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

TY - JOUR

T1 - Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

AU - Bonifacius, Agnes

AU - Lamottke, Britta

AU - Tischer-Zimmermann, Sabine

AU - Schultze-Florey, Rebecca

AU - Goudeva, Lilia

AU - Heuft, Hans-Gert

AU - Arseniev, Lubomir

AU - Beier, Rita

AU - Beutel, Gernot

AU - Cario, Gunnar

AU - Fröhlich, Birgit

AU - Greil, Johann

AU - Hansmann, Leo

AU - Hasenkamp, Justin

AU - Höfs, Michaela

AU - Hundsdoerfer, Patrick

AU - Jost, Edgar

AU - Kafa, Kinan

AU - Kriege, Oliver

AU - Kröger, Nicolaus

AU - Mathas, Stephan

AU - Meisel, Roland

AU - Nathrath, Michaela

AU - Putkonen, Mervi

AU - Ravens, Sarina

AU - Reinhardt, Hans Christian

AU - Sala, Elisa

AU - Sauer, Martin G

AU - Schmitt, Clemens

AU - Schroers, Roland

AU - Steckel, Nina Kristin

AU - Trappe, Ralf Ulrich

AU - Verbeek, Mareike

AU - Wolff, Daniel

AU - Blasczyk, Rainer

AU - Eiz-Vesper, Britta

AU - Maecker-Kolhoff, Britta

PY - 2023/6/15

Y1 - 2023/6/15

N2 - BACKGROUNDAdoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications.METHODSWe 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.RESULTSForty 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.CONCLUSIONPersonalized 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 REGISTRATIONNot applicable.FUNDINGThis 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).

AB - BACKGROUNDAdoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications.METHODSWe 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.RESULTSForty 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.CONCLUSIONPersonalized 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 REGISTRATIONNot applicable.FUNDINGThis 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).

KW - Humans

KW - Epstein-Barr Virus Infections

KW - Herpesvirus 4, Human

KW - Immunotherapy, Adoptive/methods

KW - Retrospective Studies

KW - T-Lymphocytes, Cytotoxic

KW - Unrelated Donors

U2 - 10.1172/JCI163548

DO - 10.1172/JCI163548

M3 - SCORING: Journal article

C2 - 37159273

VL - 133

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 12

M1 - e163548

ER -