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《工程(英文)》 >> 2019年 第5卷 第1期 doi: 10.1016/j.eng.2018.12.006

供体来源的CD19靶向T细胞输注可以消除异基因造血干细胞移植后对供者淋巴细胞无反应的急性B淋巴细胞白血病微小残留病

a Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University Institute of Hematology, Peking University People's Hospital, Beijing 100044, China
b Collaborative Innovation Center of Hematology, Peking University, Beijing 100084, China
c Shenzhen Geno-Immune Medical Institute, Shenzhen 518057, China
d Innovative Cellular Therapeutics Co., Ltd., Shanghai 201499, China
# These authors contributed equally to this work.

收稿日期: 2018-04-07 修回日期: 2018-12-23 录用日期: 2018-12-26 发布日期: 2019-01-11

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摘要

白血病复发仍是异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)后急性B 淋巴细胞白血病(B cell acute lymphoblastic leukemia,B-ALL)治疗失败的主要原因。allo-HSCT 后B-ALL 复发患者的中位生存期很短。微小残留病(minimal residual disease,MRD)预示着造血干细胞移植(HSCT)后白血病将复发;消除MRD 将有效防止复发。HSCT 后治疗伴有MRD 的B-ALL 的主要方法是供者淋巴细胞输注(donor lymphoblastic infusion,DLI)。然而,在出现MRD 的患者中,约三分之一的患者对DLI 并无反应,且预后恶劣。虽然供体来源的CD19 导向嵌合抗原受体(chimeric antigen receptor-modified,CAR)修饰T 细胞(CART19)可能治愈白血病,但输注此类细胞的效率与安全性尚未在经过HSCT 后出现MRD 的B-ALL 患者当中进行过考察。在2014 年9 月至2018 年2 月期间,6 名患者均一次或多次输注了HSCT 供者提供的CD19 导向CAR 修饰T 细胞。其中有5 名患者(83.33%)的MRD 阴性得到缓解,而另1 名患者对CAR T 细胞并无反应。6 名患者中有3 名至今存活,白血病也并未复发。无患者出现急性移植物抗宿主病(acute graft-versus-host disease,aGVHD),也无患者死于细胞因子释放综合征。对于在allo-HSCT 后出现MRD 的B-ALL 患者且对DLI 并无反应的患者而言,供体来源的CAR T 细胞输注似乎是一种有效而安全的干预手段。

参考文献

[ 1 ] Numata A, Fujisawa S, Itabashi M, Ishii Y, Yamamoto W, Motohashi K, et al. Favorable prognosis in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia patients following hematopoietic stem cell transplantation. Clin Transplant 2016;30(5):485–6. 链接1

[ 2 ] Yan CH, Jiang Q, Wang J, Xu LP, Liu DH, Jiang H, et al. Superior survival of unmanipulated haploidentical hematopoietic stem cell transplantation compared with chemotherapy alone used as post-remission therapy in adults with standard-risk acute lymphoblastic leukemia in first complete remission. Biol Blood Marrow Transplant 2014;20(9):1314–21. 链接1

[ 3 ] Kuhlen M, Willasch AM, Dalle JH, Wachowiak J, Yaniv I, Ifversen M, et al. Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial. Br J Haematol 2018;180(1):82–9. 链接1

[ 4 ] Spyridonidis A, Labopin M, Schmid C, Volin L, Yakoub-Agha I, Stadler M, et al. Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT. Leukemia 2012;26 (6):1211–7. 链接1

[ 5 ] Bader P, Kreyenberg H, von Stackelberg A, Eckert C, Salzmann-Manrique E, Meisel R, et al. Monitoring of minimal residual disease after allogeneic stemcell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFMSCT 2003 trial. J Clin Oncol 2015;33(11):1275–84. 链接1

[ 6 ] Terwey TH, Hemmati PG, Nagy M, Pfeifer H, Gökbuget N, Brüggemann M, et al. Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2014;20(10):1522–9. 链接1

[ 7 ] Sutton R, Shaw PJ, Venn NC, Law T, Dissanayake A, Kilo T, et al. Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia. Br J Haematol 2015;168(3):395–404. 链接1

[ 8 ] Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, et al. Interferon-a: a potentially effective treatment for minimal residual disease in acute leukemia/ myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015;21(11):1939–47. 链接1

