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

• Published in: Journal of Clinical Investigation 2023, Vol.133 (12)
• Main Authors: Bonifacius, Agnes, Lamottke, Britta, Tischer-Zimmermann, Sabine, Schultze- Florey, Rebecca, Goudeva, Lilia, Heuft, Hans-Gert, Arseniev, Lubomir, Beier, Rita, Beutel, Gernot, Cario, Gunnar, Frohlich, Birgit, Greil, Johann, Hansmann, Leo, Hasenkamp, Justin, Hofs, Michaela, Hundsdoerfer, Patrick, Jost, Edgar, Kafa, Kinan, Kriege, Oliver, Kroger, Nicolaus, Mathas, Stephan, Meisel, Roland, Nathrath, Michaela, Putkonen, Mervi, Ravens, Sarina, Reinhardt, Hans Christian, Sala, Elisa, Sauer, Ma, Schmitt, Clemens, Schroers, Roland, Steckel, Nina Kristin, Trappe, Ralf Ulrich, Verbeek, Mareike, Wolff, Daniel, Blasczyk, Rainer, Eiz-Vesper, Britta, Maecker-Kolhoff, Britta
• Format: Report
• Language: English
• Subjects: Care and treatment; Cells; Complications and side effects; Epstein-Barr virus diseases; Graft versus host reaction; Health aspects; Immunotherapy; Lymphoproliferative disorders; Methods; T cells; Transplantation
• ISSN: 0021-9738
• DOI: 10.1172/JCI163548

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 01E00802).