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。 我们现在已经开始了一项临床试验，使用匹配的相关，匹配的无关，或脐带血产品和耐受诱导预处理方案组成的Campath 1-H和白消安与西罗莫司预防移植物抗宿主病（GVHD）的免疫缺陷患者进行治疗。 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16名患者，移植了14名。12例患者使用无关供体进行移植，我们已经看到非常有限的GVHD，只有1例患者患有2级皮肤GVHD。 我们在两个案例中使用了脐带血。1例为P67缺陷CGD患者，植入失败。 相信Campath对脐带血移植物中更幼稚的T细胞防止植入的能力产生负面影响，并且已经修改了方案以在脐带血产品的情况下使用ATG。 另一名接受脐带血的患者因X连锁严重联合免疫缺陷症而接受移植。 他接受了ATG而不是Campath的条件治疗，目前已完全植入3年，没有移植物抗宿主病的证据，免疫功能正常。 我们的方案中有3例死亡，1例CGD患者死于与移植无关的肾衰竭，随后拒绝继续透析。 第二例患者有白细胞粘附缺陷，尽管有植入证据，但仍因败血症死亡。 该患者之前的移植失败，在移植时感染，并且之前的粒细胞输注也具有高度同种免疫。第三名患者因Rag 1缺乏症接受移植，移植耐受性非常好，移植成功，但因意外药物过量而死亡。 我们已经移植了一些患者持续感染，包括真菌性骨髓炎的脊柱和/或脑膜，并在某些情况下，使用粒细胞输注期间移植诱导的中性粒细胞减少症，没有不良反应。 迄今为止，所有持续感染的CGD移植患者在移植过程中没有因感染进展而导致任何显著的发病率或死亡率。 总的来说，我们的结果特别是CGD患者的总体生存率为10/11，总体植入率为10/11。 移植失败的患者自体恢复，正在考虑进行第二次移植。 我们正在接受许多转诊，预计我们将继续每年移植4-5名患者。 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。 在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，我们在移植物抗宿主病的小鼠模型中测试了这种药物。 我们已经在F1-亲代移植模型中看到了减轻GVHD发作和严重程度的益处，并发表了这些数据。进一步的研究表明，调节性T细胞（T细胞）是药物作用机制的一部分。我们还在我们的模型中使用了临床批准的腺苷激动剂（Regadenosan），以预期建立临床试点试验;然而，我们已经确定对GVHD的影响对A2 a受体非常特异。 我们现在已经与PGxHealth（正式名称为腺苷治疗）建立了一个新的CRADA，以研究A2 a受体激动剂的其他制剂，并观察到这些激动剂对体外和体内T细胞的类似作用，并将我们的结果提交给美国血液学会2010年会议。 此外，我们发现雷帕霉素也可以减少我们模型中的TH 17细胞，我们现在正在研究我们模型中的联合药物疗法。我们正在继续研究这些药物的总体机制，并希望最终将其投入临床使用。

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 (GVHD) prophylaxis. For patients receiving an unrelated product, total body irradiation is also added to the regimen. To date we have enrolled 16 patients and transplanted 14. 12 of the patients were transplanted using an unrelated donor and we have seen very limited GVHD with only one patient having Grade 2 skin GVHD. We have used cord blood in two cases. One for a patient with P67 deficient CGD and who failed to engraft. The belief is that the Campath impacted negatively with the ability of the more naive T cells in a cord blood graft preventing engraftment, and the protocol has been modified to use ATG in the case of a cord blood product. The other patient to receive cord blood was transplanted for X-linked Severe Combined Immunodeficiency. He was conditioned with ATG instead of Campath and is currently 3 years out with full engraftment, no evidence of graft versus host disease, and normal immune function. We have had three deaths on the protocol, one patient with CGD who died due to renal failure unrelated to transplant and subsequent refusal to continue dialysis. The second patient had leukocyte adhesion deficiency and died due to sepsis, despite evidence of engraftment. This patient had failed a previous transplant, was infected at the time of the transplant, and was also highly alloimmunized from previous granulocyte infusions. The third patient was transplanted for Rag 1 deficiency, tolerated transplant extremely well and engrafted successfully but died due to accidental drug overdose. We have transplanted a number of patients with ongoing infections including fungal osteomyelitis of the spine and/or meninges and in some cases have used granuloctye infusions during the period of transplant-induced neutropenia with no adverse effects. To date, all patients with CGD transplanted with an ongoing infection have done well without any significant morbidity or mortality due to infection progression during the transplant course. Overall our results for the CGD patients in particular are especially promising with an overall survival of 10 of 11, and an overall engraftment rate of 10 of 11. The patient with failure to engraft had autologous recovery and is being considered for a second transplant. We are getting many referrals and anticipate that we will continue to transplant 4-5 patients a year. 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 tested 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 have published this data. Further studies have shown a role for T regulatory cells (Tregs) as part of the mechanism of the drugs effects. We also used a clinically approved adenosine agonist (Regadenosan) in our model in anticipation of setting up a clinical pilot trial; however we have determined that the effects on GVHD are very specific to the A2a receptor. We have now established a new CRADA with PGxHealth, formally Adenosine Therapeutics, to study other formulations of the A2a receptor agonists and have seen similar effects on T regs, both invitro and invivo, by these agonists and have submitted our results for presentation to the American Society of Hematology 2010 meeting. In addition, we have found that rapamycin also works to reduce TH17 cells in our model and we are studying combination drug therapies now in our model. We are continuing to study the mechanisms of these drugs overall and hope eventually to put these into clinical use.