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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

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).

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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.

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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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