CCR5 Analyses in HIV Infected Hematology Patients undergoing Umbilical Cord Blood Allogeneic Transplantation

感染艾滋病毒的血液病患者通常被排除在异体骨之外。 骨髓/干细胞移植(AllSCT)方案。抗逆转录病毒疗法(ART)是一种高效、安全、 然而，方便的是，患者经常保持循环中的低CD4计数，并增加促炎作用 国家，以及相关的发病率和死亡率。异基因干细胞移植治疗恶性血液病大多数是治愈的 通过免疫调节效应导致的其他致命血液病患者中移植物对白血病的影响 这反映了在建立全供者期间所有移植患者的造血细胞最终被消除 嫁接。这项转化研究计划和临床试验旨在调查 输注CCR5∆32纯合子或杂合子脐带血(CB)单位，在无关的脐带血登记中确定 寻找，可能通过异基因供者免疫清除的方式消除HIV感染的受者造血细胞 恶性血液病和HIV感染患者的受者造血细胞需要一个 异基因SCT。降低脐带血后长期细胞减少的发病率和死亡率 移植时，我们还将使用NLA101，这是一种由体外组成的冷冻保存细胞疗法 扩增的CD34+造血干/祖细胞最初是从脐带血中分离出来的。十 患者将在以下研究地点进行登记和治疗：FHCRC(与其癌症联盟合作伙伴， 华盛顿大学和西雅图儿童医院)，凯斯西储大学 医院(Marcos de Lima，PI)、儿童研究所/国家儿童医学中心(Blachy 戴维拉-萨尔达纳，派)，纪念-斯隆-凯特琳癌症中心(朱丽叶·巴克，派)，加州大学- 旧金山(蒂莫西·亨利希，少年派)。我们将利用allSCT的平台进一步深入了解 异基因供者免疫细胞清除受者造血对HIV储存库的潜在清除作用 细胞，并检查这些患者的免疫重建。我们将使用最先进的高度敏感的分析方法 监测病毒RNA和细胞相关的RNA和DNA，以测量艾滋病毒储存库的腐烂程度； 集成的免疫监测方法，结合了几个高维平台(Transcriptomics， 系统血清学、多参数流式细胞术)将使我们能够识别相关性、先天和适应性 与艾滋病毒宿主的控制和腐烂有关的免疫机制。这可能会让HIV-1 感染患者在没有预期病毒的情况下停止抗逆转录病毒治疗(ART)持续一段时间 反弹，正如在9年多的时间内观察到的那样，HIV感染的白血病患者接受了 同种异基因干细胞移植结合CCR5∆32纯合子移植物(又名“柏林患者”)。这是意料之中的 在接下来的36个月里根据R34获得的数据将为设计和执行 随后进行更大规模的多点第二阶段研究。

Patients with hematologic disorders who are HIV infected are generally excluded from allogeneic bone marrow/stem cell transplant (alloSCT) protocols. Anti-retroviral therapy (ART) is highly effective, safe, and convenient, however often patients maintain low circulating CD4 counts, and an increased pro-inflammatory state, with associated morbidity and mortality. AlloSCT for hematologic malignancies is curative in the majority of patients with otherwise lethal hematologic diseases via immune mediated effects termed graft vs. leukemia that reflect ultimate elimination of all transplant patient hematopoietic cells during establishment of full donor engraftment. This translational research program and clinical trial is designed to investigate whether the infusion of CCR5∆32 homozygous or heterozygous cord blood (CB) units, identified on unrelated CB registry search, may eliminate HIV infected recipient hematopoietic cells via allogeneic donor immunologic clearance of recipient hematopoietic cells in patients with hematological malignancies and HIV infection in need of an alloSCT. To reduce the risk of morbidity and mortality associated with prolonged cytopenia after cord blood transplantation, we will also use NLA101, which is a cryopreserved cell therapy composed of ex-vivo expanded CD34+ hematopoietic stem and progenitor cells originally isolated from umbilical CB units. Ten patients will be enrolled and treated at the following study sites: FHCRC (with its Cancer Consortium partners, University of Washington and Seattle Children’s Hospital), Case Western Reserve University – University Hospitals (Marcos de Lima, PI), Children’s Research Institute/Children’s National Medical Center (Blachy Davila-Saldana, PI), Memorial-Sloan Kettering Cancer Center (Juliet Barker, PI), and University of California- San Francisco (Timothy Henrich, PI). We will utilize the platform of alloSCT to gain further insights into potential clearance of HIV reservoir by allogeneic donor immune cell elimination of recipient hematopoietic cells, and examine immune reconstitution in these patients. We will use state of the art highly sensitive assays to monitor viral RNA and cell associated RNA and DNA to measure the decay of the HIV reservoir; an integrated immune monitoring approach that combines several high dimensional platforms (Transcriptomics, systems serology, multiparametric flow cytometry) will allow us to identify correlates and innate and adaptive immune mechanisms that are associated to control and decay of the HIV reservoir. This may allow HIV-1 infected patients to discontinue antiretroviral therapy (ART) for a sustained period without expected viral rebound, as has been observed over a 9 year time period in an HIV infected patient with leukemia treated with allogeneic stem cell transplant incorporating a CCR5∆32 homozygous graft (aka ‘Berlin patient’). It is expected that data acquired under this R34 over the next 36 months will inform the design and execution of a subsequent larger multi-site phase II study.