Lymphocyte trafficking blockade in allogeneic stem-cell transplantation

同种异体干细胞移植中的淋巴细胞运输阻断

• 批准号: 8733637
• 负责人: Ran Reshef
• 金额: $ 17.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733637
• 关键词: Accounting; Acute Graft Versus Host Disease; Address; Allogenic; Biological Assay; Biopsy; Blood; Bone Marrow; Bone Tissue; CCR5 gene; Cancer Immunology Science; Cells; Cessation of life; Chemotaxis; Clinical; Clinical Trials; Drug Kinetics; Genes; Genetic Polymorphism; Genomics; Goals; Graft-Versus-Tumor Induction; Health; Hematopoietic Neoplasms; Human; Immune; Immune system; Immunity; Immunologics; Immunology procedure; Immunomodulators; Immunosuppressive Agents; Incidence; Lead; Lymphocyte; Measures; Methods; Modality; Morbidity - disease rate; Outcome; Output; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase II Clinical Trials; Phenotype; Play; Prevention; Process; Randomized Clinical Trials; Recovery; Recurrent disease; Research Design; Role; Sampling; Series; Specimen; Stem cell transplant; Surveys; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Thymus Gland; Time; Tissues; Transplantation; Transplantation Immunology; Tumor Immunity; Visceral; Work; chemokine; chemokine receptor; clinical effect; deep sequencing; design; disorder prevention; graft vs host disease; improved; in vitro Assay; innovation; migration; mortality; novel; patient oriented research; progenitor; receptor; receptor expression; reconstitution; response; standard of care; success; therapeutic target; tissue tropism; trafficking; translational study

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.

描述（由申请人提供）：同种异体干细胞移植（SCT）有效，部分原因是供体移植物的移植物 - 肿瘤（GVT）潜力〜但是，成功的SCT通常受移植物抗宿主病（GVHD）的限制。 急性GVHD是同种异体SCT后血液癌后发病和死亡率的主要原因，发生在30-70％的移植物中。 每年在全球进行28,000次同种异体移植，同种异体SCT后15％的死亡是GVHD的直接结果。预防和治疗GVHD的现有方式是免疫抑制，损害免疫恢复的，可能会限制GVT效应。 我们先前的工作表明，趋化因子受体CCR5的封锁显着降低了人类内脏GVHD。 当前提案的总体目标是利用同种异体SCT后淋巴细胞贩运的药理侵害，以获得治疗益处。中心假设是 该T细胞运输在同种异体SCT -GVHD，GVT和重建健康免疫系统的三个主要临床和免疫结局中起着核心作用。为了检验该假设，将进行临床试验以同时研究 机械和治疗终点。 实验方法围绕着对血液癌患者无关的供体SCT中CCR5封锁扩展的II期试验。 AIM 1将确定同种异体SCT后扩展CCR5阻断的临床和免疫学效应，并使用适当的药效学和基因型方法识别反应的预测指标。 AIM 2将通过进行一系列经过验证的测定法来确定扩展CCR5阻断对免疫恢复和抗肿瘤免疫的影响。 AIM 3将使用一种新型的测序技术来确定CCR5在确定效应T细胞的组织 - 热量中的作用，以调查T细胞的整个曲目并表征其表型。 使用来自2项临床试验的样品以及来自生物循环库的对照样品的使用将增加对所有3个目标的分析。该建议是高度转化的，围绕人类的临床试验，并利用适当的免疫药效方法，专门针对该建议开发，以及T-Cell克隆的基因组测序，以识别与T细胞募集到特定组织中有关的趋化因子受体特征。将以患者为导向的研究与最先进的免疫学测定法相结合，将发挥双重作用 - 我们对移植和癌症免疫学方面的贩运机制的基本了解，同时通过引入新的目标，微型免疫培训药物来改变护理标准。 如果成功，该提案可能会导致预防GVHD的范式转移，为一项随机临床试验设置Stge，该试验将依靠相同的临床和免疫学终点来衡量其成功。