Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2019; 18: 9-21
Применение профилактических инфузий СD45RA-деплетированных донорских лимфоцитов у пациентов, перенесших аллогенную трансплантацию гемопоэтических стволовых клеток с TCRαβ - и CD19-деплецией по поводу заболеваний незлокачественной природы
https://doi.org/10.24287/1726-1708-2019-18-3-9-21Аннотация
Вирусные инфекции – ведущая причина негативных исходов терапии у реципиентов аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) с TCRαβ- и CD19-деплецией трансплантата. Мы предположили, что инфузии низких доз СD45RA-деплетированных донорских лимфоцитов (ИДЛ) могут помочь в обеспечении контроля над вирусными инфекциями. Данное исследование поддержано Независимым этическим комитетом и утверждено решением Ученого совета НМИЦ ДГОИ. В работе проанализированы результаты применения низких доз ИДЛ в группе пациентов с незлокачественными гематологическими и иммунологическими заболеваниями. Медиана кратности введения клеточного продукта – 3 инфузии; медиана наблюдения для живых пациентов – 30 мес. Аллергических реакций, септических осложнений после ИДЛ не отмечено. Кумулятивная вероятность de novo острой реакции «трансплантат против хозяина» (оРТПХ) после ИДЛ составила 10%. У 21 (41%) пациента выявлен цитомегаловирус (ЦМВ) в крови; у 16 (73%) пациентов с ЦМВ-виремией вирус выявлен до 1-го введения клеток памяти. Среди пациентов, получивших ИДЛ, у 27 (53%) документировано появление вирус-специфичных лимфоцитов в периферической крови. Таким образом, введение T-клеток памяти после приживления трансплантата в дозе 25–100 ´ 103/кг массы тела реципиента в случае ТГСК от гаплоидентичного донора и 100–300 ´ 103/кг для неродственной совместимой ТГСК с TCRαβ- и СD19-деплецией – безопасный и потенциально эффективный способ обеспечения защиты от вирусных инфекций.
Список литературы
1. Румянцев А.Г., Масчан А.А. Трансплантация гемопоэтических стволовых клеток у детей. ‒ М.: МИА, 2003, 912 с.
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3. Handgretinger R. Negative depletion of CD3(+) and TcRalphabeta(+) T-cells. Curr Opin Hematol 2012; 19 (6): 434‒9. Doi: 10.1097/MOH.0b013e3283582340
4. Schumm M., Lang P., Bethge W., Faul C., Feuchtinger T., Pfeiffer M., et al. Depletion of T-cell receptor alpha/beta and CD19 positive cells from apheresis products with the CliniMACS device. Cytotherapy 2013; 15(10): 1253‒8. Doi: 10.1016/j.jcyt.2013.05.014
5. Bertaina A., Merli P., Rutella S., Pagliara D., Bernardo M.E., Masetti R., et al. HLA-haploidentical stem cell transplantation after removal of alphabeta+ T and B cells in children with nonmalignant disorders. Blood 2014; 124(5): 822‒6. Doi: 10.1182/blood-2014-03-563817
6. Balashov D., Shcherbina A., Maschan M., Trakhtman P., Skvortsova Y., Shelikhova L., et al. Single-Center Experience of Unrelated and Haploidentical Stem Cell Transplantation with TCRalphabeta and CD19 Depletion in Children with Primary Immunodeficiency Syndromes. Biol Blood Marrow Transplant 2015; 21 (11): 1955‒62. Doi: 10.1016/j.bbmt.2015.07.008
7. Maschan M., Shelikhova L., Ilushina M., Kurnikova E., Boyakova E., Balashov D., et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant 2016; 51(5): 668‒74. Doi: 10.1038/bmt.2015.343
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9. Airoldi I., Bertaina A., Prigione I., Zorzoli A., Pagliara D., Cocco C., et al. gammadelta T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-alphabeta+/CD19+ lymphocytes. Blood 2015; 125: 2349‒58.
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11. Elfeky R., Shah R.M., Unni M.N.M., Ottaviano G., Rao K., Chiesa R., et al. New graft manipulation strategies improve the outcome of mismatched stem cell transplantation in children with primary immunodeficiencies. J Allergy Clin Immunol 2019 Feb 4. pii: S0091-6749(19)30187‒3. Doi: 10.1016/j.jaci.2019.01.030
12. Laberko A., Bogoyavlenskaya A., Shelikhova L., Shekhovtsova Z., Balashov D., Voronin K., et al. Risk Factors for and the Clinical Impact of Cytomegalovirus and Epstein-Barr Virus Infections in Pediatric Recipients of TCR-alpha/beta- and CD19-Depleted Grafts. Biol Blood Marrow Transplant 2016. Doi: 10.1016/j.bbmt.2016.12.635
13. Heslop H.E., Ng C.Y., Li C., Smith C.A., Loftin S.K., Krance R.A., et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T-lymphocytes. Nat Med 1996; 2(5): 551‒5.
