Novel Biologic Therapies for BMT: Mechanistic Evaluation in Rhesus Macaques

BMT 的新型生物疗法：恒河猴的机制评估

• 批准号: 7785384
• 负责人: Leslie S Kean
• 金额: $ 83.44万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7785384
• 关键词: Acute Graft Versus Host Disease; Address; Adhesions; Adoptive Immunotherapy; Adult; Antibodies; Aplastic Anemia; Biological Markers; Biological Models; Biological Response Modifier Therapy; Bone Marrow; Bone Marrow Transplantation; Canis familiaris; Cell Adhesion; Cessation of life; Childhood; Clinic; Clinical; Clinical Trials; Diagnosis; Disease; Donor person; Evaluation; Face; Genetic; Graft Rejection; Hematological Disease; Human; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunophenotyping; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Inborn Errors of Metabolism; Intervention; Investigation; Lead; Life; Macaca mulatta; Malignant - descriptor; Minority; Modeling; Mus; Non-Malignant; Organ Transplantation; Outcome; Pathway interactions; Patients; Phenotype; Plague; Population; Pre-Clinical Model; Preclinical Testing; Prevention; Primates; Prophylactic treatment; Public Health; Regimen; Registries; Regulatory T-Lymphocyte; Research Proposals; Risk; Serum; Siblings; Sickle Cell Anemia; Solid; Source; T-Lymphocyte; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Treatment Protocols; base; clinical application; disorder prevention; immune activation; insight; leukemia; novel; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): Bone marrow transplantation (BMT) represents the best chance for cure for a large number of malignant and non-malignant hematologic diseases. However, BMT implementation is currently limited by the many critical complications that accompany this potentially life-saving therapy. This is especially true for the majority of patients (70-80%) who lack MHC-matched sibling donors, and thus face risky, unrelated and/or MHC-mismatched 'alternative-donor' transplants (AD-BMT). Three major complications have plagued the implementation of AD-BMT. They are: (1) The increased risk of graft rejection. (2) The high rate of acute graft-versus-host-disease (aGvHD) that occurs in the setting of MHC-mismatched BMT; and (3) the profound immunosuppression that patients face after transplant, which renders them highly susceptible to infectious and malignant death in the immediate and long-term post-transplant periods. Prevention and treatment of these three complications represents the major unmet clinical need in BMT. One of the most significant barriers to progress in addressing these complications has been the lack of a preclinical model through which novel biologic therapeutic strategies, developed for human use, can be thoroughly and mechanistically investigated prior to clinical trials. Thus, due to the fact that (1) most novel therapies for BMT (including T cell costimulation blockade, T cell adhesion blockade and adoptive immunotherapy with regulatory T cells) cannot be accurately tested in either murine or canine models for aGvHD and (2) there has been no other translational BMT model available to test these biologics prior to clinical use, they have remained under-analyzed and under-utilized in clinical BMT, despite their burgeoning use in other disease states. In order to address the unmet need for their detailed, translational and mechanistic investigation we have developed a novel primate model of AD-BMT, capable both of dissecting mechanism as well as providing the critical translational bridge to clinical application of novel therapies. In this proposal, we describe experiments using the primate model which will determine both mechanism and efficacy of T cell costimulation blockade, T cell adhesion blockade, and regulatory T cell adoptive immunotherapy on the outcome of AD-BMT. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation (BMT) is the treatment of choice for many of the thousands of pediatric and adult patients each year who are diagnosed with both malignant and non-malignant hematologic diseases, including leukemia, aplastic anemia, sickle cell disease, as well as the genetic immunodeficiencies and other inborn errors of metabolism. While BMT represents the best hope for cure for these devastating disorders, it is a treatment that is fraught with complications, which continue to severely limit its wide-spread application, especially for the large majority of patients (70-80%) which lack an MHC-matched sibling bone marrow donor and thus must be transplanted using an 'alternative-donor BMT' (AD-BMT): while some of these patients without a matched sibling donor will find a highly matched unrelated donor from the registry, the wait-time to activate these donors is often prohibitive (for patients with the most aggressive malignant diseases), and many minority populations still lack adequate donors in the registry, making them far less likely to find a matched unrelated donor than patients from the ethnic majority. This research proposal thus has direct relevance to world-wide public health, in that it seeks to understand the mechanisms and efficacy of new biologic therapies for AD-BMT, in order to develop safer, and more efficacious therapeutic regimens for the thousands of patients requiring this treatment each year.

描述（由申请人提供）：骨髓移植（BMT）代表了治愈大量恶性和非恶性血液学疾病的最佳机会。但是，BMT实施目前受到这种潜在挽救生命疗法的许多关键并发症的限制。对于缺乏MHC匹配的兄弟姐妹供体的大多数患者（70-80％），因此尤其如此，因此面临风险，无关和/或MHC不匹配的“替代性折扣”移植（AD-BMT）。三个主要的并发症困扰着AD-BMT的实施。它们是：（1）移植排斥的风险增加。 （2）在MHC不匹配的BMT的情况下发生的高急性移植物抗宿主疾病（AGVHD）； （3）患者在移植后面临的深刻免疫抑制，这使他们在直接和长期移植后期的直接和长期长期的死亡中极易受到感染和恶性死亡的影响。这三种并发症的预防和治疗代表了BMT的主要未满足临床需求。解决这些并发症的进展最重要的障碍之一是缺乏临床前模型，通过该模型可以通过该模型在临床试验之前对供人类使用的新型生物学治疗策略进行彻底和机械的研究。因此，由于（1）（1）BMT的大多数新型疗法（包括T细胞共刺激阻滞，T细胞粘附阻滞和调节性T细胞的产物免疫疗法）在AGVHD的鼠类或犬模型中无法准确测试，并且（2）在临床上没有其他频繁的临床模型，并且在临床上进行了频繁的频率，并且无法进行临床。 BMT尽管在其他疾病状态中迅速使用。为了满足其详细，翻译和机械研究的未满足需求，我们开发了一种新型的AD-BMT灵长类动物模型，能够解剖机制，并为新疗法的临床应用提供了关键的翻译桥梁。在此提案中，我们使用灵长类动物模型描述了实验，该模型将确定T细胞共刺激阻滞，T细胞粘附阻滞和调节性T细胞的产物免疫疗法的机制和功效，以实验AD-BMT的结果。 PUBLIC HEALTH RELEVANCE: Bone marrow transplantation (BMT) is the treatment of choice for many of the thousands of pediatric and adult patients each year who are diagnosed with both malignant and non-malignant hematologic diseases, including leukemia, aplastic anemia, sickle cell disease, as well as the genetic immunodeficiencies and other inborn errors of metabolism.尽管BMT代表了治愈这些毁灭性疾病的最佳希望，但它是一种充满并发症的治疗方法，它继续严重限制其广泛的应用，尤其是对于大多数患者（70-80％）（70-80％），缺乏MHC匹配的siblow bone骨头捐赠者，因此必须使用某个替代性的患者（因此）（因此）（因此）（又有一定的患者）（AD-BMMMT）（AD）：兄弟姐妹捐赠者会发现注册表的高度匹配的无关捐助者，激活这些捐赠者的等待时间通常是令人难以置信的（对于患有最激进的恶性疾病的患者），并且许多少数人群在注册表中仍然缺乏足够的捐助者，这使得他们比从民族多数患者中找到匹配的捐助者的可能性要少得多。因此，这项研究建议与全球公共卫生有直接的相关性，因为它试图了解AD-BMT的新生物疗法的机制和功效，以便为每年需要此治疗的成千上万患者开发更安全，更有效的治疗方案。