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

摘要-项目1 首批1,092例晚期血液病患者近期预后的综合分析 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。 移植物抗宿主病(GVHD)相关原因。分析进一步表明，急性移植物抗宿主病没有 与GVT效应有统计学意义的关联。这表明避免急性移植物抗宿主病将减少 无复发死亡率(NRM)的风险，而不增加复发的风险。相比之下，慢性移植物抗宿主病 与GVT效应高度相关；然而，这种好处被NRM抵消，这在很大程度上是 由于在长期治疗慢性移植物抗宿主病期间发生感染。因此，挑战不是 预防慢性移植物抗宿主病，因为这可能会增加复发的风险，但要更有效地治疗它，使两者 治疗持续时间和相关的发病率和NRM风险减少，而GVT效应 维护好了。拟议的研究将使用DLA不相合的犬造血细胞移植(Hct)。 长期将新的急性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、可复制和临床相关的大型动物 慢性移植物抗宿主病模型。拥有急性GVHD和慢性GVHD的可复制模型使我们处于 更好地了解、治疗和预防GVH反应的独特地位。在这两种犬模型中，T细胞 尽管标准的移植后免疫抑制，激活的发生与临床上人类患者的情况一样， 这会导致急性或慢性移植物抗宿主病。相互关联的机械论研究将告诉我们独特的 表型和功能性T细胞信号将预示静止期或移植物抗宿主病，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类- 与调节细胞表面决定簇相互作用的特异性单抗和融合蛋白 在T细胞上，它们有望实现比以往任何时候更特异的免疫反应干预 可能与目前的药物免疫抑制有关。我们希望在建议中得到指导 通过可能确定T细胞特异性上调时间的机制研究进行的治疗研究 具有以下特征的抗原： ▪共刺激功能可能被阻断； ▪下调-可以激活的调节功能；或 ▪无调节功能，但可作为放射免疫治疗的靶点。 我们认为，建议合理使用生物制剂来预防急性GVHD和治疗慢性GVHD GVHD是非常新颖的，而且，在犬模型中成功的治疗可以转化为有益的 在项目2和项目3的主持下移植的人类患者。

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.