14. Papadopoulou A., Gerdemann U., Katari U.L., Tzannou I., Liu H., Martinez C., et al. Activity of broad-spectrum T-cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Sci Transl Med 2014; 6 (242): 242‒83. Doi: 10.1126/scitranslmed.3008825
15. Peggs K.S., Verfuerth S., Pizzey A., Khan N., Guiver M., Moss P.A., et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 2003; 362 (9393): 1375‒7. Doi: 10.1016/S0140-6736(03)14634-X
16. Schmitt A., Tonn T., Busch D.H., Grigoleit G.U., Einsele H., Odendahl M., et al. Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T-cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation. Transfusion 2011; 51 (3): 591‒9. Doi: 10.1111/j.1537-2995.2010.02940.x
17. Bleakley M., Heimfeld S., Loeb K.R., Jones L.A., Chaney C., Seropian S., et al. Outcomes of acute leukemia patients transplanted with naive T-cell-depleted stem cell grafts. J Clin Invest 2015; 125 (7): 2677‒89. Doi: 10.1172/JCI81229
18. Shook D.R., Triplett B.M., Eldridge P.W., Kang G., Srinivasan A., Leung W. Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability. Pediatr Blood Cancer 2015; 62 (4): 666‒73. Doi: 10.1002/pbc.25352
19. Teschner D., Distler E., Wehler D., Frey M., Marandiuc D., Langeveld K., et al. Depletion of naive T-cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis. Bone Marrow Transplant 2014; 49 (1): 138‒44. Doi: 10.1038/bmt.2013.114
20. Touzot F., Neven B., Dal-Cortivo L., Gabrion A., Moshous D., Cros G., et al. CD45RA depletion in HLA-mismat-ched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: A preliminary study. J Allergy Clin Immunol 2015; 135(5): 1303‒9 e1301‒3. Doi: 10.1016/j.jaci.2014.08.019
21. Bleakley M., Heimfeld S., Jones L.A., Turtle C., Krause D., Riddell S.R., et al. Engineering human peripheral blood stem cell grafts that are depleted of naive T-cells and retain functional pathogen-specific memory T-cells. Biol Blood Marrow Transplant 2014; 20 (5): 705‒16. Doi: 10.1016/j.bbmt.2014.01.032
22. Brodszki N., Turkiewicz D., Toporski J., Truedsson L., Dykes J. Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. Orphanet J Rare Dis 2016; 11: 5. Doi: 10.1186/s13023-016-0385-3
23. Maschan M., Blagov S., Shelikhova L., Shekhovtsova Z., Balashov D., Starichkova J., et al. Low-dose donor memory T-cell infusion after TCR alpha/beta depleted unrelated and haploidentical transplantation: results of a pilot trial. Bone Marrow Transplant 2018 Mar; 53 (3): 264‒73. Doi: 10.1038/s41409-017-0035-y
24. Благов С.Л., Шелихова Л.Н., Осипова Е.Ю., Киселева В.В., Казаченок А.С., Шеховцова Ж.Б. Применение инфузий T-клеток памяти с целью профилактики вирусных инфекций у пациентов с гемобластозами, перенесших аллогенную трансплантацию гемопоэтических стволовых клеток с деплецией α/β-Т-лимфоцитов. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2018, 17 (2): 9‒20.
25. Przepiorka D., Weisdorf D., Martin P., Klingemann H.G., Beatty P., Hows J., et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15 (6): 825‒8.
26. Melenhorst J.J., Leen A.M., Bollard C.M., Quigley M.F., Price D.A., Rooney C.M., et al. Allogeneic virus-specific T-сells with HLA alloreactivity do not produce GVHD in human subjects. Blood 2010; 116 (22): 4700‒2. Doi: 10.1182/blood-2010-06-289991
27. Melenhorst J.J., Scheinberg P., Williams A., Ambrozak D.R., Keyvanfar K., Smith M., et al. Alloreactivity across HLA barriers is mediated by both naive and antigen-experienced T cells. Biol Blood Marrow Transplant 2011; 17 (6): 800‒9. Doi: 10.1016/j.bbmt.2010.12.711
28. D'Orsogna L.J., Roelen D.L., Doxiadis I.I., Claas F.H. Alloreactivity from human viral specific memory T-cells. Transpl Immunol 2010; 23 (4): 149‒55. Doi: 10.1016/j.trim.2010.06.008
29. D'Orsogna L.J., van der Meer-Prins E.M., Zoet Y.M., Roelen D.L., Doxiadis I.I., Claas F.H. Detection of allo-HLA cross-reactivity by virus-specific memory T-cell clones using single HLA-transfected K562 cells. Methods Mol Biol 2012; 882: 339‒49. Doi: 10.1007/978-1-61779-842-9_19.
