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，使用匹配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。 2007年，我们启动了一项临床方案，使用白花丹、坎帕特和小剂量TBI治疗了44名CGD患者，其中39人接受了无关的供体移植。研究结果最近发表在《临床免疫学杂志》上。(Para et al.JCI)。总体而言，我们对CGD患者的结果特别有希望，47人中有38人总体存活，38人中有35人长期植入率可评估。我们也是唯一一个移植了P40形式CGD的患者的中心，在这个独特的亚组中显示出难治性结肠炎的完全逆转。在这项研究的后续工作中，我们在先前结果的基础上开启了一项新的方案，使用更高的细胞剂量和移植后的环磷酰胺来减轻由于更高的细胞剂量而增加的GvHD风险。在这一点上，我们已经招募了6名患者参加该方案，其中一名患者因其潜在的进行性肺部疾病而提前死亡。1例患者由于细胞剂量低而未接受移植后的环磷酰胺治疗，尽管有早期植入，但在第85天被排斥。他仍然活着，身体很好。其他四名患者情况良好，到目前为止只有一名患者患有轻微的皮肤GvHD。 2014年底，我们还启动了一项使用单倍体相合供者的临床试验，并移植了一名没有匹配供者的患者。这位患者的持续感染对所有涉及心脏的标准治疗都是无效的，因此我们进行了亲代移植，并在移植后使用环磷酰胺。我们获得了良好的植入，仅有有限的移植物抗宿主病。这名患者现已出院近2年，感染已完全消失，并已在出版物中进行了描述。(J Clin免疫。2015年10月；35(7)：675-80)。我们共招募了7名接受该方案的患者，但在最后3名患者中经历了严重的GvHD，其中两名患者死于与GvHD相关的并发症。第三名患者从GvHD中恢复后情况良好。该方案现已结束，目前正在准备一项修正案，以继续进行单倍体相合移植，但对其进行修改，试图减少严重GvHD的发生率。 为了确定CGD移植的总体结果，我们已经成为初级免疫缺陷治疗联盟(J Allants Clin免疫)的一部分。2014年2月；133(2)：335-47)，并启动了一项合作协议，以审查北美CGD移植的结果。我们已经招募了100多名先前移植的患者，并正在准备一份关于这些患者积累的一些数据的手稿。我们还一直在获取移植前后的粪便样本进行微生物组分析，这是与艾米莉亚·法尔科内(NIAID)和朱莉·塞格雷(NHGRI)合作进行的一项子研究。 在相关的实验室临床前研究中，我们一直在研究腺苷A2a受体激动剂用于预防或治疗移植物抗宿主病(GVHD)。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。在我们的F1亲本移植模型中，我们已经看到了减轻GVHD的发病和严重程度的益处，并在《白细胞生物学杂志》上发表了这一数据。进一步的研究表明，T调节细胞(Tregs)是药物作用机制的一部分。 我们现在已经与Lewis和Clark制药公司(正式名称为腺苷治疗公司/PGxHealth/森林实验室)建立了CRADA，以研究A2a受体激动剂的其他配方，并在体外和体内观察到这些激动剂对Tregs的类似效果。这项数据发表在《免疫学杂志》(J。2013年1月1日；第190(1)：458-68)最近，我们发表了一种新的方法，在开始活体小鼠研究之前，以更快和更有效的方式评估这些激动剂(科学代表2017年3月20日；7：44816)。 我们还与UHSUS的Gabriel Dvesklar合作，研究妊娠特异性糖蛋白-1(PSG-1)作为一种免疫调节剂和GvHD的可能治疗方法。初步的体外和体内研究表明，在使用该蛋白治疗的小鼠模型中，GvHD的减少是有希望的。Sharma博士已经在美国血液学学会(ASH)的年度会议上展示了其中的一些数据，我们已经发表了一篇论文，其中包括我们对这些化合物的一些分析，第二篇手稿正在准备中，内容是关于它在GvHD小鼠模型中的应用。(《公共科学图书馆·综合》2016年7月7日；11(7)) 最后，我们一直在评估GvHD对大脑的一些影响，这个项目涉及到IRTA Sarah Bryant，她在实验室工作到今年夏天，她向ASH会议提交了一份摘要。

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. In 2007 we initiated a clinical protocol using busulfan, Campath and low dose TBI and treated 44 patients with CGD, 39 of whom received an unrelated donor graft. and the results were recently published in the Journal of Clinical Immunology. (Parta et al. JCI). Overall our results for the CGD patients in particular are especially promising with an overall survival of 38 out of 47 and an overall long term engraftment rate of 35 out of 38 evaluable. We are also the only centre to have transplanted patients with the P40 form of CGD demonstrating complete reversal of refractory colitis in this unique subset. In follow up to that study we have opened a new protocol modeling on our previous results using a higher cell dose and post transplant cyclophosphamide to mitigate the increased risk of GvHD from the higher cell dose. At this point, we have enrolled 6 patients on this protocol with one death early due to his underlying progressive pulmonary disease. One patient did not receive the post transplant cyclophosphamide due to a low cell dose and although had early engraftment, rejected at day 85. He remains alive and well. The other four patients are doing well with only one patient having mild GvHD of the skin to date. At the end of 2014, we also initiated a clinical trial using haploidentical donors and transplanted a patient with no matched donors available. This patient had an ongoing infection refractory to all standard therapy involving the heart and we therefore proceeded with a parental graft and using post-transplant cyclophosphamide. We obtained good engraftment with only limited graft versus host disease. This patient is now almost 2 years out with complete resolution of his infection and has been described in publication. (J Clin Immunol. 