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

接受脐带血同种异体移植的 HIV 感染血液学患者的 CCR5 分析

• 批准号: 9978092
• 负责人: FILIPPO MILANO
• 金额: --
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978092
• 关键词: Address; Allogenic; Berlin; Biological Assay; Blood; Blood Cells; Bone Marrow; Bone Marrow Stem Cell Transplantation; CCR5 gene; CD34 gene; CD4 Lymphocyte Count; California; Cell Therapy; Cells; Characteristics; Child; Clinical Trials; Cryopreservation; Cryopreserved Cell; DNA; Data; Engraftment; Enrollment; Flow Cytometry; Genes; HIV; HIV Infections; HIV resistance; HIV-1; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoietic; Hematopoietic stem cells; Homeostasis; Homologous Transplantation; Immune; Immune Tolerance; Immune system; Immunity; Immunologic Monitoring; Incidence; Inflammatory; Infusion procedures; Kinetics; Life; Malignant Neoplasms; Measures; Mediating; Medical; Medical center; Memorial Sloan-Kettering Cancer Center; Methods; Monitor; Morbidity - disease rate; Neonatal; Patients; Pediatric Hospitals; Phase I/II Trial; Protocols documentation; RNA; Registries; Reporting; Research; Research Institute; Resistance; Risk; Safety; San Francisco; Serologic tests; Site; Spottings; Stem cell transplant; System; T-Cell Depletion; Testing; Therapeutic; Time; Tissues; Transplant Recipients; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Universities; University Hospitals; Washington; adaptive immune response; antiretroviral therapy; base; cytopenia; design; graft vs host disease; graft vs leukemia effect; high dimensionality; immune clearance; immune reconstitution; insight; latent HIV reservoir; leukemia; leukemia treatment; mortality; phase 2 study; post-transplant; reconstitution; safety testing; standard of care; stem cells; transcriptomics; translational research program; viral RNA; viral rebound

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.

感染HIV的血液病患者通常被排除在同种异体骨之外 骨髓/干细胞移植（alloSCT）方案。抗逆转录病毒疗法（ART）是一种高效，安全， 方便，但通常患者维持低循环CD 4计数，并增加促炎性细胞因子， 国家，以及相关的发病率和死亡率。AlloSCT治疗血液系统恶性肿瘤在大多数情况下是治愈性的 通过免疫介导效应（称为移植物vs.白血病）导致的其他致命性血液病患者 这反映了在建立完全供体过程中所有移植患者造血细胞的最终消除 移植。这项转化研究计划和临床试验旨在研究 输注CCR 5 ≥ 32个纯合子或杂合子脐带血（CB）单位，在不相关CB登记研究中确定 搜索，可以消除艾滋病毒感染的受体造血细胞通过同种异体供体免疫清除， 接受造血细胞治疗的恶性血液病和HIV感染患者需要 alloSCT。降低脐带血输注后与长期血细胞减少相关的发病率和死亡率风险 移植，我们还将使用NLA 101，这是一种冷冻保存的细胞疗法，由离体 最初从脐带CB单位分离的扩增的CD 34+造血干细胞和祖细胞。十 患者将在以下研究地点登记和治疗：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-大学 医院（Marcos de Lima，PI），儿童研究所/国家儿童医疗中心（Blachy Davila-Saldana，PI）、纪念斯隆凯特琳癌症中心（Juliet Barker，PI）和加州大学- San弗朗西斯科（Timothy Henrich，PI）.我们将利用alloSCT平台进一步了解 通过同种异体供体免疫细胞清除受体造血干细胞的潜在清除HIV储库 细胞，并检查这些患者的免疫重建。我们将使用最先进的高灵敏度检测 监测病毒RNA和细胞相关RNA和DNA，以测量HIV储存库的衰变; 结合了几个高维平台的综合免疫监测方法（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，先天性和适应性 免疫机制与HIV宿主的控制和衰变有关。这可能会让HIV-1 感染患者停止抗逆转录病毒治疗（ART）持续一段时间， 反弹，如在9年的时间段内在用以下药物治疗的患有白血病的HIV感染患者中观察到的 同种异体干细胞移植物，包括CCR 5 β 32纯合移植物（又称“柏林患者”）。预计 在未来36个月内根据R34获得的数据将为设计和执行提供信息， 后续更大的多中心II期研究。