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Immunotherapy

Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT

Leukemia volume 31, pages 2161–2171 (2017)Cite this article

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Abstract

Cytomegalovirus (CMV) infection is a common, potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed prospectively the safety and efficacy of stem cell-donor- or third-party-donor-derived CMV-specific T cells for the treatment of persistent CMV infections after allo-HSCT in a phase I/IIa trial. Allo-HSCT patients with drug-refractory CMV infection and lacking virus-specific T cells were treated with a single dose of ex vivo major histocompatibility complex-Streptamer-isolated CMV epitope-specific donor T cells. Forty-four allo-HSCT patients receiving a T-cell-replete (D+ repl; n=28) or T-cell-depleted (D+ depl; n=16) graft from a CMV-seropositive donor were screened for CMV-specific T-cell immunity. Eight D+ depl recipients received adoptive T-cell therapy from their stem cell donor. CMV epitope-specific T cells were well supported and became detectable in all treated patients. Complete and partial virological response rates were 62.5% and 25%, respectively. Owing to longsome third-party donor (TPD) identification, only 8 of the 57 CMV patients transplanted from CMV-seronegative donors (D−) received antigen-specific T cells from partially human leukocyte antigen (HLA)-matched TPDs. In all but one, TPD-derived CMV-specific T cells remained undetectable. In summary, adoptive transfer correlated with functional virus-specific T-cell reconstitution in D+ depl patients. Suboptimal HLA match may counteract expansion of TPD-derived virus-specific T cells in D− patients.

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Acknowledgements

This work was supported by the Federal Ministry of Education and Research and the SFB (Sonderforschungsbereich/Collaborative Research Centre) TR36 (TP-A10).

Author information

Author notes

  1. M Neuenhahn, J Albrecht, D H Busch and G U Grigoleit: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany

    M Neuenhahn, J Albrecht, F Schlott, G Dössinger, M Schiemann, S Lakshmipathi & D H Busch

  2. Clinical Cooperation Group ‘Immune Monitoring’, Helmholtz Center Munich (Neuherberg) and Technische Universität München, Munich, Germany

    M Neuenhahn, J Albrecht & D H Busch

  3. Clinical Cooperation Group ‘‘Antigen-specific Immunotherapy’’, Helmholtz Center Munich (Neuherberg) and Technische Universität München, Munich, Germany

    M Neuenhahn, M Schiemann & D H Busch

  4. DZIF – National Centre for Infection Research, Munich, Germany

    M Neuenhahn & D H Busch

  5. Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany

    M Odendahl & T Tonn

  6. Institute of Anaesthesiology, Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Munich, Germany

    K Martin

  7. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    D Bunjes & S Harsdorf

  8. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    E M Weissinger

  9. Department of Hematology and Oncology, St Franziskus-Hospital, Flensburg, Germany

    H Menzel

  10. Department of Internal Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    M Verbeek

  11. Medical Clinic Hematology, Oncology and Tumorimmunology, Charité Campus Benjamin Franklin, Berlin, Germany

    L Uharek

  12. Bone Marrow Transplantation Unit UKE, Hamburg, Germany

    N Kröger

  13. III. Medical Department, Hematology, Oncology and Pneumology, University Medical Center Mainz, Mainz, Germany

    E Wagner

  14. Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany

    G Kobbe & T Schroeder

  15. GMP Core Facility, University of Heidelberg, Heidelberg, Germany

    M Schmitt

  16. Internal Medicine I, José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical School, Homburg, Saar, Germany

    G Held

  17. Department of Internal Medicine III, Haematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany

    W Herr

  18. Juno Cell Therapeutics, formerly Stage Cell Therapeutics, Goettingen, Germany

    L Germeroth

  19. Institute for Transfusion Medicine and Immunohematology, Johann Wolfgang Goethe University, and German Red Cross Blood Donor Service, Frankfurt, Germany

    H Bonig

  20. Transfusion Medicine, Medical Faculty Carl Gustav Carus, Technische Universität Dresden (TUD), Dresden, Germany

    T Tonn

  21. Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany

    T Tonn

  22. Department of Internal Medicine II, University Hospital Würzburg, Wuerzburg, Germany

    H Einsele & G U Grigoleit

  23. Focus Group ‘Clinical Cell Processing and Purification’, Institute for Advanced Study, Technische Universität München, Munich, Germany

    D H Busch

Authors
  1. M Neuenhahn
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  2. J Albrecht
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  3. M Odendahl
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  4. F Schlott
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  5. G Dössinger
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  6. M Schiemann
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  7. S Lakshmipathi
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  8. K Martin
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  9. D Bunjes
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  11. E M Weissinger
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  13. M Verbeek
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  14. L Uharek
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  15. N Kröger
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  16. E Wagner
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  17. G Kobbe
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  18. T Schroeder
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  19. M Schmitt
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  20. G Held
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  21. W Herr
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  23. H Bonig
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  24. T Tonn
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  25. H Einsele
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  26. D H Busch
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  27. G U Grigoleit
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Corresponding author

Correspondence to M Neuenhahn.

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Competing interests

LG is an employee of and holds shares in Stage Cell Therapeutics, Göttingen, Germany; now Juno Therapeutics GmbH, Munich, Germany. DHB invented the Streptamer technology and holds shares of Juno Cell Therapeutics Inc. The other authors declare no conflict of interest.

Additional information

Author contributions

MN, JA, MO, GD, FS, SL, HB, TT, KM and MS performed purification or monitoring analyses; JA, MN and GUG analyzed the data; UG, DHB, HE and LG conceived the study; MN, MO, JA and DHB planned the monitoring experiments; GUG, DHB, SH, EMW, HM, MV, LU, NK, EW, GK, MS and GH were responsibly involved in patient treatment; DHB, HE, TT, HB and LG performed and supervised the clinical cell selection; MN, JA, HB, HE, GUG and DHB wrote the paper.

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Neuenhahn, M., Albrecht, J., Odendahl, M. et al. Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT. Leukemia 31, 2161–2171 (2017). https://doi.org/10.1038/leu.2017.16

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