ROCK inhibitor suppression of GVHD with retention of GVL response

ROCK 抑制剂抑制 GVHD 并保留 GVL 反应

基本信息

批准号：
8319306
负责人：
SUJATHA IYENGAR
金额：
$ 22.01万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319306
关键词：
Ablation Acute Acute Disease Acute Graft Versus Host Disease Address Adjuvant Therapy Adverse effects Alloantigen Allogeneic Bone Marrow Transplantation Allogenic Antigens Antineoplastic Agents Autoimmunity Blood Cells Bone Marrow Transplantation Cardiovascular system Cause of Death Cells Cessation of life Clinical Clinical Trials Clonal Deletion Complication Control Animal Data Development Disease Donor person Dose Drug usage Effectiveness Elements Enzymes Epithelial Failure Functional disorder Goals Graft Rejection Hematopoiesis Histocompatibility Histopathology Homing Immune Immune response Immunosuppression Immunosuppressive Agents Immunotherapy Infection Left Leukocytes Life Liver Lung Malignant Neoplasms Marrow Measures Mediating Minor Minor Histocompatibility Antigens Modeling Monitor Morbidity - disease rate Mus Myeloid Leukemia Myeloproliferative disease Organ Outcome Patients Permeability Pharmaceutical Preparations Phase I Clinical Trials Phosphorylation Phosphotransferases Predisposition Prevention ROCK1 gene Records Regimen Regulation Relapse Relative (related person)Research Residual state Risk Role Safety Schedule Severities Siblings Site Skin Stem cells Steroids Survivors System T-Cell Depletion T-Lymphocyte Techniques Testing Tight Junctions Tissues Transplantation Tumor Burden Vasodilator Agents Work cancer therapy cell motility chronic graft versus host disease compare effectiveness cost cytokine drug testing effective therapy experience fasudil graft failure graft vs host disease graft vs leukemia effect healthy volunteer immunopathology immunoregulation inhibitor/antagonist leukemia mortality mouse model novel permissiveness prevent purge response rho small molecule success telmisartan trafficking treatment duration tumor weapons

项目摘要

DESCRIPTION (provided by applicant): Bone marrow transplantation (BMT) following ablation of the patient's hematapoietic system is a life-saving treatment for several types of leukemia. Acute graft vs. host disease (GVHD) is a serious complication in more than a third of bone marrow transplants (BMTs) between MHC matched donors and recipients, and the proximate cause of death in ~ 15% of BMT patients. Purging infused marrow of all donor T cells largely eliminates GVHD, but results in more frequent stem cell failure to engraft, and higher rates of leukemia relapse. The inverse correlation between GVHD and relapse is attributable to the graft vs. leukemia (GVL) response, whereby donor T cells recognize host alloantigens on residual leukemia cells. It is unclear whether sufficient numbers of donor T cells recognize leukemia specific antigens to afford protection in the absence of alloreactivity, but this issue is presently moot, since a technique for efficiently removing all alloreactive cells while retaining leukemia specific cells is not yet available. The severity of GVHD depends on the strength of the alloreactive response, the ability of donor T cells to infiltrate target organs (skin, gut, liver, lungs), and the susceptibility of those tissues to immune mediated damage. Given the problems inherent in eliminating alloreactive donor cells, the optimal theoretical approach might be to limit their access to host sites most susceptible to immunopathology, and/or most likely to induce reactivity. Our approach may accomplish this by inhibition of Rho associated coiled coil kinases (ROCK1&2) enzymes crucial for cytoskeletal function during leukocyte motility and loosening of endothelial and epithelial tight junctions. Three small molecule ROCK inhibitors will be tested in MHC and minor histocompatibility antigen (miHA) disparate BMT mouse models. Two inhibitors of ROCK1&2 (Telmisartan and Fasudil) have extensive clinical safety records as vasodilators. The third, SLx2119 is ROCK2 specific, and has just passed Phase 1 clinical trials on the path to development as an anti-cancer drug. Our preliminary data indicate that 10 days (but not 1 day) of Fasudil is highly protective against acute MHC disparate GVHD, without inducing allotolerance that could compromise beneficial GVL. We propose to extend this observation by testing the three mentioned drugs in both MHC and miHA models in 1 vs. 2 week schedules, to find the shortest duration of treatment that maximally suppresses GVHD. The optimal schedule for each drug will be used to suppress GVHD in the presence of infused host- syngeneic leukemia cells, and tumor burden will be monitored in treated and untreated mice. We hypothesize that ROCK inhibition will interfere with donor T cell alloactivation and/or trafficking to primary sites of GVHD, and that interference with alloactivation will not hinder donor T cells from finding and attacking more accessible leukemia cells. Our objective is to determine at least one schedule of ROCK inhibitor that suppresses GVHD while sparing GVL function. Using ROCK inhibitors for GVHD is novel, and success would accelerate our long term goal of using ROCK inhibitors with BMT, to treat leukemias and other tumors.

