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Efficacy of MSC for steroid-refractory acute GVHD associates with MSC donor age and a defined molecular profile

Bone Marrow Transplantation volume 55, pages 2188–2192 (2020)Cite this article

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Identifying optimal MSC properties would allow for selecting the best product for patients and subsequently increase success rate. MSC for our clinical trial and hospital exemption program were all generated from rest material from pediatric and adult BM programs with the very same production process. Therefore, no major product variables have been observed, except that clinical characteristics of the twelve MSC donors showed in contrast to many other MSC programs [5] a rather wide range of MSC donor age (range 2–33, median 9.5). Donor age of MSC has been reported to associate with different molecular properties [6]. We therefore hypothesized that different MSC properties derived from young versus adult donors might impact clinical outcomes. Consequently, from patients receiving MSC derived from a single donor (n = 77), donors have been clustered based on their median age into cohorts below or above 10 years (Table 1). Cox regression analysis did not show MSC donor age to statistically impact the cumulative incidence of CR-GVHD (p value 0.119), as reported previously for other biomarkers [2]. However, a significant survival benefit for patients treated with MSC derived from young (<10 years of age) compared to older (>10 years) MSC donors (Fig. 1b, log-rank p value 0.039, n = 77) was observed. In the multivariate analysis patient age (HR 1.022, CI 1.006–1.039, p = 0.0087), severity of GVHD/liver GVHD (HR 1.356, CI 1.069–1.719, p = 0.012) and MSC donor age (HR 2.006, CI 1.091–3.687, p = 0.025) remained significantly predictive independent variables for OS (Supplementary Table 1).

Several biological properties of MSC could contribute to the age-related effects observed in the clinic. Therefore, cell viability of cultured MSC as surrogate marker for fitness was tested, as well as their ability to suppress an immune reaction. However, neither differences in cell viability nor ex vivo T-cell suppressive capacity of MSC in mixed lymphocyte reaction did associate with 1-year OS (Supplementary Fig. 1). We did also not observe major differences in circulating immune subsets in a selection of patients receiving MSC from young or old donors (Supplementary Fig. 2).

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Fig. 1: Overall survival of the different clinical cohorts and molecular profile of MSC from young donors.

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Acknowledgements

The authors thank the research technicians S. Heijhuurs, S. Hol, and Z. Stachova for processing patient materials and 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 LEW (UU 2011-5250) and UU 2015-7601 to JK.

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Author notes

  1. These authors contributed equally: Lotte E. van der Wagen, Alberto Miranda-Bedate

Authors and Affiliations

  1. Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

    Lotte E. van der Wagen & Jürgen Kuball

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

    Lotte E. van der Wagen, Alberto Miranda-Bedate, Anke Janssen, Febilla Fernando, Nagesha Appukudige, Sanne van Dooremalen, Jaap Jan Boelens & Jürgen Kuball

  3. Cell Therapy Facility, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

    Kasper Westinga & Colin de Haar

  4. Pediatric Blood and Marrow Transplant Program Prinses Maxima Centre for Pediatric Oncology, Utrecht, the Netherlands

    Rick Admiraal

  5. Center for Molecular Medicine and Regenerative Medicine Center UMC Utrecht, Utrecht University, Utrecht, the Netherlands

    Magdalena J. Lorenowicz

  6. Department of Hematology, UMC Groningen, Groningen, the Netherlands

    Gerwin Huls

  7. Department of Hematology, Amsterdam University Medical Centers, loc. VUmc Amsterdam, Amsterdam, the Netherlands

    Jeroen J. W. M. Janssen

  8. Department of Hematology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands

    Annoek E. C. Broers

  9. Department of Hematology, Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands

    Walter J. F. M. van der Velden

  10. Department of Internal Medicine, Isala klinieken Zwolle, Zwolle, the Netherlands

    Rien van Marwijk Kooy

  11. Department of Hematology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands

    Mette D. Hazenberg

  12. Department of Hematology, Princess Maxima Centrum, Utrecht, the Netherlands

    Caroline Lindemans

  13. Department of Pediatrics, Stem Cell Transplant and Cellular Therapies Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jaap Jan Boelens

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Contributions

LEW, SD, and MJL performed experiments; LEW, AMB, FF, NA, and RA analyzed results and made the figures; LEW, JJB, and JK designed the research, LEW, JK, KW, CH, CL, and JJB were responsible for patient care, LEW, AJ, AMB, GH, JJ, AB, WV, RMK, MH, and JK wrote the paper.

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Correspondence to Jürgen Kuball.

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Conflict of interest

JK is cofounder and scientific advisor of GADETA and inventor on different patents dealing with gdTCRs and their ligands as well as isolation strategies. The other authors declare no competing financial interests. JK receives research support from GADETA, Novartis and Miltenyi Biotech.

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van der Wagen, L.E., Miranda-Bedate, A., Janssen, A. et al. Efficacy of MSC for steroid-refractory acute GVHD associates with MSC donor age and a defined molecular profile. Bone Marrow Transplant 55, 2188–2192 (2020). https://doi.org/10.1038/s41409-020-0910-9

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