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Immunotherapy

Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation—a phase I/II study

Leukemia volume 34, pages 831–844 (2020)Cite this article

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Abstract

Prophylactic infusion of selected donor T cells can be an effective method to restore specific immunity after T-cell-depleted allogeneic stem cell transplantation (TCD-alloSCT). In this phase I/II study, we aimed to reduce the risk of viral complications and disease relapses by administrating donor-derived CD8pos T cells directed against cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus antigens, tumor-associated antigens (TAA) and minor histocompatibility antigens (MiHA). Twenty-seven of thirty-six screened HLA-A*02:01pos patients and their CMVpos and/or EBVpos donors were included. Using MHC-I-Streptamers, 27 T-cell products were generated containing a median of 5.2 × 106 cells. Twenty-four products were administered without infusion-related complications at a median of 58 days post alloSCT. No patients developed graft-versus-host disease during follow-up. Five patients showed disease progression without coinciding expansion of TAA/MiHA-specific T cells. Eight patients experienced CMV- and/or EBV-reactivations. Four of these reactivations were clinically relevant requiring antiviral treatment, of which two progressed to viral disease. All resolved ultimately. In 2/4 patients with EBV-reactivations and 6/8 patients with CMV-reactivations, viral loads were followed by the expansion of donor-derived virus target-antigen-specific T cells. In conclusion, generation of multi-antigen-specific T-cell products was feasible, infusions were well tolerated and expansion of target-antigen-specific T cells coinciding viral reactivations was illustrated in the majority of patients.

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Acknowledgements

The authors thank patients, donors and medical staff involved in this clinical trial; Lisette Bogers and Susan Collins for excellent managing of clinical study data; Employees of the Laboratory for Stem Cell Therapy, Laboratory for Specialized Hematology and the Interdivisional GMP Facility of the LUMC for logistical, technical and GMP assistance. This study was financially supported by the European Union’s seventh Framework Program (FP/2007–2013) under grant agreement number 601722 and by Dutch Cancer Society grant UL 2008-4263.

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Authors and Affiliations

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

    Marthe C. J. Roex, Peter van Balen, Lois Hageman, Esther van Egmond, Sabrina A. J. Veld, Conny Hoogstraten, Ellis van Liempt, Hendrik Veelken, Constantijn J. M. Halkes, Inge Jedema & J. H. Frederik Falkenburg

  2. Juno Therapeutics GmbH, a Celgene Company, Munich, Germany

    Lothar Germeroth

  3. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    Jaap J. Zwaginga

  4. Center for Clinical Transfusion Research, Sanquin Research, Leiden, The Netherlands

    Jaap J. Zwaginga

  5. Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

    Liesbeth C. de Wreede

  6. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    Pauline Meij

  7. Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands

    Ann C. T. M. Vossen

  8. Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany

    Sophia Danhof & Hermann Einsele

  9. Department of Hematology, Medical Spectrum Twente, Enschede, The Netherlands

    M. Ron Schaafsma

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  1. Marthe C. J. Roex
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Contributions

JHFF, IJ, CJMH, LCW, SD, and HE developed the clinical study concept; CJMH, PB, JHFF, HV, and MRS enrolled study participants and monitored patients clinically; EL, IJ, EE, and SAJV wrote the protocols for multi-antigen-specific T-cell product generation; JJZ was responsible for donor leukapheresis logistics and release; LG provided MHC-I-Streptamer technology equipment; PM was involved in GMP logistics and product release; LH, EE, SAJV, CH,EL, and MCJR generated multi-antigen-specific T-cell products and performed in-depth analysis of the T-cell products; PB, CJMH, and MCJR administered the T-cell products to the patients; LH, SAJV, MCJR, ACTMV, and IJ performed laboratory monitoring; PB, JHFF, CJMH, IJ, and MCJR collected clinical/laboratory follow-up data and performed analysis; LCW assisted with statistical analysis; MCJR, IJ, and JHFF wrote the manuscript; all authors reviewed the manuscript.

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Correspondence to Marthe C. J. Roex.

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LG is senior vice president and managing director of Juno Therapeutics GmbH, a Celgene company (Munich, Germany). The remaining authors declare that they have no conflict of interest.

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Roex, M.C.J., van Balen, P., Germeroth, L. et al. Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation—a phase I/II study. Leukemia 34, 831–844 (2020). https://doi.org/10.1038/s41375-019-0600-z

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