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Ali M, Giannakopoulou E, Li Y, et al. T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes. Nat Biotechnol. 2021;doi: 10.1038/s41587-021-01089-x.
Ali, M., Giannakopoulou, E., Li, Y., Lehander, M., Virding Culleton, S., Yang, W., Knetter, C., Odabasi, M. C., Bollineni, R. C., Yang, X., Foldvari, Z., Böschen, M. L., Taraldsrud, E., Strønen, E., Toebes, M., Hillen, A., Mazzi, S., de Ru, A. H., Janssen, G. M. C., Kolstad, A., Tjønnfjord, G. E., Lie, B. A., Griffioen, M., Lehmann, S., Osnes, L. T., Buechner, J., Garcia, K. C., Schumacher, T. N., van Veelen, P. A., Leisegang, M., Jacobsen, S. E. W., Woll, P., & Olweus, J. (2021). T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes. Nature biotechnology, . https://doi.org/10.1038/s41587-021-01089-x
Ali, Muhammad, et al. "T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes." Nature biotechnology vol. (2021). doi: https://doi.org/10.1038/s41587-021-01089-x
Ali M, Giannakopoulou E, Li Y, Lehander M, Virding Culleton S, Yang W, Knetter C, Odabasi MC, Bollineni RC, Yang X, Foldvari Z, Böschen ML, Taraldsrud E, Strønen E, Toebes M, Hillen A, Mazzi S, de Ru AH, Janssen GMC, Kolstad A, Tjønnfjord GE, Lie BA, Griffioen M, Lehmann S, Osnes LT, Buechner J, Garcia KC, Schumacher TN, van Veelen PA, Leisegang M, Jacobsen SEW, Woll P, Olweus J. T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes. Nat Biotechnol. 2021 Dec 06; doi: 10.1038/s41587-021-01089-x. Epub 2021 Dec 06. PMID: 34873326.
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Nat Biotechnol. 2021 Dec 06; doi: 10.1038/s41587-021-01089-x. Epub 2021 Dec 06.

T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

Nature biotechnology

Muhammad Ali, Eirini Giannakopoulou, Yingqian Li, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Cathrine Knetter, Mete Can Odabasi, Ravi Chand Bollineni, Xinbo Yang, Zsofia Foldvari, Maxi-Lu Böschen, Eli Taraldsrud, Erlend Strønen, Mireille Toebes, Amy Hillen, Stefania Mazzi, Arnoud H de Ru, George M C Janssen, Arne Kolstad, Geir Erland Tjønnfjord, Benedicte A Lie, Marieke Griffioen, Sören Lehmann, Liv Toril Osnes, Jochen Buechner, K Christopher Garcia, Ton N Schumacher, Peter A van Veelen, Matthias Leisegang, Sten Eirik W Jacobsen, Petter Woll, Johanna Olweus

Affiliations

  1. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
  2. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  3. Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
  4. Charité - Universitätsmedizin Berlin, Institute of Immunology, Berlin, Germany.
  5. Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  6. Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  7. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  8. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
  9. Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
  10. Department of Haematology, Oslo University Hospital and KG Jebsen Center for B cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  11. Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.
  12. Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
  13. Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
  14. Department of Immunology, Oslo University Hospital, Oslo, Norway.
  15. Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
  16. Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, the Netherlands.
  17. David and Etta Jonas Center for Cellular Therapy, The University of Chicago, Chicago, IL, USA.
  18. German Cancer Consortium, partner site Berlin, Berlin, Germany.
  19. German Cancer Research Center, Heidelberg, Germany.
  20. Karolinska University Hospital, Stockholm, Sweden.
  21. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  22. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. [email protected].
  23. K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. [email protected].

PMID: 34873326 DOI: 10.1038/s41587-021-01089-x

Abstract

Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

© 2021. The Author(s).

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