Targeting CCR7 for the Prevention/Treatment of GvHD

靶向 CCR7 预防/治疗 GvHD

• 批准号: 8372352
• 负责人: Jonathan S. Serody
• 金额: $ 37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-02 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372352
• 关键词: Acute; Acute Graft Versus Host Disease; Acute leukemia; Address; Adoption; Adverse effects; Allogenic; Anti-Infective Agents; Antigen-Presenting Cells; Biology; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Calcineurin; Calcineurin inhibitor; Canis familiaris; Cellular Immunity; Chemicals; Clinical Research; Clinical Trials; Collaborations; Cyclosporine; Data; Defect; Disease; Drug usage; Engraftment; Evaluation; Glucocorticoids; Goals; HLA Antigens; Homologous Transplantation; Human; Immigration; Immunosuppressive Agents; Incidence; Individual; Indolent; Inflammatory; Lead; Ligands; Lymphoid Tissue; Lymphoma; Malignant lymphoid neoplasm; Mediating; Methotrexate; Modeling; Mus; Organ; Pancytopenia; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Prevention; Prevention Research; Prevention approach; Prevention therapy; Production; Property; Purines; Recurrence; Regimen; Regulatory T-Lymphocyte; Relapse; Research Personnel; S Phase; Secondary to; Signal Transduction; Site; Spleen; Stem cell transplant; Syndrome; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Tacrolimus; Transplantation; Work; chemokine; chemokine receptor; chronic graft versus host disease; drug discovery; graft vs host disease; high risk; in vivo; inhibitor/antagonist; interest; lymph nodes; migration; neoplastic cell; novel; novel strategies; pathogen; prevent; prophylactic; purine; receptor; response; tumor

DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (Allo-SCT) is still the most effective form of therapy for the treatment of patients with high risk or relapsed acute leukemia, bone marrow failure syndromes, congenital bone marrow production defects, and is increasingly used as a potential curative therapy for patients with low grade lymphoid malignancies. Allo-SCT is limited in most transplant centers to the treatment of individuals with a perfect or one antigen HLA mismatch with the donor because of the high risk of acute GvHD found after greater mismatched transplants. Even with prophylactic therapy, the incidence of acute GvHD is 30-70%. Additionally, the treatment of acute GvHD has not changed markedly in thirty years and consists primarily of glucocorticoids, which are associated with a significant number of side-effects and complications. Our group has been interested in a new approach to the prevention or treatment of acute GvHD. This approach targets the early activation of donor T cells that occurs in recipient lymphoid tissue and is mediated by interactions with host antigen presenting cells. This interaction mediates both the activation and proliferation of donor T cells. We have found that the chemokine receptor, CCR7, expressed by donor T cells is critically important for the migration of donor T cells to lymph nodes and the interaction of those T cells with APCs in the spleen. Blocking the function of CCR7 prevented acute GvHD without interfering with the anti-tumor properties mediated by donor T cells. This has led our group to isolate pharmacological compounds that block the activity of CCR7 as an approach to prevent or treat GvHD. Thus, we are not targeting the migration of T cells to GvHD target organs mediated by a large number of chemokine ligands/receptors but the migration of naive T cells to secondary lymphoid tissue, which is mediated specifically by CCR7. Over the past 18 months, we have identified four compounds that block the function and signaling of both human and murine CCR7. We have preliminary data presented in this proposal that our lead compounds, R71921a and b, can prevent acute GvHD in a haploidentical transplant model and that this activity is similar to that found using the drug tacrolimus. This proposal is focused on determining if these inhibitors and two other compounds can prevent GvHD without inhibiting the anti-tumor or anti-infective properties of donor T cells and to determine the mechanism by which these compounds function. Additional studies will determine if our lead compounds can treat ongoing acute GvHD, can enhance the function of calcineurin inhibitors, and do not impact on the ability of regulatory T cells to prevent acute and chronic GvHD. If these studies are successful, we will pursue, in a separate proposal, evaluations of the human CCR7 inhibitors in canine studies of allo-SCT. The overall goals of this work are to develop these inhibitors as a potential new therapy for the prevention or treatment of acute GvHD. We believe that targeting CCR7 may offer the "holy grail" approach sought by transplant investigators for over 30 years by preventing acute GvHD while preserving the GvL response. PUBLIC HEALTH RELEVANCE: GvHD remains the biggest barrier to the wider adoption of allogeneic SCT as a therapy. Our work focuses on a novel group of compounds that can block GvHD by targeting the chemokine receptor, CCR7. Successful completion of this proposal would lead to a phase I/II clinical trial of these compounds.

描述（由申请人提供）：同种异体干细胞移植（Allo-SCT）仍然是治疗高风险或复发性急性白血病，骨髓衰竭综合症，先天性骨髓生产缺陷的最有效疗法的形式，并且越来越多地用作低级别乳液乳酸乳腺症患者的潜在治疗疗法。在大多数移植中心，Allo-SCT受到了患有A 由于在更大的不匹配移植后发现急性GVHD的高风险，因此与捐赠者的抗原HLA不匹配或抗原HLA不匹配。即使进行预防性疗法，急性GVHD的发生率也为30-70％。此外，急性GVHD的治疗在三十年中没有明显变化，主要由糖皮质激素组成，糖皮质激素与大量副作用和并发症有关。我们的小组对一种新的预防或治疗急性GVHD感兴趣。该方法靶向受体淋巴组织中发生的供体T细胞的早期激活，并通过与宿主抗原呈递细胞的相互作用介导。这种相互作用介导了供体T细胞的激活和增殖。 我们发现，供体T细胞表达的趋化因子受体CCR7对于供体T细胞向淋巴结的迁移至关重要，而这些T细胞与脾脏中的APC的相互作用至关重要。阻止CCR7的功能阻止了急性GVHD，而不会干扰由供体T细胞介导的抗肿瘤特性。这导致我们的小组隔离了药理化合物，从而阻止CCR7的活性作为预防或治疗GVHD的方法。因此，我们不是针对T细胞向由大量趋化的配体/受体介导的GVHD靶器官的迁移，而是幼稚T细胞向继发性淋巴组织的迁移，这是由CCR7特别介导的。在过去的18个月中，我们确定了四种阻断人和鼠CCR7功能和信号的化合物。我们在本提案中提供了初步数据，即我们的铅化合物R71921A和B可以防止在单倍性移植模型中急性GVHD，并且该活性与使用药物他克莫司的发现相似。该建议的重点是确定这些抑制剂和其他两种化合物是否可以防止GVHD，而无需抑制供体T细胞的抗肿瘤或抗感染特性，并确定这些化合物起作用的机制。其他研究将确定我们的铅化合物是否可以治疗持续的急性GVHD，可以增强钙调蛋白抑制剂的功能，并且不会影响调节性T细胞防止急性和慢性GVHD的能力。如果这些研究成功，我们将在另一项建议中追求对Allo-SCT犬研究中人类CCR7抑制剂的评估。这项工作的总体目标是开发这些抑制剂，作为预防或治疗急性GVHD的潜在新疗法。我们认为，针对CCR7可能会通过防止急性GVHD在保留GVL响应的同时，提供30多年的移植调查人员寻求的“圣杯”方法。 公共卫生相关性：GVHD仍然是广泛采用同种异体SCT作为一种疗法的最大障碍。我们的工作着重于一组新的化合物，可以通过靶向趋化因子受体CCR7来阻止GVHD。该提案的成功完成将导致这些化合物的I/II期临床试验。