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Activity of ex vivo graft and DLI Engineering within the last decade increases, a survey from the EBMT Cellular Therapy & Immunobiology Working Party

Bone Marrow Transplantation volume 58, pages 719–722 (2023)Cite this article

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“Graft engineering” is used since decades to reduce graft-versus-host-disease (GVHD) and enhance graft-versus-leukemia (GVL) effects after allogeneic stem cell transplantation (allo-HCT) [1]. Clinical-grade magnetic beads and devices do not only allow to specifically enrich or deplete allografts, but also eliminate the GVHD-causing repertoires of donor lymphocyte infusions (DLI). Graft engineering can be performed by selection of CD34+ cells or depletion of T cells [1]. In the past decade, CD3 depletion has been frequently replaced by specific αβT cell depletion, as preserved donor γδT cells combined with NK cells decrease infections and maintain GVL effects early after transplantation [1]. CD45RA-depleted grafts have been proposed as a next step to further avoid toxicities and maintain activity against many infections, as CD45RA-positive naive T cells are the major cause of GVHD [2]. After allo-HCT, prophylactic and pre-emptive DLI are administered routinely to prevent infections and reduce the risk of relapse. Dosing of DLI is usually linked to timing and donor match grade, with lower doses early after allo-HCT and/or haploidentical donors to avoid GVHD while still inducing GVL [3]. The difficulty to truly balance GVHD/GVL-effects by only adjusting timing and dosing of DLI is illustrated in several recent surveys analyzing practice and outcome of DLI [4, 5], which highlight also the substantial variations in daily practice of prophylactic and preemptive unmodified DLI. To more appropriately balance GVHD/GVL-effects, CD45RA-depleted DLI has been explored in multiple centers to enable earlier DLIs.

To better understand the development of the field of graft engineering within the context of many competing transplantation platforms, the EBMT Cellular Therapy & Immunobiology Working Party (CTIWP) conducted a survey among EBMT centers to inventory graft and DLI engineering modalities, as well as reimbursement conditions between January 2011 and December 2020. Information on the number of patients receiving graft engineering (e.g. CD34 selection, αβTCR depletion, αβTCR/CD19 depletion, CD3 depletion, CD3/CD19 depletion and CD45RA depletion) and DLI (e.g. Treg depletion, CD45RA depletion, administration selection of antigen specific T cells or other types of DLI modification were) was obtained from the centers. Responses were received from 115 participating EBMT centers, active in 30 countries (response rate 27%). 36% (n = 41) of the responding centers performed graft engineering (adults n = 10; pediatrics n = 18; adults & pediatrics n = 13) (Table 1A).

Table 1 A. Clinical practice of graft engineering. B. Clinical practice of modified donor lymphocyte infusions (DLI).
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Data availability

The data that support the findings of this study are available from EBMT Cellular Therapy & Immunobiology Working Party but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of EBMT Cellular Therapy & Immunobiology Working Party.

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Acknowledgements

We thank all the participating EBMT affiliated centers listed in Supplementary Material.

Funding

Funding for this study was provided by the KWF UU 2015-7553 to MdW; KWF, UU 2018-11393, UU 2018-11979, UU 2020-12586, UU 2021- 13043 to JK and 2021-13493 to MdW and JK.

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Authors and Affiliations

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

    M. A. de Witte & J. Kuball

  2. EBMT Statistical Unit, Leiden, The Netherlands

    J. E. Mooyaart

  3. EBMT Leiden Study Unit, Leiden, The Netherlands

    J. D. Hoogenboom

  4. Institut Paoli-Calmettes, Centre de Lutte Contre le Cancer; Centre d’Investigations Cliniques en Biothérapies, Université d’Aix-Marseille, Inserm, CBT 1409, Marseille, France

    C. Chabannon

  5. Service d’Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), INSERM, Paris, France

    F. Malard

  6. San Raffaele Scientific Institute, Hematology and Bone marrow Transplantation Unit, Milan, Italy

    A. Ruggeri

Authors
  1. M. A. de Witte
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  7. J. Kuball
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Contributions

JM and JH collected data. MdW, JM and JK analyzed data. MdW, JM, AR and JK designed the study. MdW, CC, FM, AR, JK wrote the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to J. Kuball.

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Competing interests

JK is inventor on multiple patents dealing with gdTCRs, ligands, isolation strategies of engineered immune cells. JK is cofounder and shareholder of Gadeta (www.gadeta.nl). JK and MdW received research, advisor and clinical study support from Miltenyi Biotech. JK received further research support from Novartis and Gadeta.

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Supplemental data of ‘Activity of ex vivo graft and DLI Engineering within the last decade increases, a survey from the EBMT Cellular Therapy & Immunobiology Working Party’

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de Witte, M.A., Mooyaart, J.E., Hoogenboom, J.D. et al. Activity of ex vivo graft and DLI Engineering within the last decade increases, a survey from the EBMT Cellular Therapy & Immunobiology Working Party. Bone Marrow Transplant 58, 719–722 (2023). https://doi.org/10.1038/s41409-023-01953-1

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