Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation

Abstract

Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant. 2006;38:291–7.

    Article  Google Scholar 

  2. Singh AK, McGuirk JP. Allogeneic stem cell transplantation: a historical and scientific overview. Cancer Res. 2016;76:6445–51.

    Article  CAS  Google Scholar 

  3. Appelbaum FR. Hematopoietic-cell transplantation at 50. N. Engl J Med. 2007;357:1472–5.

    Article  CAS  Google Scholar 

  4. Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19:e260–e72.

    Article  Google Scholar 

  5. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2017;64:87–91.

    Article  Google Scholar 

  6. Afessa B, Peters SG. Major complications following hematopoietic stem cell transplantation. Semin Respir Crit Care Med. 2006;27:297–309.

    Article  Google Scholar 

  7. Einsele H, Ljungman P, Boeckh M. How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation. Blood. 2020;135:1619–29.

    Article  Google Scholar 

  8. Tzannou I, Leen AM. Preventing stem cell transplantation-associated viral infections using T-cell therapy. Immunotherapy. 2015;7:793–810.

    Article  CAS  Google Scholar 

  9. Smith CJ, Quinn M, Snyder CM. CMV-specific CD8 T cell differentiation and localization: implications for adoptive therapies. Front Immunol. 2016;7:352.

    PubMed  PubMed Central  Google Scholar 

  10. Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science. 1992;257:238–41.

    Article  CAS  Google Scholar 

  11. Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N. Engl J Med. 2012;333:1038–44.

    Article  Google Scholar 

  12. O’Reilly RJ, Prockop S, Hasan AN, Koehne G, Doubrovina E. Virus-specific T-cell banks for ‘off the shelf’ adoptive therapy of refractory infections. Bone Marrow Transplant. 2016;51:1163–72.

    Article  Google Scholar 

  13. Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet. 2003;362:1375–7.

    Article  Google Scholar 

  14. Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM, et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood. 2010;116:4360–7.

    Article  CAS  Google Scholar 

  15. Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H, et al. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med. 2005;202:379–86.

    Article  CAS  Google Scholar 

  16. Blyth E, Clancy L, Simms R, Ma CK, Burgess J, Deo S, et al. Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation. Blood. 2013;121:3745–58.

    Article  CAS  Google Scholar 

  17. Bollard CM, Heslop HE. T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood. 2016;127:3331–40.

    Article  CAS  Google Scholar 

  18. Koehne G, Hasan A, Doubrovina E, Prockop S, Tyler E, Wasilewski G, et al. Immunotherapy with donor T cells sensitized with overlapping pentadecapeptides for treatment of persistent cytomegalovirus infection or viremia. Biol Blood Marrow Transpl. 2015;21:1663–78.

    Article  CAS  Google Scholar 

  19. Rauser G, Einsele H, Sinzger C, Wernet D, Kuntz G, Assenmacher M, et al. Rapid generation of combined CMV-specific CD4(+) and CD8(+) T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood. 2004;103:3565–72.

    Article  CAS  Google Scholar 

  20. Tzannou I, Watanabe A, Naik S, Daum R, Kuvalekar M, Leung KS, et al. “Mini” bank of only 8 donors supplies CMV-directed T cells to diverse recipients. Blood Adv. 2019;3:2571–80.

    Article  CAS  Google Scholar 

  21. Neuenhahn M, Albrecht J, Odendahl M, Schlott F, Dössinger G, Schiemann 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. 2017;31:2161–71.

    Article  CAS  Google Scholar 

  22. Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, Antin JH, et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood. 2013;121:5113–23.

    Article  CAS  Google Scholar 

  23. Withers B, Blyth E, Clancy LE, Yong A, Gottlieb DJ. Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells. Blood Adv. 2017;1:2193–205.

    Article  CAS  Google Scholar 

  24. Holtappels R, Böhm V, Podlech J, Reddehase MJ. CD8 T-cell-based immunotherapy of cytomegalovirus infection: “proof of concept” provided by the murine model. Med Microbiol Immunol. 2008;197:125–34.

    Article  Google Scholar 

  25. Blyth E, Withers B, Clancy L, Gottlieb D. CMV-specific immune reconstitution following allogeneic stem cell transplantation. Virulence. 2016;7:967–80.

    Article  CAS  Google Scholar 

  26. Klenerman P, Oxenius A. T cell responses to cytomegalovirus. Nat Rev Immunol. 2016;16:367–77.

    Article  CAS  Google Scholar 

  27. Gratama JW, van Esser JW, Lamers CH, Tournay C, Löwenberg B, Bolhuis RL, et al. Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection. Blood. 2001;98:1358–64.