描述（由申请人提供）：消融患者造血系统后的骨髓移植（BMT）是一种挽救多种白血病的生命治疗方法。在MHC匹配的供体和受体之间，急性移植与宿主病（GVHD）是严重的并发症，而BMT患者中，MHC匹配的捐助者和受体匹配的骨髓移植（BMT）是严重的并发症。清除所有供体T细胞的注入骨髓在很大程度上消除了GVHD，但导致干细胞不植入的频率更高，白血病复发率更高。 GVHD与复发之间的反相关性归因于移植物与白血病（GVL）反应，从而供体T细胞识别残留白血病细胞上的宿主同种抗原。目前尚不清楚是否有足够数量的供体T细胞识别白血病特异性抗原在没有异种反应性的情况下提供保护，但是目前这一问题是毫无意义的，因为一种用于有效去除所有同种异体反应性细胞而保留白血病特异性细胞的技术尚不可用。 GVHD的严重程度取决于同种反应反应的强度，供体T细胞浸润靶器官（皮肤，肠道，肝脏，肺）的能力以及这些组织对免疫介导的损伤的敏感性。鉴于消除同种反应性供体细胞所固有的问题，最佳理论方法可能是限制他们对最容易受到免疫病理学最受影响的宿主位点的访问和/或最有可能诱导反应性的。我们的方法可以通过抑制RHO相关的盘绕线圈激酶（ROCK1和2）酶来实现这一目标，这对于白细胞运动过程中的细胞骨架功能至关重要，并松开内皮和上皮紧密连接。将在MHC和较小的组织相容性抗原（MIHA）不同的BMT小鼠模型中测试三个小分子岩抑制剂。 Rock1和2的两个抑制剂（Telmisartan和Fasudil）具有广泛的临床安全记录，作为血管扩张剂。第三，SLX2119是岩石2的特异性，并且刚刚通过了第1阶段的临床试验作为抗癌药物的发育途径。我们的初步数据表明，Fasudil的10天（但不是1天）对急性MHC不同的GVHD具有高度保护性，而不会诱导可能损害有益GVL的同倍耐受性。我们建议通过在1比2周的时间表中测试MHC和MIHA模型中提到的三种药物来扩展这一观察结果，以找到最大程度地抑制GVHD的治疗持续时间。每种药物的最佳时间表将用于抑制在注入宿主 - 合成性白血病细胞的情况下抑制GVHD，并且将在处理和未处理的小鼠中监测肿瘤负担。我们假设岩石抑制作用会干扰供体T细胞同酶和/或运输到GVHD的主要部位，并且对同酶激活的干扰不会阻止供体T细胞发现和攻击更易于访问的白血病细胞。我们的目标是确定至少一个抑制GVHD时抑制GVL功能的岩石抑制剂的时间表。使用岩石抑制剂进行GVHD是新颖的，成功将加速我们将岩石抑制剂与BMT，治疗白血病和其他肿瘤的长期目标。