2015 Oct;35(7):675-80). We enrolled a total of 7 patients on this protocol but experienced severe GvHD in the last three patients with two of the patients succumbing to complications related to GvHD. The third patient is doing well having recovered from the GvHD. This protocol is now closed and an amendment is being prepared to continue with haploidentical transplants but with lmodifications to try to decrease the incidence of severe GvHD. In order to determine the outcomes of transplant for CGD in general, we have become a part of the Primary Immune Deficiency Treatment Consortium ( J Allergy Clin Immunol. 2014 Feb;133(2):335-47) and have initiated a collaborative protocol to review the results of transplant done for CGD in North America. We have enrolled over 100 previously transplanted patients and are preparing a manuscript on some of the data accrued from these patients. We have also been obtaining stool samples pre and post transplant for microbiome analysis, which is a substudy being done in collaboration with Emilia Falcone (NIAID) and Julie Segre (NHGRI). In related laboratory pre-clinical studies, we have been investigating the use of an adenosine A2a receptor agonist to prevent or treat graft versus host disease (GVHD). Prior studies have shown that agonists specific to this receptor improve outcomes in ischemia models of tissue damage. We have seen benefit in attenuating the onset and severity of GVHD in our F1-parental transplant model and have published this data in the Journal of Leukocyte Biology. Further studies have shown a role for T regulatory cells (Tregs) as part of the mechanism of the drugs effects. We have now established a CRADA with Lewis and Clark Pharmaceuticals (formally Adenosine Therapeutics/PgxHealth/Forest Labs) to study other formulations of the A2a receptor agonists and have seen similar effects on Tregs, both in vitro and in vivo, by these agonists. This data was published in the Journal of Immunology (J Immunol. 2013 Jan 1;190(1):458-68) More recently, we have published a new method to assess these agonists in a more rapid and efficient manner prior to beginning in vivo murine studies (Sci Rep. 2017 Mar 20;7:44816). We also had a collaboration with Gabriel Dvesklar of UHSUS to study Pregnancy Specific Glycoprotein -1 (PSG-1) as an immunomodulator and a possible therapy for GvHD. Preliminary in vitro and in vivo studies have been promising with reduced GvHD seen in our mouse models treated with the protein. Dr Sharma has presented some of this data at the annual American Society of Hematology (ASH) meeting and we have published one paper with some of our analysis of these compounds and a second manuscript is in preparation regarding its use in our GvHD murine models. (PLoS One.2016 Jul 7;11(7)) Finally, we have been evaluating some of the effects of GvHD on the brain in a project involving, Sarah Bryant, an IRTA who worked in the lab until this summer and who has submitted an abstract to the ASH meeting.