Clinical Trials of Allogeneic Transplantation for Inherited Immune Deficiencies

该项目涉及使用造血干细胞移植治疗遗传性免疫缺陷的治疗性临床试验。我们之前报道了成功地使用非消融性条件调节实现了成功的长期植入和治愈CGD患者，使用相合的同胞供者作为造血干细胞移植的来源。这种方法的问题之一是移植物失败率高(30%)或植入率很低。2004年，我们对我们之前移植的X-CGD儿童进行了随访移植，该儿童获得了高水平的供体T细胞移植，但长期骨髓移植不到1%。我们证明，仅用10 mg/kg的白花丹就能成功地将淋巴系和髓系的供体嵌合转化为几乎100%的供体嵌合体。这强烈支持使用这种方法来挽救低植入率，而不是使用完全去除骨髓和淋巴的调节方案来进行这种挽救治疗。 我们现在已经开始了一项临床试验，使用匹配的亲属、匹配的非亲属或脐带血产品治疗免疫缺陷患者，并使用由CamPath 1-H和白消安与西罗莫司组成的耐受诱导条件方案预防移植物抗宿主疾病。对于接受无关产品的患者，全身照射也被添加到方案中。到目前为止，我们已经招募了四名患者。第一个患者，32岁男性，患有X连锁CGD和潜在的肾功能障碍，接受了来自非亲属捐赠者的10/10的人类白细胞抗原相合的骨髓产品。患者植入缓慢，并伴有较长时间的中性粒细胞减少和血小板减少。此外，他在接受一剂双菌胺后发生了肾功能衰竭，原因是推测是真菌感染。虽然患者接受了来自同一捐赠者的第二个干细胞产品，并通过嵌合体分析实现了完全植入，但患者随后拒绝进一步治疗，特别是透析，并在移植后95天因尿毒症和高钾血症而过期。第二例患者是一名15岁男性，患有X-SCID和潜在的MAI感染，之前4次无条件单倍体移植失败。对于他的调理，他接受了ATG而不是CamPath，因为他只有一种脐带血产品可供选择，鉴于他潜在的T细胞缺陷以及与脐带血产品相关的T细胞恢复较慢，因此选择使用半衰期较短的T细胞消除剂。除此之外，他同时接受了辐射和丁硫丹治疗，并按照协议接受了西罗莫司的治疗。患者目前在移植后30天内完全植入，到目前为止情况良好。预计出院日期为移植后38天。另外两名患者正在等待移植前的工作完成。 与此同时，我们一直在研究腺苷A2a受体激动剂的使用。先前的研究表明，针对该受体的激动剂可以改善组织损伤的缺血模型的结果。与弗吉尼亚大学的研究人员合作，他们提供了一种名为ATLe146的特定激动剂，我们一直在移植物抗宿主病的小鼠模型中测试这种药物。在我们的F1亲本移植模型中，我们已经看到了减轻移植物抗宿主病的发生和严重程度的益处，实验正在进行中，以进一步阐明其益处的确切机制。我们还开始尝试使用同样的移植模型进一步确定树突状细胞在移植物抗宿主病中的作用。最后，我们正在开发一项临床前试验，将该药物用于治疗慢性GVHD，并最终在移植方案中预防GVHD。使用我们实验室与John Gallin博士和Kol Zarember博士建立的水泡模型，我们计划局部应用该药物，以评估其对炎症和细胞对损伤信号的反应的影响。

This project involves the conduct of therapeutic clinical trials for the treatment of inherited immune deficiencies using hematopoietic stem cell transplantation. We previously reported the successful use of non-ablative conditioning to achieve successful long term engraftment and cure of CGD patients using HLA-matched sibling donors as the source of the hematopoietic stem cell graft. One of the problems with this approach was the high rate (30%) of graft failure or very low engraftment. In 2004 we performed a follow up transplant on an X-CGD child previously transplanted by us who had achieved high level donor T cell engraftment but less than 1% long term myeloid engraftment. We demonstrated successful permanent conversion to almost 100% donor chimerism in the lymphoid and myeloid lineages using conditioning with only busulfan at 10 mg/kg. This strongly supports the use of this approach to rescue low engraftment rather than using a fully myelo- and lympho-ablative conditioning regimen for such salvage therapy. We have now opened a clinical trial to treat patients with immunodeficiencies using either a matched related, matched unrelated, or cord blood product and a tolerance inducing conditioning regimen consisting of Campath 1-H and busulfan with sirolimus for graft versus host disease prophylaxis. For patients receiving an unrelated product, total body irradiation is also added to the regimen. To date we have enrolled four patients. The first patient, a 32 year old male with X linked CGD and underlying renal dysfunction, received a 10 out of 10 HLA matched bone marrow product from an unrelated donor. The patient had slow engraftment with a prolonged period of neutropenia and thrombocytopenia. In addition he developed renal failure after receiving one dose of ambisome for a presumed fungal infection. Although the patient received a second stem cell product from the same donor, and achieved full engraftment by chimerism analysis, the patient subsequently declined further treatment, specifically dialysis, and subsequently expired due to uremia and hyperkalemia at 95 days post transplant. The second patient is a 15 year old male with X-SCID and underlying MAI infection who has failed 4 previous attempts an unconditioned haplotransplantation. For his conditioning, he received ATG instead of the Campath as he had only a cord blood product available to him and given his underlying T cell deficiency along with a slower T cell recovery associated with cord blood products, it was opted to use a T cell depleting agent with a shorter half life. He otherwise received both the radiation and busulfan and has been maintained on sirolimus as per protocol. The patient is currently 30 days post transplant with full engraftment, and doing well to date. The anticipated date of discharge will be 38 days post transplant. The other two patients are awaiting completion of their work up prior to transplant. Meanwhile, we have been investigating the use of an adenosine A2a receptor agonist. Prior studies have shown that agonists specific to this receptor improve outcomes in ischemia models of tissue damage. In collaboration with the investigators at the University of Virginia who have supplied a specific agonist known as ATLe146, , we have been testing this drug in a murine model of graft versus host disease. We have seen benefit in attenuating the onset and severity of GVHD in our F1-parental transplant model and experiments are undergoing to further elucidate the exact mechanism of its benefit. We have also begun working on trying to further define the role of dendritic cells in GVHD using this same transplant model. Finally we are in the process of developing a pre clinical trial to use this drug for the treatment of chronic GVHD and eventually as a prevention of GVHD in the transplant regimen. Using a blister model established in our lab with Dr John Gallin and Kol Zarember, we plan to apply the drug topically to assess its effects on inflammation and cellular responses to damage signals.