ADOPTIVE CELLULAR THERAPY AFTER ALLOGENEIC BMT

现在普遍认为异基因骨髓移植的成功可以是 归因于消融方案的抗肿瘤作用和 供体移植物介导的残留白血病的免疫控制在……里面 试图利用同种异体免疫系统根除 或抑制恶性细胞，项目1中的研究检查了 IL-2短期给药增强抗白血病免疫能力的研究 用供体骨髓植入后。最近发生了几起 供者输注白细胞引起缓解的报告 慢性粒细胞白血病复发患者术后供者造血功能的建立 异基因骨髓移植。然而，几乎所有获得缓解的患者 在输注未分离的同种异体淋巴细胞后， 严重的GVHD。供者抗白血病作用的关系 淋巴细胞输注与移植物抗宿主病及其供体机制 淋巴细胞诱导白血病消退的机制尚未得到证实。 这两个问题将是今后研究的重点。 项目。为了开发采用细胞疗法的新方法，我们有 开始临床试验，利用选定的人群输注 供者淋巴细胞。CD8耗竭输注后的初步结果 淋巴细胞(3x10(7)CD4+细胞/公斤)对 异基因骨髓移植后复发稳定期CML患者。回应 发生在输液后8-12周，但没有患者出现急性或 慢性移植物抗宿主病。一名经过全面评估的有反应的患者， 从血液学复发状态转为分子缓解期(PCR 阴性)在2周内。 这些初步结果支持了这样一种假设，即 目的：选择性地诱导无GVHD的移植物抗白血病(GVL)。进一步 将进行研究以确定细胞免疫机制。 供者淋巴细胞在体内介导移植物抗宿主病。与这些结合在一起 研究我们将开发方法来选择和扩展这些 体内和体外免疫效应细胞在过继细胞中的应用 心理治疗。除了慢性粒细胞白血病，这些研究还将包括患有 CLL.这些代表了生物学上不同的髓系和淋巴系。 恶性肿瘤，但两者都是敏感的聚合酶链式反应技术可以 用于识别有持续性残留病的患者，并 监测免疫疗法的效果。此外，随着在以下方面取得进展 对于复发性疾病患者的治疗，还将进一步研究 开始于在治疗前有微小残留疾病的患者 临床复发的发展。 提出了三个具体目标： 1.过继细胞治疗的临床试验进展 异基因骨髓移植。 2.移植物抗白血病(GVL)反应的特征 异基因骨髓移植后接受供者淋巴细胞输注的患者。 3.体外选育和扩增新方法的发展 用于过继细胞治疗的抗白血病效应细胞。

It is now generally recognized that success of allogeneic BMT can be attributed to both anti-neoplastic effects of the ablative regimen and immunologic control of residual leukemia mediated by the donor graft. In an attempt to exploit the allogeneic immune system's ability to eradicate or suppress malignant cells, studies in Project 1 have examined the ability of IL-2 to enhance anti-leukemia immunity when administered soon after engraftment with donor marrow. There have been several recent reports of donor leukocyte infusions inducing remissions with re- establishment of donor hematopoiesis in patients with relapsed CML after allogeneic BMT. However, almost all patients who achieved remission following infusion of unseparated allogeneic lymphocytes also developed severe GVHD. The relationship between the anti-leukemic effects of donor lymphocyte infusions and GVHD as well as the mechanisms whereby donor lymphocytes induce regression of leukemia have not yet been established. These two issues will be the major focus of future studies in this project. To develop new approaches for adoptive cellular therapy, we have initiated clinical trials utilizing infusion of selected populations of donor lymphocytes. Preliminary results following infusion of CD8 depleted lymphocytes (3x10(7) CD4+ cells/kg) have demonstrated responses in patients with relapsed stable phase CML after allogeneic BMT. Responses occurred 8-12 weeks post infusion, but no patients have developed acute or chronic GVHD. One responding patient that has been fully evaluated, converted from a state of hematologic relapse to molecular remission (PCR negative) over a 2 week period. These preliminary results support the hypothesis that it will be possible to selectively induce graft vs. leukemia (GVL) without GVHD. Further studies will be undertaken to define the cellular immune mechanisms whereby donor lymphocytes mediate GVL in vivo. In conjunction with these studies we will develop methods for both selecting and expanding these immune effector cells in vivo and in vitro for use in adoptive cellular therapy. In addition to CML, these studies will also include patients with CLL. These represent biologically distinct myeloid and lymphoid malignancies but both are diseases in which sensitive PCR techniques can be used to identify patients with persistent residual disease and to monitor the effects of immune therapy. Moreover, as progress is made in the treatment of patients with relapsed disease, further studies will be initiated in patients with minimal residual disease prior to the development of clinical relapse. 3 Specific Aims are proposed: 1. Development of clinical trials of adoptive cellular therapy after allogeneic BMT. 2. Characterization of the graft versus leukemia (GVL) response in patients receiving donor lymphocyte infusions after allogeneic BMT. 3. Development of new approaches for in vitro selection and expansion of anti-leukemia effector cells for adoptive cellular therapy.