30. Triplett B.M., Shook D.R., Eldridge P., Li Y., Kang G., Dallas M., et al. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Bone Marrow Transplant 2015; 50 (7): 968‒77. Doi: 10.1038/bmt.2014.324
31. Jain N.A., Lu K., Ito S., Muranski P., Hourigan C.S., Haggerty J., et al. The clinical and financial burden of pre-emptive management of cytomegalovirus disease after allogeneic stem cell transplantation-implications for preventative treatment approaches. Cytotherapy 2014; 16 (7): 927‒33. Doi: 10.1016/j.jcyt.2014.02.010
Pediatric Hematology/Oncology and Immunopathology. 2019; 18: 9-21
Low-dose infusions of CD45RA depleted donor lymphocytes after TCRα/β-depleted transplantation in patients with non-malignant disorders
https://doi.org/10.24287/1726-1708-2019-18-3-9-21Abstract
Viral infections are frequent causes of failure among the recipients of the HSCT with graft TCRα/β and CD19depletion. Adoptive transfer of memory T-cells by CD45RA-depleted donor lymphocytes infusions (memory DLI) may be useful in control of viral infections. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. The work reflects the retrospective data analysis of 51 patients with non-malignant disorders who had received low dose memory DLI after HSCT. Up to 3 doses of donor lymphocytes were administered. Median follow-up for alive patients was 30 (18–49) months. We did not observe any allergic reactions, septic complications after memory DLI. The cumulative incidence of a de novo acute GVHD after DLI was 10% (95% CI: 4–22). Among 41% patients (n = 21) was detected CMV in the blood. In 73% of them (n = 16) CMV was detected before first DLI. Among patients who received DLI, 53% (n = 27) had documented appearance of virus-specific lymphocytes in peripheral blood (ELISPOT assay).Thus, the infusion of memory T-cells at a dose of 25–100 αβ 103/kg body weight of the recipient for CD3+ in the case of HSCT from a haploidentical donor and 100–300 αβ 103/kg for an unrelated HSCT. Infusions of low dose memory T-lymphocytes after transplant engraftment are safe, potentially effective and constitute a simple measure to prevent infections in the setting of alpha/beta T-cell-depleted transplantation.
References
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4. Schumm M., Lang P., Bethge W., Faul C., Feuchtinger T., Pfeiffer M., et al. Depletion of T-cell receptor alpha/beta and CD19 positive cells from apheresis products with the CliniMACS device. Cytotherapy 2013; 15(10): 1253‒8. Doi: 10.1016/j.jcyt.2013.05.014
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6. Balashov D., Shcherbina A., Maschan M., Trakhtman P., Skvortsova Y., Shelikhova L., et al. Single-Center Experience of Unrelated and Haploidentical Stem Cell Transplantation with TCRalphabeta and CD19 Depletion in Children with Primary Immunodeficiency Syndromes. Biol Blood Marrow Transplant 2015; 21 (11): 1955‒62. Doi: 10.1016/j.bbmt.2015.07.008
7. Maschan M., Shelikhova L., Ilushina M., Kurnikova E., Boyakova E., Balashov D., et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant 2016; 51(5): 668‒74. Doi: 10.1038/bmt.2015.343
8. Zvyagin I.V., Mamedov I.Z., Tatarinova O.V., Komech E.A., Kurnikova E.E., Boyakova E.V., et al. Tracking T-cell immune reconstitution after TCRalphabeta/CD19-depleted hematopoietic cells transplantation in children. Leukemia 2016. Doi: 10.1038/leu.2016.321
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12. Laberko A., Bogoyavlenskaya A., Shelikhova L., Shekhovtsova Z., Balashov D., Voronin K., et al. Risk Factors for and the Clinical Impact of Cytomegalovirus and Epstein-Barr Virus Infections in Pediatric Recipients of TCR-alpha/beta- and CD19-Depleted Grafts. Biol Blood Marrow Transplant 2016. Doi: 10.1016/j.bbmt.2016.12.635
13. Heslop H.E., Ng C.Y., Li C., Smith C.A., Loftin S.K., Krance R.A., et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T-lymphocytes. Nat Med 1996; 2(5): 551‒5.
