Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors
Agnes Bonifacius, Britta Lamottke, Sabine Tischer-Zimmermann, Rebecca Schultze-Florey, Lilia Goudeva, Hans-Gert Heuft, Lubomir Arseniev, Rita Beier, Gernot Beutel, Gunnar Cario, Birgit Fröhlich, Johann Greil, Leo Hansmann, Justin Hasenkamp, Michaela Höfs, Patrick Hundsdoerfer, Edgar Jost, Kinan Kafa, Oliver Kriege, Nicolaus Kröger, Stephan Mathas, Roland Meisel, Michaela Nathrath, Mervi Putkonen, Sarina Ravens, Hans Christian Reinhardt, Elisa Sala, Martin G. Sauer, Clemens Schmitt, Roland Schroers, Nina Kristin Steckel, Ralf Ulrich Trappe, Mareike Verbeek, Daniel Wolff, Rainer Blasczyk, Britta Eiz-Vesper, Britta Maecker-Kolhoff
Agnes Bonifacius, Britta Lamottke, Sabine Tischer-Zimmermann, Rebecca Schultze-Florey, Lilia Goudeva, Hans-Gert Heuft, Lubomir Arseniev, Rita Beier, Gernot Beutel, Gunnar Cario, Birgit Fröhlich, Johann Greil, Leo Hansmann, Justin Hasenkamp, Michaela Höfs, Patrick Hundsdoerfer, Edgar Jost, Kinan Kafa, Oliver Kriege, Nicolaus Kröger, Stephan Mathas, Roland Meisel, Michaela Nathrath, Mervi Putkonen, Sarina Ravens, Hans Christian Reinhardt, Elisa Sala, Martin G. Sauer, Clemens Schmitt, Roland Schroers, Nina Kristin Steckel, Ralf Ulrich Trappe, Mareike Verbeek, Daniel Wolff, Rainer Blasczyk, Britta Eiz-Vesper, Britta Maecker-Kolhoff
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Clinical Research and Public Health

Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

Abstract

BACKGROUND Adoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications.METHODS We provide results of a personalized T cell manufacturing program evaluating donor, patient, T cell product, and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T lymphocyte (EBV-CTL) products from stem cell donors (SCDs), related third-party donors (TPDs), or unrelated TPDs from the allogeneic T cell donor registry (alloCELL) at Hannover Medical School were manufactured by immunomagnetic selection using a CliniMACS Plus or Prodigy device and the EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated, and patient outcome and side effects were retrieved by retrospective chart analysis.RESULTS Forty clinical-grade EBV-CTL products from SCDs, related TPDs, or unrelated TPDs were generated for 37 patients with refractory EBV infections or EBV-associated malignancies with and without a history of transplantation, within 5 days (median) after donor identification. Thirty-four patients received 1–14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to a complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients’ blood were detectable in 16 of 18 monitored patients (89%) after transfer, and their presence correlated with clinical response.CONCLUSION Personalized clinical-grade manufacture of EBV-CTL products via immunomagnetic selection from SCDs, related TPDs, or unrelated TPDs in a timely manner is feasible. Overall, EBV-CTLs were clinically effective and well tolerated. Our data suggest EBV-CTL transfer as a promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT, as well as patients with preexisting organ dysfunction.TRIAL REGISTRATION Not applicable.FUNDING This study was funded in part by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), Wilhelm-Sander-Stiftung (reference 2015.097.1), Ellen-Schmidt-Program of Hannover Medical School, and German Federal Ministry of Education and Research (reference 01EO0802).

Authors

Agnes Bonifacius, Britta Lamottke, Sabine Tischer-Zimmermann, Rebecca Schultze-Florey, Lilia Goudeva, Hans-Gert Heuft, Lubomir Arseniev, Rita Beier, Gernot Beutel, Gunnar Cario, Birgit Fröhlich, Johann Greil, Leo Hansmann, Justin Hasenkamp, Michaela Höfs, Patrick Hundsdoerfer, Edgar Jost, Kinan Kafa, Oliver Kriege, Nicolaus Kröger, Stephan Mathas, Roland Meisel, Michaela Nathrath, Mervi Putkonen, Sarina Ravens, Hans Christian Reinhardt, Elisa Sala, Martin G. Sauer, Clemens Schmitt, Roland Schroers, Nina Kristin Steckel, Ralf Ulrich Trappe, Mareike Verbeek, Daniel Wolff, Rainer Blasczyk, Britta Eiz-Vesper, Britta Maecker-Kolhoff

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Figure 5

Immune monitoring in individual patients by IFN-γ ELISpot assay.

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Immune monitoring in individual patients by IFN-γ ELISpot assay. Periphe...
Peripheral blood samples obtained from patients (identification number indicated on the y axis) at different time points after first EBV-CTL transfer (indicated on the x axis; in weeks) were subjected to IFN-γ ELISpot assay using EBV_EBNA-1 (light blue) and EBV_Consensus (dark blue) to restimulate EBV-specific memory T cells. Lower circles indicate results from direct EBV_EBNA-1 ELISpot; upper circles indicate results from EBV_EBNA-1 ELISpot after expansion. For each patient, lower circles indicate results from direct EBV_EBNA-1 ELISpot; upper circles indicate results from EBV_EBNA-1 ELISpot after expansion. For each patient, lower squares indicate results from direct EBV_Consensus ELISpot, upper squares indicate results from EBV_Consensus ELISpot after expansion. Square brackets (]) indicate combined stimulation with both EBV_EBNA-1 and EBV_Consensus. Empty symbols indicate that no specific T cells were detected, while filled symbols indicate that specific T cells were detected. The vertical dashed line and triangles indicate time points of T cell transfer. No. 36: green triangles indicate T cell transfer from a second manufacturing process (no. 24). Schematics of human figures on the right indicate the type of transplant (red circle: HSCT; kidney shape: SOT) and clinical response (green: CR; light green: PR; yellow: SD; orange: PD).