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Adoptive transfer of cellular immunity against cytomegalovirus by virus-specific lymphocytes from a third-party family donor

Bone Marrow Transplantation volume 53, pages 1351–1355 (2018)Cite this article

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Infection remains a major challenge after hematopoietic stem cell transplantation [1]. In transplant recipients, reactivation of herpes viruses, especially of the human cytomegalovirus (CMV), is associated with severe and fatal complications. CMV is a life-long persisting virus with a seroprevalence between 45 and 100% in the general adult population [2]. Whereas symptomatic CMV infection of healthy individuals is rare, in immunodeficient patients, such as transplant recipients, CMV infection or reactivation commonly manifests as a life-threatening disease affecting different organ systems. Transplant recipients with CMV viremia are usually treated with antiviral drugs [3]. However, myelotoxicity as well as mutations of the viral DNA sequence may limit the use of these drugs [3,4,5]. Thus, in selected cases alternative therapeutic options are mandatory.

It was then decided to treat the patient with CMV-specific lymphocytes of her HLA haploidentical sister who was CMV IgG-positive. Manufacturing of CMV-specific T cells was carried out at Hannover Medical School with the CliniMACS® Plus Instrument and GMP PepTivator® HCMVpp65 for antigenic restimulation, as described previously [6, 7]. Enrichment of IFN-γ-secreting CMV-specific T cells was performed by immunomagnetic separation using the CliniMACS Cytokine Capture System (Miltenyi Biotec, Bergisch Gladbach, Germany), consisting of the CliniMACS Catchmatrix and IFN-γ Enrichment Reagents. The final T-cell product had a viability of 80% with a purity of 41.8% CMV-specific IFN-γ+ T cells. Selection of the donor was based on the CMV serostatus and the presence of CMV-specific T cells as specified in Table 1. The patient received 2.5 × 104 CD3+ cells/kg body weight (12.3 ml) of CMV-VSTs on day 96 after PBSCT. CMV DNA, cellular CMV immunity, and leukocyte numbers were monitored before and after transfer of CMV-specific T cells. To determine viral load, CMV DNA was purified from blood samples using the Abbott m2000sp automated nucleic acid extraction system (Abbott, Wiesbaden, Germany). The viral load was quantified with the Abbott m2000rt real-time PCR system using the Abbott RealTime CMV amplification reagent kit according to the manufacturer’s instructions. The detection limit of this assay is 40 copies (62.4 IU)/ml.

Table 1 Cytomegalovirus (CMV)-specific donor T cells
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Acknowledgements

We are grateful to Monika Huben, Anja König, Nicole Neuman, Martina Praast, and Dörthe Rokitta for their excellent technical assistance.

Author contributions

D.W.B., B.E.V., M.L., R.B., and M.K. were involved in the conception and design of the study. M.K., N.K.S., V.K., and D.W.B. provided the samples. M.L., M.K., B.M.K., M.F., and A.H. were involved in the collection and assembly of data. B.E.V., B.M.K., and R.B.L. were involved in the donor selection, quality control of the CMV-VSTs, and the final release of the T-cell product. M.L. and M.K. were involved in data analysis and interpretation. M.L., M.K., and P.H.O. wrote the manuscript. All the authors gave final approval of the manuscript.

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Authors and Affiliations

  1. Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Monika Lindemann, Andreas Heinold & Peter A. Horn

  2. Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany

    Britta Eiz-Vesper, Sabine Tischer & Rainer Blasczyk

  3. Department of Bone Marrow Transplantation, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Nina K. Steckel, Vesna Klisanin, Dietrich W. Beelen & Michael Koldehoff

  4. Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Melanie Fiedler

  5. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    Britta Maecker-Kolhoff

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Correspondence to Monika Lindemann.

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Lindemann, M., Eiz-Vesper, B., Steckel, N.K. et al. Adoptive transfer of cellular immunity against cytomegalovirus by virus-specific lymphocytes from a third-party family donor. Bone Marrow Transplant 53, 1351–1355 (2018). https://doi.org/10.1038/s41409-018-0209-2

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