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications
Abstract: 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. © The author(s).
Keywords: controlled study; protein expression; human cell; nonhuman; antineoplastic agents; positron emission tomography; antineoplastic agent; sensitivity and specificity; binding affinity; t lymphocyte; t-lymphocytes; mouse; metabolism; tumor localization; animal experiment; animal model; in vivo study; antineoplastic activity; cytotoxicity; correlation analysis; isotope labeling; tissue distribution; dosimetry; lymphoma; patient safety; reporter gene; adoptive transfer; radioisotope; radioimmunotherapy; radioisotopes; adoptive immunotherapy; immunotherapy, adoptive; cd19 antigen; single chain fragment variable antibody; alpha radiation; procedures; yttrium 86; cell engineering; tetraxetan; hapten; alpha-particles; human; female; article; positron emission tomography-computed tomography; positron emission tomography computed tomography; theranostic; theranostic nanomedicine; chimeric antigen receptor t-cell immunotherapy; car-t cells; t cell tracking
Journal Title: Theranostics
Volume: 13
Issue: 15
ISSN: 1838-7640
Publisher: Ivyspring International Publisher  
Date Published: 2023-01-01
Start Page: 5469
End Page: 5482
Language: English
DOI: 10.7150/thno.87489
PUBMED: 37908719
PROVIDER: scopus
PMCID: PMC10614694
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Simone Krebs -- Source: Scopus
Citation Impact
MSK Authors
  1. Nai-Kong Cheung
    627 Cheung
  2. Michael R Mcdevitt
    142 Mcdevitt
  3. Darren Veach
    87 Veach
  4. Heiko Schoder
    489 Schoder
  5. Sebastien Monette
    138 Monette
  6. Steven M Larson
    941 Larson
  7. Sarah Marie Cheal
    46 Cheal
  8. Simone Susanne Krebs
    45 Krebs
  9. Adam Leon Kesner
    42 Kesner
  10. Lukas M Carter
    58 Carter
  11. Megan Dacek
    17 Dacek
  12. Christopher Bourne
    13 Bourne
  13. Keifer Gary Kurtz
    9 Kurtz
  14. Laura Eibler
    4 Eibler
  15. Shireen Shiraz Khayat
    2 Khayat