14. Papadopoulou A., Gerdemann U., Katari U.L., Tzannou I., Liu H., Martinez C., et al. Activity of broad-spectrum T-cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Sci Transl Med 2014; 6 (242): 242‒83. Doi: 10.1126/scitranslmed.3008825
15. Peggs K.S., Verfuerth S., Pizzey A., Khan N., Guiver M., Moss P.A., et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 2003; 362 (9393): 1375‒7. Doi: 10.1016/S0140-6736(03)14634-X
16. Schmitt A., Tonn T., Busch D.H., Grigoleit G.U., Einsele H., Odendahl M., et al. Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T-cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation. Transfusion 2011; 51 (3): 591‒9. Doi: 10.1111/j.1537-2995.2010.02940.x
17. Bleakley M., Heimfeld S., Loeb K.R., Jones L.A., Chaney C., Seropian S., et al. Outcomes of acute leukemia patients transplanted with naive T-cell-depleted stem cell grafts. J Clin Invest 2015; 125 (7): 2677‒89. Doi: 10.1172/JCI81229
18. Shook D.R., Triplett B.M., Eldridge P.W., Kang G., Srinivasan A., Leung W. Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability. Pediatr Blood Cancer 2015; 62 (4): 666‒73. Doi: 10.1002/pbc.25352
19. Teschner D., Distler E., Wehler D., Frey M., Marandiuc D., Langeveld K., et al. Depletion of naive T-cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis. Bone Marrow Transplant 2014; 49 (1): 138‒44. Doi: 10.1038/bmt.2013.114
20. Touzot F., Neven B., Dal-Cortivo L., Gabrion A., Moshous D., Cros G., et al. CD45RA depletion in HLA-mismat-ched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: A preliminary study. J Allergy Clin Immunol 2015; 135(5): 1303‒9 e1301‒3. Doi: 10.1016/j.jaci.2014.08.019
21. Bleakley M., Heimfeld S., Jones L.A., Turtle C., Krause D., Riddell S.R., et al. Engineering human peripheral blood stem cell grafts that are depleted of naive T-cells and retain functional pathogen-specific memory T-cells. Biol Blood Marrow Transplant 2014; 20 (5): 705‒16. Doi: 10.1016/j.bbmt.2014.01.032
22. Brodszki N., Turkiewicz D., Toporski J., Truedsson L., Dykes J. Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. Orphanet J Rare Dis 2016; 11: 5. Doi: 10.1186/s13023-016-0385-3
23. Maschan M., Blagov S., Shelikhova L., Shekhovtsova Z., Balashov D., Starichkova J., et al. Low-dose donor memory T-cell infusion after TCR alpha/beta depleted unrelated and haploidentical transplantation: results of a pilot trial. Bone Marrow Transplant 2018 Mar; 53 (3): 264‒73. Doi: 10.1038/s41409-017-0035-y
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25. Przepiorka D., Weisdorf D., Martin P., Klingemann H.G., Beatty P., Hows J., et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15 (6): 825‒8.
26. Melenhorst J.J., Leen A.M., Bollard C.M., Quigley M.F., Price D.A., Rooney C.M., et al. Allogeneic virus-specific T-sells with HLA alloreactivity do not produce GVHD in human subjects. Blood 2010; 116 (22): 4700‒2. Doi: 10.1182/blood-2010-06-289991
27. Melenhorst J.J., Scheinberg P., Williams A., Ambrozak D.R., Keyvanfar K., Smith M., et al. Alloreactivity across HLA barriers is mediated by both naive and antigen-experienced T cells. Biol Blood Marrow Transplant 2011; 17 (6): 800‒9. Doi: 10.1016/j.bbmt.2010.12.711
28. D'Orsogna L.J., Roelen D.L., Doxiadis I.I., Claas F.H. Alloreactivity from human viral specific memory T-cells. Transpl Immunol 2010; 23 (4): 149‒55. Doi: 10.1016/j.trim.2010.06.008
29. D'Orsogna L.J., van der Meer-Prins E.M., Zoet Y.M., Roelen D.L., Doxiadis I.I., Claas F.H. Detection of allo-HLA cross-reactivity by virus-specific memory T-cell clones using single HLA-transfected K562 cells. Methods Mol Biol 2012; 882: 339‒49. Doi: 10.1007/978-1-61779-842-9_19.
30. Triplett B.M., Shook D.R., Eldridge P., Li Y., Kang G., Dallas M., et al. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Bone Marrow Transplant 2015; 50 (7): 968‒77. Doi: 10.1038/bmt.2014.324
31. Jain N.A., Lu K., Ito S., Muranski P., Hourigan C.S., Haggerty J., et al. The clinical and financial burden of pre-emptive management of cytomegalovirus disease after allogeneic stem cell transplantation-implications for preventative treatment approaches. Cytotherapy 2014; 16 (7): 927‒33. Doi: 10.1016/j.jcyt.2014.02.010
