Waller E K, Boyer M
Bone Marrow and Stem Cell Transplantation Center, Emory University, Atlanta, GA, USA.
Bone Marrow Transplant. 2000 May;25 Suppl 2:S20-4. doi: 10.1038/sj.bmt.1702347.
Recipients of T cell-depleted allogeneic bone marrow transplants have increased risks of relapse and graft rejection. The addition of donor T cells to the TCD allograft will decrease the risk of graft rejection but will increase the risk of graft-versus-host disease (GVHD). Relapse of leukemia or lymphoma following allogeneic bone marrow transplantation can be successfully treated with post-transplant infusions of donor lymphocytes. A relatively small number of donor T cells can have a profound anti-tumor effect and facilitate engraftment, but has an unpredictable potential for severe GVHD. An alternative to using viable immunocompetent donor immune cells to facilitate engraftment and to treat relapsed patients are donor lymphocytes that have been treated to limit their ability to proliferate and cause GVHD. T cells treated with irradiation retain cytotoxic activity against tumor cells and host immune cells. We have tested the hypothesis that allogeneic donor T cells treated with low-dose irradiation will facilitate engraftment and mediate an anti-leukemia effect in a mouse model of bone marrow transplantation. Multiple infusions of irradiated allogeneic donor lymphocytes in the peri-transplant period had graft-enhancing activity without resulting in GVHD. Murine recipients of irradiated allogeneic splenocytes and allogeneic bone marrow had stable donor-derived hematopoiesis without a significant contribution of irradiated donor cells to the T cell compartment. Removing T cells from the allogeneic splenocytes prior to irradiation largely eliminated their graft facilitating activity. Based upon the promising results of the pre-clinical murine studies, we initiated a phase I clinical trial of multiple infusions of irradiated allogeneic lymphocytes in patients who had relapsed after allogeneic BMT. Of 12 patients treated to date on this study, three have shown objective responses of their leukemia or lymphoma to multiple infusions of irradiated donor lymphocytes. We have initiated a new phase I clinical study to test the efficacy of multiple infusions of irradiated allogeneic cytotoxic T cells to facilitate engraftment in allogeneic transplantation. Successive cohorts of patients will be transplanted with allogeneic stem cells alone, or a combination of allogeneic stem cells and increasing numbers of irradiated allogeneic T cells. Irradiated allogeneic lymphocytes that retain short-term allo-specific cytotoxicity and lack the potential for clonal expansion in vivo can be considered as a novel form of immunotherapy with defined pharmacokinetics.
去除T细胞的异基因骨髓移植受者复发和移植物排斥风险增加。在去除T细胞的同种异体移植物中加入供体T细胞会降低移植物排斥风险，但会增加移植物抗宿主病（GVHD）的风险。异基因骨髓移植后白血病或淋巴瘤的复发可用移植后输注供体淋巴细胞成功治疗。相对少量的供体T细胞可产生显著的抗肿瘤作用并促进植入，但引发严重GVHD的可能性不可预测。使用有活力的免疫活性供体免疫细胞促进植入和治疗复发患者的替代方法是经过处理以限制其增殖能力和引发GVHD能力的供体淋巴细胞。经照射处理的T细胞保留对肿瘤细胞和宿主免疫细胞的细胞毒性活性。我们在骨髓移植小鼠模型中测试了低剂量照射处理的异基因供体T细胞将促进植入并介导抗白血病作用的假设。在移植期周围多次输注经照射的异基因供体淋巴细胞具有增强移植物的活性且未导致GVHD。接受经照射的异基因脾细胞和异基因骨髓的小鼠受者具有稳定的供体来源造血功能，经照射的供体细胞对T细胞区室的贡献不大。在照射前从异基因脾细胞中去除T细胞在很大程度上消除了它们促进移植物的活性。基于临床前小鼠研究的有前景的结果，我们启动了一项I期临床试验，对异基因骨髓移植后复发的患者多次输注经照射的异基因淋巴细胞。在这项研究中，迄今为止接受治疗的12名患者中有3名对多次输注经照射的供体淋巴细胞表现出白血病或淋巴瘤的客观反应。我们启动了一项新的I期临床研究，以测试多次输注经照射的异基因细胞毒性T细胞在异基因移植中促进植入的疗效。连续的患者队列将单独接受异基因干细胞移植，或接受异基因干细胞与数量不断增加的经照射异基因T细胞的联合移植。保留短期同种异体特异性细胞毒性且缺乏体内克隆扩增潜力的经照射异基因淋巴细胞可被视为一种具有明确药代动力学的新型免疫疗法。
