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.

  • Letter
  • Published:

Stem cell transplantation

Posttransplant cyclophosphamide after allogeneic hematopoietic cell transplantation mitigates the immune activation induced by previous nivolumab therapy

Leukemia volume 34, pages 3420–3425 (2020)Cite this article

Subjects

Abstract

Patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT) after the use of PD-1 inhibitors seem to be at a higher risk of developing acute graft-versus-host disease (aGHVD) through etiopathogenetic mechanisms not fully elucidated. Herein, we investigated the effect of nivolumab administered prior to allo-HCT on the following early T-cell reconstitution and its modulation by the GVHD prophylaxis (tacrolimus/sirolimus vs. posttransplant cyclophosphamide [PTCY]). In all nivolumab-exposed patients we detected circulating nivolumab in plasma for up to 56 days after allo-HCT. This residual nivolumab was able to bind and block PD-1 on T-cells at day 21 after allo-HCT, inducing a T cell activation that was differentially modulated depending on the GVHD prophylactic regimen. Among patients receiving tacrolimus/sirolimus, nivolumab-exposed patients had a higher incidence of severe aGVHD and a more effector T-cell profile compared with anti-PD-1-naïve patients. Conversely, patients receiving PTCY-based prophylaxis showed a similar risk of aGVHD and T-cell profile irrespective of the previous nivolumab exposure. In conclusion, nivolumab persists in plasma after transplantation, binds to allogeneic T cells and generates an increased T-cell activation. This T-cell activation status can be mitigated with the use of PTCY, thus reducing the risk of aGVHD.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Circulating levels of nivolumab are detectable after allo-HCT and block PD-1 expression on CD4 and CD8 T cells.
Fig. 2: PTCY-based prophylaxis induces a more tolerant T cell profile at day 21 after allo-HCT in patients pre-treated with nivolumab.

Similar content being viewed by others

References

  1. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.

    Article  Google Scholar 

  2. Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, et al. Nivolumab for relapsed/refractory classic hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol. 2018;36:1428–39.

    Article  CAS  Google Scholar 

  3. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwai Y, Yagita H, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. 2003;171:1272–7.

    Article  CAS  Google Scholar 

  4. Holderried Taw, Fraccaroli A, Schumacher M, Heine A, Brossart P, Stelljes M, et al. The role of checkpoint blockade after allogeneic stem cell transplantation in diseases other than Hodgkin’s Lymphoma. Bone Marrow Transpl. 2019;54:1662–7.

    Article  CAS  Google Scholar 

  5. Merryman RW, Kim HT, Zinzani PL, Carlo-Stella C, Ansell SM, Perales MA, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017;129:1380–8.

    Article  CAS  Google Scholar 

  6. Schoch LK, Cooke KR, Wagner-Johnston ND, Gojo I, Swinnen LJ, Imus P, et al. Immune checkpoint inhibitors as a bridge to allogeneic transplantation with post-transplant cyclophosphamide. Blood Adv. 2018;2:2226–9.

    Article  Google Scholar 

  7. Kanakry CG, Coffey DG, Towlerton AM, Vulic A, Storer BE, Chou J, et al. Origin and evolution of the T cell repertoire after post-transplantation cyclophosphamide. JCI Insight. 2016;1:e86252.

    Article  Google Scholar 

  8. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Investig. 2019;129:2357–73.

    Article  Google Scholar 

  9. Kanakry CG, Ganguly S, Zahurak M, Bolanos-Meade J, Thoburn C, Perkins B, et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to post-transplantation cyclophosphamide. Sci Transl Med. 2013;5:211ra157.

    Article  Google Scholar 

  10. Ikegawa S, Meguri Y, Kondo T, Sugiura H, Sando Y, Nakamura M, et al. PTCy ameliorates GVHD by restoring regulatory and effector T-cell homeostasis in recipients with PD-1 blockade. Blood Adv. 2019;3:4081–94.

    Article  Google Scholar 

  11. Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115:3224–30.

    Article  CAS  Google Scholar 

  12. Parody R, Lopez-Corral L, Lopez-Godino O, Martinez C, Martino R, Solano C, et al. GvHD prophylaxis with tacrolimus plus sirolimus after reduced intensity conditioning allogeneic transplantation: results of a multicenter study. Bone Marrow Transpl. 2016;51:1524–6.

    Article  CAS  Google Scholar 

  13. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.

    Article  CAS  Google Scholar 

  14. Ni X, Song Q, Cassady K, Deng R, Jin H, Zhang M, et al. PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells. J Clin Investig. 2017;127:1960–77.

    Article  Google Scholar 

  15. Kanakry CG, O’Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, et al. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32:3497–505.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the patients and healthy individuals from the Vall d’Hebron University Hospital that enrolled in the study, as well as the Cellex Foundation for providing research facilities and equipment. This work was supported by the Instituto de Salud Carlos III Fondo de Investigaciones Sanitarias (FIS16/01433, PB; PI17/00950, MC, and PI17/00943, FB) and co-financed by the European Regional Development Fund (ERDF). A PERIS 2018–2020 grant from the Generalitat de Catalunya (BDNS357800, PB), Asociación Española Contra el Cáncer (Ideas Semilla 2019, P.B and LABAE18014CRES, MC) and Gilead Fellowships (GLD16/00144, GLD18/00047, FB). MC holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012–12018).

Author information

Authors and Affiliations

  1. Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital (HUVH), Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    Juan C. Nieto, Elisa Roldán, Isabel Jiménez, Laura Fox, Júlia Carabia, Guillermo Ortí, Lluís Puigdefàbregas, Laura Gallur, Gloria Iacoboni, Priyanka Raheja, Ana Pérez, Sabela Bobillo, Olga Salamero, Carlos Palacio, David Valcárcel, Marta Crespo, Francesc Bosch & Pere Barba

Authors
  1. Juan C. Nieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisa Roldán
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabel Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Júlia Carabia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guillermo Ortí
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lluís Puigdefàbregas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Laura Gallur
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gloria Iacoboni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Priyanka Raheja
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ana Pérez
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sabela Bobillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Olga Salamero
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Carlos Palacio
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. David Valcárcel
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Marta Crespo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Francesc Bosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Pere Barba
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: JCN, MC, and PB Technical procedures: JCN Sample processing and data collection: ER, IJ, LF, JC, GO, LLP, LG, GI, PR, AP, OS, and CP. Data analysis and interpretation: JCN, SB, DV, FB, MC, and PB. Manuscript writing: All authors. Final approval of manuscript: All authors.

Corresponding author

Correspondence to Pere Barba.

Ethics declarations

Conflict of interest

PB declares having received honoraria from Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, not related with the present article. MC has received research funding from Karyopharm, Pharmacyclics, Roche, Arqule and AstraZeneca, not related with the present article. FB has received research funding and honoraria from Roche, Celgene, Takeda, AstraZeneca, Novartis, Abbie and Janssen, not related with the present article.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nieto, J.C., Roldán, E., Jiménez, I. et al. Posttransplant cyclophosphamide after allogeneic hematopoietic cell transplantation mitigates the immune activation induced by previous nivolumab therapy. Leukemia 34, 3420–3425 (2020). https://doi.org/10.1038/s41375-020-0851-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-0851-8

This article is cited by

Search

Advanced search

Quick links