Lymphocyte trafficking blockade in allogeneic stem-cell transplantation

描述（由申请人提供）：同种异体干细胞移植（SCT）的有效性部分归因于供体移植物的移植物抗肿瘤（GvT）潜力，然而，成功的SCT通常受到移植物抗宿主病（GvHD）的限制。 急性GvHD是血液癌症异基因SCT后发病和死亡的主要原因，发生在30-70%的移植中。 全球每年进行28，000例同种异体移植，15%的同种异体SCT后死亡是GvHD的直接结果。用于预防和治疗GvHD的现有模式是免疫抑制的，损害免疫恢复并且可能限制GvT效应。 我们先前的工作已经证明，阻断趋化因子受体CCR 5可显著降低人类内脏GvHD。 目前建议的首要目标是利用异基因SCT后淋巴细胞运输的药物控制来获得治疗益处。核心假设是 T细胞运输在同种异体SCT的三个主要临床和免疫学结果- GvHD、GvT和健康免疫系统的重建中起核心作用。为了验证这一假设，将进行一项临床试验，以同时研究 机制和治疗终点。 该实验方法围绕着在血液癌症患者的无关供体SCT中延长CCR 5阻断的II期试验。 目的1将确定同种异体SCT后延长CCR 5阻断的临床和免疫学效果，并使用适当的药效学和基因型方法确定反应的预测因子。 目的2将通过进行一系列经验证的测定来确定延长的CCR 5阻断对免疫恢复和抗肿瘤免疫的影响。 目的3将确定CCR 5在决定效应T细胞的组织嗜性中的作用，使用新的测序技术来调查T细胞的整个库并表征其表型。 使用来自2项临床试验的样本以及来自生物样本库的对照样本将增加所有3个目标分析的把握度。该提案是高度翻译的，围绕人类临床试验，并利用专门为此提案开发的适当的免疫药效学方法，以及T细胞克隆的基因组测序来鉴定参与T细胞募集到特定组织中的趋化因子受体签名。将以患者为导向的研究与最先进的免疫学检测相结合将具有双重作用-促进我们对移植和癌症免疫学中贩运机制的基本理解，同时通过引入一类新的靶向，最低限度的免疫抑制药物来改变护理标准。 如果成功，这一提议可能会导致GvHD预防的范式转变，为随机临床试验奠定基础，该试验将依赖于相同的临床和免疫学终点来衡量其成功。

DESCRIPTION (provided by applicant): Allogeneic stem-cell transplantation (SCT) is effective in part due to the graft-versus-tumor (GvT) potential of the donor graft~ however, successful SCT is often limited by graft-versus-host disease (GvHD). Acute GvHD is a major cause of morbidity and mortality after allogeneic SCT for blood cancers, occurring in 30-70% of transplants. With 28,000 allogeneic transplants performed worldwide each year, 15% of deaths following allogeneic SCT are a direct result of GvHD. Existing modalities for both prevention and treatment of GvHD are immunosuppressive, impair immune recovery and may limit the GvT effect. Our prior work has demonstrated that blockade of CCR5, a chemokine receptor, significantly decreased visceral GvHD in humans. The overarching goal of the current proposal is to exploit pharmacologic contro of lymphocyte trafficking after allogeneic SCT for therapeutic benefit. The central hypothesis is that T-cell trafficking plays a central role in the three major clinical and immunologic outcomes of allogeneic SCT - GvHD, GvT and reconstitution of a healthy immune system. To test this hypothesis, a clinical trial will be conducted in order to simultaneously investigate mechanistic and therapeutic endpoints. The experimental approach revolves around a phase II trial of extended CCR5 blockade in unrelated donor SCT for patients with blood cancers. Aim 1 will determine the clinical and immunologic effects of extended CCR5 blockade after allogeneic SCT and identify predictors of response using appropriate pharmacodynamic and genotypic methods. Aim 2 will determine the effect of extended CCR5 blockade on immune recovery and anti-tumor immunity by conducting a series of validated assays. Aim 3 will identify the role of CCR5 in determining the tissue-tropism of effector T-cells, using a novel sequencing technology to survey the entire repertoire of T-cells and characterize their phenotype. The use of samples from 2 clinical trials together with control samples from a biospecimen bank will add power to the analysis of all 3 aims. This proposal is highly translational, revolves around a human clinical trial, and takes advantage of appropriate immune pharmacodynamic methods, developed specifically for this proposal, and genomic sequencing of T-cell clones to identif the chemokine receptor signature that is involved in T-cell recruitment into specific tissues. Combining patient-oriented research with state of the art immunologic assays will have a dual role - fuel our basic understanding of trafficking mechanisms in transplantation and cancer immunology, and at the same time change the standard of care by introducing a new class of targeted, minimally immunosuppressive medications to the field. If successful, this proposal may lead to a paradigm shift in the prevention of GvHD, setting the stge for a randomized clinical trial that will rely on the same clinical and immunologic endpoints to measure its success.