AUTOLOGOUS GRAFT VS HOST DISEASE

自体骨髓移植（BMT）是有效的治疗方法 用于高危淋巴瘤和急性白血病患者。 AutoblastBMT在某些方面也显示出有希望的初步结果。 对药物有反应的实体瘤，如乳腺癌和卵巢癌。肿瘤 复发是自体骨髓移植失败的主要原因。 细胞毒性制备方案的修改未产生影响 对自体骨髓移植后肿瘤复发的影响。此外，委员会认为， 目前用于BMT的细胞毒性方案处于或接近非- 血液学剂量限制性毒性阻碍了 这些准备方案的强度。创新办法 提高自体BMT的抗肿瘤活性， needed. 一种类似于移植物抗宿主病（GVHD）的综合征， 环孢素（CsA）诱导的动物模型中的自体 GVHD。动物研究表明，这种综合征会产生 抗肿瘤活性类似于用同种异体GVHD所见， 严重的移植后死亡率。该综合征由以下因素介导： 针对Ia抗原的自身反应性T淋巴细胞。两种动物 模型和临床数据表明， 增强与自体GVHD相关的抗肿瘤作用， 调节效应细胞和/或靶细胞。干扰素， 上调肿瘤细胞上Ia抗原表达，低剂量 IL-2增强自体GVHD的抗肿瘤作用，而不 增加毒性。本提案的总体目标 继续研究自体移植物抗宿主病的抗肿瘤作用 在临床前模型和临床上。特别是动物模型 将被用来进一步调查负责的机制， 自体移植物抗宿主病抗肿瘤作用及研究方法 用于增强抗肿瘤效果，特别是通过增强肿瘤 细胞识别CsA诱导自体GVHD的临床研究 将基于从临床前开发的原则， 问题研究监测免疫调节作用的实验室研究 自体移植物抗宿主病将指导临床试验，特别是 最好的手段，以提高抗肿瘤疗效的自体 GVHD。

Autologous bone marrow transplantation (BMT) is effective therapy for patients with high-risk lymphomas and acute leukemias. Autologous BMT has also shown promising preliminary results in some drug-responsive solid tumors like breast and ovarian cancer. Tumor recurrence is the major cause of autologous BMT failure. Modification of cytotoxic preparative regimens has not made impact on occurrence of tumor relapse after autologous BMT. Moreover, currently used cytotoxic regimens for BMT are at or near non- hematologic dose-limiting toxicity hindering a further increase in the intensity of these preparative regimens. Innovative approaches for improving the antitumor activity of autologous BMT are therefore needed. A syndrome similar to graft-versus-host disease (GVHD) can be induced with cyclosporine (CsA) in animal models of autologous GVHD. The animal studies demonstrate that this syndrome generates antitumor activity similar to that seen with allogeneic GVHD without significant post-transplant mortality. This syndrome is mediated by autoreactive T-lymphocytes directed against Ia antigens. Both animal models and clinical data demonstrate that it should be possible to amplify the antitumor effect associated with autologous GVHD by modulating the effector and/or the target cells. The interferons, that upregulate Ia antigen expression on tumor cells, and low-dose IL-2 enhance the antitumor effect of autologous GVHD, without increasing toxicity. The overall aim of this aim of this proposal is to continue studies on the antitumor effect of autologous GVHD in preclinical models and clinically. Specifically, animal models will be used to further investigate the mechanisms responsible for the antitumor effect of autologous GVHD and to examine approaches for enhancing the antitumor effect particularly by enhancing tumor cell recognition. Clinical studies of CsA-induced autologous GVHD will be based on the principles developed from the preclinical studies. Laboratory studies monitoring the immunomodulatory effects of autologous GVHD will guide the clinical trials, particularly as to the best means to enhance the antitumor efficacy of autologous GVHD.