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）是有效的，部分原因是供体移植物具有移植物抗肿瘤（GvT）的潜力，然而，成功的SCT往往受到移植物抗宿主病（GvHD）的限制。急性GvHD是异体造血干细胞移植治疗血癌后发病和死亡的主要原因，发生在30-70%的移植中。全世界每年进行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。现有的预防和治疗GvHD的方式是免疫抑制，损害免疫恢复，并可能限制GvT的作用。我们之前的工作已经证明，阻断CCR5（一种趋化因子受体）可显著降低人类内脏GvHD。当前建议的总体目标是利用同种异体SCT后淋巴细胞运输的药理学控制来获得治疗效益。中心假设是

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.