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Immunotherapy

Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells

Leukemia volume 29, pages 1839–1846 (2015)Cite this article

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Abstract

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II–IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485–5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144–4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389–0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

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Acknowledgements

We thank the research technicians S Heijhuurs, S Hol and Z Stachova for processing patient materials and also thank the multiplex immunoassay core facility at the UMC Utrecht for their cooperation. This work was partly supported by a grant from the Dutch Cancer Society to LEvdW (UU 2011-5250).

Author Contributions

LCJtB, CM, LEvdW, JK, JJB and CAL designed, interpreted and analyzed the data. CM, LEvdW and MP performed experiments. CM, LEvdW, LCJtB and JK wrote the manuscript. NMW, ICMS-C, JK, LCJtB and JJB designed the study. EJP, ES, KAT, KW, MB, AECB, MLHC, GI, JJJ, CH, SZ, GH, MP and NMW provided suggestions on the experiments and commented on the manuscript.

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Author notes

  1. L C J te Boome, C Mansilla and L E van der Wagen: LCJtB, CM and LEvdW contributed equally to this work and share first authorship.

  2. N M Wulffraat and I C M Slaper-Cortenbach: NMW and ICMS-C contributed equally to this work.

Authors and Affiliations

  1. Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands

    L C J te Boome, L E van der Wagen, E J Petersen, M L H Cuijpers & J Kuball

  2. UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    C Mansilla, L E van der Wagen, C A Lindemans, E Spierings, K A Thus, M Plantinga, J J Boelens, N M Wulffraat & J Kuball

  3. UMC Utrecht, Paediatrics – Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands,

    C A Lindemans, M Bierings, J J Boelens & N M Wulffraat

  4. Department of Clinical Pharmacy – Cell Therapy Facility, UMC Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands,

    K Westinga & I C M Slaper-Cortenbach

  5. Department of Haematology, Erasmus MC Rotterdam, Rotterdam, The Netherlands,

    A E C Broers

  6. Department of Haematology, UMC Groningen, Groningen, The Netherlands,

    G W van Imhoff

  7. Department of Haematology, VU MC, Amsterdam, The Netherlands

    J J Janssen

  8. Department of Haematology, AMC, Amsterdam, The Netherlands

    C Huisman & S Zeerleder

  9. Department of Haematology, Radboud UMC Nijmegen, Amsterdam, The Netherlands

    G Huls

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  1. L C J te Boome
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Correspondence to J Kuball.

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te Boome, L., Mansilla, C., van der Wagen, L. et al. Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells. Leukemia 29, 1839–1846 (2015). https://doi.org/10.1038/leu.2015.89

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