Targeting CCR7 for the Prevention/Treatment of GvHD

描述（由申请人提供）：同种异体干细胞移植（Allo-SCT）仍然是治疗高危或复发性急性白血病、骨髓衰竭综合征、先天性骨髓生成缺陷患者的最有效治疗形式，并且越来越多地用作低度淋巴恶性肿瘤患者的潜在治愈性治疗。在大多数移植中心，Allo-SCT仅限于治疗患有 完美的或一个抗原HLA与供体不匹配，因为在更大的不匹配移植后发现急性GvHD的高风险。即使采用预防性治疗，急性GvHD的发生率也为30- 70%。此外，急性GvHD的治疗在三十年内没有明显变化，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相关。我们小组一直对预防或治疗急性GvHD的新方法感兴趣。这种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。这种相互作用介导供体T细胞的活化和增殖。 我们已经发现，由供体T细胞表达的趋化因子受体CCR 7对于供体T细胞向淋巴结的迁移以及这些T细胞与脾脏中的APC的相互作用至关重要。阻断CCR 7的功能可以预防急性GvHD，而不会干扰供体T细胞介导的抗肿瘤特性。这使得我们的研究小组分离出阻断CCR 7活性的药理学化合物，作为预防或治疗GvHD的方法。因此，我们不靶向由大量趋化因子配体/受体介导的T细胞向GvHD靶器官的迁移，而是靶向由CCR 7特异性介导的幼稚T细胞向次级淋巴组织的迁移。在过去的18个月里，我们已经确定了四种化合物，可以阻断人类和小鼠CCR 7的功能和信号传导。我们在该提案中提供了初步数据，即我们的先导化合物R71921 a和B可以在单倍相合移植模型中预防急性GvHD，并且该活性与使用药物他克莫司发现的活性相似。该提案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细胞的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。进一步的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，是否可以增强钙调磷酸酶抑制剂的功能，并且不影响调节性T细胞预防急性和慢性GvHD的能力。如果这些研究是成功的，我们将在一个单独的提案中，在犬allo-SCT研究中对人CCR 7抑制剂进行评价。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，靶向CCR 7可能提供移植研究人员30多年来寻求的“圣杯”方法，即预防急性GvHD，同时保持GvL反应。

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.