Targeting CCR7 for the Prevention/Treatment of GvHD

描述(申请人提供)：异基因干细胞移植(Allo-SCT)仍然是治疗高危或复发的急性白血病、骨髓衰竭综合征、先天性骨髓生成缺陷患者的最有效的治疗形式，并越来越多地被用作治疗低级别淋巴系统恶性肿瘤的潜在治疗方法。在大多数移植中心，异基因干细胞移植仅限于治疗患有 完全或某一抗原与供者完全不匹配，因为在较大的不匹配移植后发现急性GvHD的高风险。即使采取预防治疗，急性移植物抗宿主病的发生率仍为30-70%。此外，急性GvHD的治疗30年来没有明显变化，主要是糖皮质激素，这与大量的副作用和并发症有关。我们小组一直对预防或治疗急性移植物抗宿主病的新方法感兴趣。这种方法针对发生在受者淋巴组织中的供者T细胞的早期激活，并通过与宿主抗原提呈细胞的相互作用来调节。这种相互作用既调节供者T细胞的激活，又调节供者T细胞的增殖。 我们发现，供体T细胞表达的趋化因子受体CCR7对供体T细胞向淋巴结的迁移以及这些T细胞与脾内APC的相互作用至关重要。阻断CCR7功能可预防急性移植物抗宿主病，但不影响供体T细胞介导的抗肿瘤特性。这导致我们的团队分离出阻断CCR7活性的药理化合物，作为预防或治疗GvHD的方法。因此，我们针对的不是大量趋化因子配体/受体介导的T细胞向GvHD靶器官的迁移，而是原始T细胞向次级淋巴组织的迁移，这是由CCR7特异性地介导的。在过去的18个月里，我们已经确定了四种化合物，它们可以阻断人和小鼠CCR7的功能和信号。我们在这项提案中提供了初步数据，我们的先导化合物R71921a和b可以在单倍体相合的移植模型中预防急性GvHD，并且这种活性与使用药物他克莫司的相似。这项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在不抑制供体T细胞抗肿瘤或抗感染特性的情况下预防GvHD，并确定这些化合物发挥作用的机制。其他研究将确定我们的先导化合物是否可以治疗正在进行的急性GvHD，是否可以增强钙调神经磷酸酶抑制剂的功能，并且不会影响调节性T细胞预防急性和慢性GvHD的能力。如果这些研究成功，我们将在一项单独的提案中继续评估人类CCR7抑制剂在犬类allo-SCT研究中的作用。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移植物抗宿主病的潜在新疗法。我们认为，靶向CCR7可能提供移植研究人员30多年来一直寻求的“圣杯”方法，通过预防急性GvHD，同时保留GVL反应。 公共卫生相关性：GVHD仍然是广泛采用同种异体干细胞移植作为治疗方法的最大障碍。我们的工作集中在一组新的化合物上，这些化合物可以通过靶向趋化因子受体CCR7来阻断GvHD。这项提议的成功完成将导致这些化合物的I/II期临床试验。

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.