Clinical Trials of Allogeneic Transplantation for Inherited Immune Deficiencies

该项目涉及利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。我们先前报道了使用HLA匹配的同胞供体作为造血干细胞移植物的来源，成功地使用非消融性预处理来实现CGD患者的成功长期植入和治愈。 这种方法的问题之一是移植失败率高（30%）或植活率极低。在2004年，我们对一名先前由我们移植的X-CGD儿童进行了随访移植，该儿童已经实现了高水平的供体T细胞植入，但长期骨髓植入率低于1%。 我们证明了仅使用10 mg/kg白消安预处理，淋巴和骨髓谱系中几乎100%的供体嵌合体成功永久转化。 这强烈支持使用这种方法来挽救低植入，而不是使用完全骨髓和淋巴消融预处理方案进行这种挽救治疗。 我们现在已经开展了一项临床试验，使用匹配的相关、匹配的无关或脐带血产品和由Campath 1-H和白消安与西罗莫司组成的耐受诱导预处理方案治疗免疫缺陷患者，用于预防移植物抗宿主病。 对于接受不相关产品的患者，还将全身照射添加到方案中。到目前为止，我们已经招募了四名患者。 第一位患者是一位32岁的男性，患有X连锁CGD和潜在的肾功能不全，接受了来自无关供体的10/10 HLA匹配的骨髓产物。 患者植入缓慢，伴中性粒细胞减少症和血小板减少症持续时间延长。 此外，他在接受一剂ambisome治疗疑似真菌感染后发生肾衰竭。 尽管患者接受了来自同一供体的第二种干细胞产品，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，并随后在移植后95天因尿毒症和高钾血症而死亡。 第二位患者是一名15岁的男性，患有X-SCID和潜在的MAI感染，他之前4次尝试非条件单倍移植失败。 对于他的调节，他接受了ATG而不是Campath，因为他只有脐带血产品，并且考虑到他的潜在T细胞缺乏沿着与脐带血产品相关的T细胞恢复较慢，选择使用半衰期较短的T细胞消耗剂。 除此之外，他接受了放疗和白消安，并按照方案维持西罗莫司治疗。 患者目前在移植后30天完全植入，并且迄今为止表现良好。 预计出院日期为移植后38天。另外两名患者正在等待完成移植前的检查。 同时，我们一直在研究腺苷A2 a受体激动剂的用途。 先前的研究已经表明，特异于该受体的激动剂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，他们提供了一种称为ATLe 146的特异性激动剂，我们一直在移植物抗宿主病的小鼠模型中测试这种药物。 我们已经看到在我们的F1亲本移植模型中减轻GVHD的发作和严重程度的益处，并且正在进行实验以进一步阐明其益处的确切机制。 我们也开始尝试使用相同的移植模型进一步确定树突状细胞在GVHD中的作用。 最后，我们正在开发一项临床前试验，使用这种药物治疗慢性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.