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

被引：20

作者：

Bonifacius, Agnes ^{[1
]}

Lamottke, Britta ^{[2
]}

Tischer-Zimmermann, Sabine ^{[1
]}

Schultze-Florey, Rebecca ^{[2
]}

Goudeva, Lilia ^{[1
]}

Heuft, Hans-Gert ^{[1
]}

Arseniev, Lubomir ^{[3
]}

Beier, Rita ^{[2
]}

Beutel, Gernot ^{[4
]}

Cario, Gunnar ^{[5
]}

Froehlich, Birgit ^{[6
]}

Greil, Johann ^{[7
]}

Hansmann, Leo ^{[8
]}

Hasenkamp, Justin ^{[9
]}

Hoefs, Michaela ^{[10
]}

Hundsdoerfer, Patrick ^{[11
]}

Jost, Edgar ^{[12
,13
]}

Kafa, Kinan ^{[14
]}

Kriege, Oliver ^{[15
]}

Kroeger, Nicolaus ^{[16
]}

Mathas, Stephan ^{[17
,18
,19
,20
,21
]}

Meisel, Roland ^{[22
]}

Nathrath, Michaela ^{[23
,24
,25
]}

Putkonen, Mervi ^{[26
]}

Ravens, Sarina ^{[27
]}

Reinhardt, Hans Christian ^{[28
]}

Sala, Elisa ^{[29
]}

Sauer, Martin G. ^{[2
]}

Schmitt, Clemens ^{[8
]}

Schroers, Roland ^{[30
]}

Steckel, Nina Kristin ^{[28
]}

Trappe, Ralf Ulrich ^{[31
]}

Verbeek, Mareike ^{[32
]}

Wolff, Daniel ^{[33
]}

Blasczyk, Rainer ^{[1
]}

Eiz-Vesper, Britta ^{[1
,34
]}

Maecker-Kolhoff, Britta ^{[2
,34
]}

机构：

[1] Hannover Med Sch, Inst Transfus Med & Transplant Engn, Hannover, Germany

[2] Hannover Med Sch, Dept Pediat Hematol & Oncol, Hannover, Germany

[3] Hannover Med Sch, Cellular Therapy Ctr, Hannover, Germany

[4] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany

[5] Univ Hosp Schleswig Holstein, Dept Pediat, Kiel, Germany

[6] Univ Childrens Hosp Muenster, Klin Kinder & Jugend Med, Pediat Hematol & Oncol, Munster, Germany

[7] Univ Childrens Hosp Heidelberg, Heidelberg, Germany

[8] Charite Univ Med Berlin, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany

[9] Georg August Univ, Univ Med Gottingen, Clin Hematol & Oncol, Gottingen, Germany

[10] Univ Hosp Essen, Dept Pediat 3, Pediat Hematol & Oncol, Essen, Germany

[11] Charite Univ Med Berlin, Dept Pediat Oncol & Hematol, Berlin, Germany

[12] Univ Med Ctr RWTH Aachen, Dept Hematol Oncol Hemostaseol & Stem Cell Transp, Aachen, Germany

[13] Ctr Integrated Oncol Aachen Bonn Cologne Dusseldo, Aachen, Germany

[14] Martin Luther Univ Halle Wittenberg, Dept Pediat 1, Halle, Germany

[15] Johannes Gutenberg Univ Mainz, Med Ctr, Dept Med Haematol Internal Oncol & Pneumol 3, Mainz, Germany

[16] Univ Med Ctr Hamburg, Dept Stem Cell Transplantat, Hamburg, Germany

[17] Charite Univ Med Berlin, Hematol Oncol & Tumor Immunol, Berlin, Germany

[18] Free Univ Berlin, Berlin, Germany

[19] Humboldt Univ, Berlin, Germany

[20] Mol Med Helmholtz Assoc, Max Delbruck Ctr, MDC, Grp Biol Malignant Lymphomas, Berlin, Germany

[21] Expt & Clin Res Ctr ECRC, Cooperat MDC & Charite, Berlin, Germany

[22] Heinrich Heine Univ Dusseldorf, Med Fac, Dept Pediat Oncol Hematol & Clin Immunol, Div Pediat Stem Cell Therapy, Dusseldorf, Germany

[23] Klinikum Kassel, Dept Pediat Oncol, Kassel, Germany

[24] Tech Univ Munich, Klinikum Rechts Isar, Childrens Canc Res Ctr, Munich, Germany

[25] Tech Univ Munich, Dept Pediat, Munich, Germany

[26] Turku Univ Hosp, Dept Hematol & Stem Cell Transplantat, Turku, Finland

[27] Hannover Med Sch, Inst Immunol, Hannover, Germany

[28] Univ Hosp Essen, West German Canc Ctr, Dept Hematol & Stem Cell Transplantat, Essen, Germany

[29] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany

[30] Knappschaftskrankenhaus Univ Hosp, Dept Hematol & Oncol, Bochum, Germany

[31] Evangelisches Diakonie Krankenhaus, German Posttransplant Lymphoproliferat Dis PTLD S, Dept Internal Med Hematol & Oncol 2, Bremen, Germany

[32] Tech Univ Munich, Klinikum Rechts Isar, Sch Med, Clin & Policlin Internal Med 3, Munich, Germany

[33] Univ Hosp Regensburg, Dept Internal Med 3, Regensburg, Germany

[34] German Ctr Infect Res DZIF, Braunschweig, Germany

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 12期

关键词：

EPSTEIN-BARR-VIRUS; POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISEASE; RISK-FACTORS; RECIPIENTS; DISORDERS; INFECTIONS; IMMUNITY; THERAPY; PTLD;

D O I：

10.1172/JCI163548

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：15

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