    Article  CAS  Google Scholar 

  28. Wills MR, Poole E, Lau B, Krishna B, Sinclair JH. The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies? Cell Mol Immunol. 2015;12:128–38.

    Article  CAS  Google Scholar 

  29. Reddehase MJ, Mutter W, Münch K, Bühring HJ, Koszinowski UH. CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol. 1987;61:3102–8.

    Article  CAS  Google Scholar 

  30. Cwynarski K, Ainsworth J, Cobbold M, Wagner S, Mahendra P, Apperley J, et al. Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. Blood. 2001;97:1232–40.

    Article  CAS  Google Scholar 

  31. Reddehase MJ, Mutter W, Koszinowski UH. In vivo application of recombinant interleukin 2 in the immunotherapy of established cytomegalovirus infection. J Exp Med. 1987;165:650–6.

    Article  CAS  Google Scholar 

  32. Reddehase MJ, Jonjić S, Weiland F, Mutter W, Koszinowski UH. Adoptive immunotherapy of murine cytomegalovirus adrenalitis in the immunocompromised host: CD4-helper-independent antiviral function of CD8-positive memory T lymphocytes derived from latently infected donors. J Virol. 1988;62:1061–5.

    Article  CAS  Google Scholar 

  33. Einsele H, Roosnek E, Rufer N, Sinzger C, Riegler S, Löffler J, et al. Infusion of cytomegalovirus (CMV)–specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood. 2002;99:3916–22.

    Article  CAS  Google Scholar 

  34. Pei XY, Zhao XY, Chang YJ, Liu J, Xu LP, Wang Y. et al. Cytomegalovirus-specific T-cell transfer for refractory cytomegalovirus infection after haploidentical stem cell transplantation: the quantitative and qualitative immune recovery for cytomegalovirus. J Infect Dis. 2017;216:945–56.

    Article  CAS  Google Scholar 

  35. Zhao XY, Pei XY, Chang YJ, Yu XX, Xu LP, Wang Y, et al. First-line therapy with donor-derived human cytomegalovirus (HCMV)-specific T cells reduces persistent HCMV infection by promoting antiviral immunity after allogenic stem cell transplantation. Clin Infect Dis. 2020;70:1429–37.

    Article  CAS  Google Scholar 

  36. Xu L, Chen H, Chen J, Han M, Huang H, Lai Y, et al. The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J Hematol Oncol. 2018;11:33.

    Article  Google Scholar 

  37. Fabrizio VA, Rodriguez-Sanchez MI, Mauguen A, Dahi PB, Doubrovina E, O’Reilly RJ, et al. Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses. Blood Adv. 2021;5:496–503.

    Article  CAS  Google Scholar 

  38. Yaguchi T, Kobayashi A, Inozume T, Morii K, Nagumo H, Nishio H, et al. Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses. Cell Mol Immunol. 2018;15:953–62.

    Article  CAS  Google Scholar 

  39. Thomas S, Klobuch S, Podlech J, Plachter B, Hoffmann P, Renzaho A, et al. Evaluating human T-Cell therapy of cytomegalovirus organ disease in HLA-transgenic mice. PLoS Pathog 2015;11:e1005049.

Download references

Acknowledgements

We thank Immunotech Biopharm Ltd. and iCELL Co. Ltd. for their aid in the organization of the clinical-grade expansion of CMV-CTLs. The authors thank every patient involved in the study and every faculty member of Peking University People’s Hospital who participated in this study. This work was supported by the National Key Research and Development Program of China (grant number 2017YFA0104500), the National Natural Science Foundation of China (grant numbers 81900137, 81530046 81930004, and 82070184), the Innovative Research Groups of the National Natural Science Foundation of China (grant number 81621001), and Peking University People’s Hospital Research and Development Funds (grant number RDY2019-34, RS2021-01).

Author information

Authors and Affiliations

Authors

Contributions

HXJ and ZXY conceived and designed the study; PXY and LXF performed the experiments and collected and analyzed the data; SQN participated in the animal experiments; LM, MXD, SYQ, CYH, XLP, and YW performed the clinical study; CYJ, LKY, and ZXH helped design the study; HXJ and PXY wrote the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Xiao-Jun Huang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pei, XY., Liu, XF., Zhao, XY. et al. Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation. Cell Mol Immunol 19, 482–491 (2022). https://doi.org/10.1038/s41423-021-00829-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-021-00829-y

Keywords

This article is cited by

Search

Quick links