[ 9 ] Yan CH, Liu DH, Xu LP, Liu KY, Zhao T, Wang Y, et al. Modified donor lymphocyte infusion-associated acute graft-versus-host disease after haploidentical T-cell-replete hematopoietic stem cell transplantation: incidence and risk factors. Clin Transplant 2012;26(6):868–76. 链接1

[10] Pochon C, Oger E, Michel G, Dalle JH, Salmon A, Nelken B, et al. Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react. Br J Haematol 2015;169 (2):249–61. 链接1

[11] Yan CH, Wang JZ, Liu DH, Xu LP, Chen H, Liu KY, et al. Chemotherapy followed by modified donor lymphocyte infusion as a treatment for relapsed acute leukemia after haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion: superior outcomes compared with chemotherapy alone and an analysis of prognostic factors. Eur J Haematol 2013;91 04–14. 链接1

[12] Yan CH, Wang Y, Wang JZ, Chen YH, Chen Y, Wang FR, et al. Minimal residual disease- and graft-vs.-host disease-guided multiple consolidation chemotherapy and donor lymphocyte infusion prevent second acute leukemia relapse after allotransplant. J Hematol Oncol 2016;9(1):87. 链接1

[13] Davies JK, Singh H, Huls H, Yuk D, Lee DA, Kebriaei P, et al. Combining CD19 redirection and alloanergization to generate tumor-specific human T cells for allogeneic cell therapy of B-cell malignancies. Cancer Res 2010;70 (10):3915–24. 链接1

[14] Brudno JN, Somerville RPT, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remission of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol 2016;34(10):1112–21. 链接1

[15] Chen Y, Cheng Y, Suo P, Yan C, Wang Y, Chen Y, et al. Donor-derived CD19- targeted T cell infusion induces minimal residual disease-negative remission in relapsed B-cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation. Br J Haematol 2017;179(4):598–605. 链接1

[16] Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 2006;38(4):291–7. 链接1

[17] Liu DH, Xu LP, Liu KY, Wang Y, Chen H, Han W, et al. Long-term outcomes of unmanipulated haploidentical HSCT for paediatric patients with acute leukaemia. Bone Marrow Transplant 2013;48(12):1519–24. 链接1

[18] Yan CH, Xiu LP, Liu DH, Chen H, Wang Y, Liu KY, et al. Immunosuppression for 6–8 weeks after modified donor lymphocyte infusion reduced acute graftversus-host disease without influencing graft-versus-leukemia effect in haploidentical transplant. Chin Med J 2014;127:3602–9. 链接1

[19] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124(2):188–95. 链接1

[20] Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 2016;127(26):3321–30. 链接1

[21] Huff CA, Fuchs EJ, Smith BD, Blackford A, Garrett-Mayer E, Brodsky RA, et al. Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions. Biol Blood Marrow Transplant 2006;12(4):414–21. 链接1

[22] Lovisa F, Zecca M, Rossi B, Campeggio M, Magrin E, Giarin E, et al. Pre- and post-transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia. Br J Haematol 2018;180 (5):680–93. 链接1

[23] Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY, et al. Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2012;91 (2):183–92. 链接1

[24] Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, et al. IFN-a is effective for treatment of minimal residual disease in patients with acute leukemia after allogeneic hematopoietic stem cell transplantation: results of a registry study. Biol Blood Marrow Transplant 2017;23(8):1303–10. 链接1

[25] Ma X, Wu DP, Sun AN, Qiu HY, Fu ZZ, Wu XJ, et al. The value of monitoring minimal residual disease in the patients with donor lymphocyte infusion as intervention of relapsed/refractory acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. Am J Hematol 2010;85 (2):141–2. 链接1

[26] Reis M, Ogonek J, Qesari M, Borges NM, Nicholson L, Preußner L, et al. Recent developments in cellular immunotherapy for HSCT-associated complications. Front Immunol 2016;7:500. 链接1

[27] Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med 2017;23(2):242–9. 链接1

[28] Jacoby E, Yang Y, Qin H, Chien CD, Kochenderfer JN, Fry TJ. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD. Blood 2016;127(10):1361–70. 链接1

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