Project 1: Preventing Acute GVHD and Treating Chronic GVHD in a Canine Model

摘要-项目1 最近对1,092例晚期血液病患者的结局进行了综合分析， 在当前项目2和3的赞助下移植的恶性肿瘤显示，五分之一的患者死亡 移植物vs.-宿主疾病（GVHD）相关原因。分析进一步表明，急性GVHD没有 与GVT效应的统计学显著相关。这表明避免急性GVHD可以减少 非复发死亡率（NRM）的风险，而不增加复发的风险。相比之下，慢性GVHD 与GVT效应高度显著相关;然而，这种益处被NRM抵消，NRM在很大程度上 这是由于在慢性GVHD的长期治疗期间发生的感染。所以我们面临的挑战不是 预防慢性GVHD，因为这可能会增加复发的风险，但更有效地治疗它， 治疗持续时间和相关的发病率和NRM风险降低，而GVT效应 树立政治意识拟议的研究将使用DLA不匹配的犬造血细胞移植（HCT） 该模型在将新型急性GVHD预防和治疗转化为 诊所此外，我们现在已经建立了唯一简单的，可重复的，临床相关的大型动物 慢性GVHD模型。具有急性GVHD和慢性GVHD的可重复模型使我们处于一个 独特的立场，以更好地了解，治疗和预防GVH反应。在这两种犬模型中，T细胞 活化的发生与临床上在人类患者中一样，尽管有标准的移植后免疫抑制， 然后导致急性或慢性GVHD。关联机制研究将告诉我们 表型和功能性T细胞特征，将预测静止期或GVHD，并可能 治疗干预的目标。在目前的资助期内，我们开发了一套独特的犬- 与调节细胞表面决定簇相互作用的特异性单克隆抗体（mAb）和融合蛋白 T细胞有望比以往更特异地干预免疫反应， 可能与当前的药理学免疫抑制有关。我们希望在拟议的 通过可能确定T细胞特异性免疫调节上调时间的机制研究进行治疗研究。 抗原具有： ⑶可能被阻断的共刺激功能; 下调-可被激活的调节功能;或 无调节功能，但可作为放射免疫治疗的靶点。 我们认为，合理使用生物制剂预防急性GVHD和治疗慢性GVHD的建议， 移植物抗宿主病是非常新颖的，而且，在犬模型中成功的治疗可以转化为受益 在项目2和项目3的赞助下移植的人类患者。

ABSTRACT - PROJECT 1 A recent comprehensive analysis of outcomes among the first 1,092 patients with advanced hematologic malignancies transplanted under the auspices of current Projects 2 and 3 showed that one-fifth of patients died of graft-vs.-host disease (GVHD)-related causes. The analysis further showed that acute GVHD had no statistically significant associations with GVT effects. This suggested that avoiding acute GVHD would reduce the risk of non-relapse mortality (NRM) without increasing the risk of relapse. In contrast, chronic GVHD was highly significantly associated with GVT effects; however, this benefit was offset by NRM, which was largely due to infections occurring during the lengthy period of treatment for chronic GVHD. So the challenge is not to prevent chronic GVHD, since that might increase the risk of relapse, but to treat it more effectively so that both the duration of treatment and the associated risks of morbidity and NRM are reduced while GVT effects are maintained. The proposed studies will use a DLA-mismatched canine hematopoietic cell transplantation (HCT) model that has a long-standing track record of translating novel acute GVHD prevention and treatment into the clinic. Moreover, we have now established the only simple, reproducible, and clinically relevant large animal model of chronic GVHD. Having reproducible models of both acute GVHD and of chronic GVHD places us in a unique position to better understand, treat, and prevent GVH reactions. In these two canine models, T-cell activation occurs as it does clinically in human patients, despite standard postgrafting immunosuppression, which then results in either acute or chronic GVHD. Linked mechanistic studies will tell us about unique phenotypic and functional T-cell signatures that will be predictive of quiescence or of GVHD and might be targets of therapeutic interventions. In the current funding period, we have developed a unique set of canine- specific monoclonal antibodies (mAbs) and fusion proteins interacting with regulatory cell-surface determinants on T-cells that hold promise of enabling more-specific interventions in immune responses than have been possible with current pharmacological immunosuppression. We expect to be guided in the proposed therapeutic studies by mechanistic studies which might determine the time of upregulation of T-cell-specific antigens that have: ▪ Costimulatory function which may be blocked; ▪ Down-regulatory function that can be activated; or ▪ No regulatory function, but which can be used as targets for radioimmunotherapy. We believe that the proposed rational use of biologic agents to prevent acute GVHD and to treat chronic GVHD is highly novel and, moreover, that therapy successful in the canine model can be translated to benefit human patients transplanted under the auspices of Projects 2 and 3.