Nonmyeloablative allogeneic PBSC in globin disorders

非清髓性同种异体 PBSC 在珠蛋白疾病中的应用

• 批准号: 10012679
• 负责人: John Tisdale
• 金额: $ 103.47万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10012679
• 关键词: Ablation; Acute; Adult; Age; Allogeneic Bone Marrow Transplantation; Allogenic; Allografting; Animal Model; Blood; CD3 Antigens; Child; Chimerism; Clinical Protocols; Clinical Trials; Comorbidity; Cross-Sectional Studies; Cyclophosphamide; Cyclosporine; Data Analyses; Disease; Disease-Free Survival; Disseminated Malignant Neoplasm; Dose; Engraftment; Frequencies; Gene Transfer; Genes; Genotype; Globin; Goals; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobinopathies; Heterozygote; Human; Immune response; Immunosuppression; Individual; Institutional Review Boards; Investigation; Life Expectancy; Lung diseases; Marrow; Mathematics; Measures; Mendelian disorder; Modeling; Mus; Neurocognitive; Neuropsychological Tests; Non-Malignant; Organ; Organ failure; Outcome Measure; Pain; Patients; Peripheral Blood Stem Cell; Phenotype; Production; Prospective Studies; Protocols documentation; Publishing; Quality of life; Regimen; Renal function; Reporting; Research Personnel; Respiratory physiology; Risk; Running; Severities; Siblings; Sickle Cell Anemia; Sickle Cell Trait; Signal Transduction; Sirolimus; Source; Stroke; Supportive care; T-Lymphocyte; Testing; Thalassemia; Time; Toxic effect; Transplant Recipients; Transplantation; allograft rejection; base; chronic graft versus host disease; clinical application; conditioning; curative treatments; design; follow-up; graft vs host disease; heart function; hematopoietic engraftment; hydroxyurea; improved; irradiation; mortality; mouse model; peripheral blood; programs; safety and feasibility; secondary analysis; secondary endpoint; secondary outcome; tenure track

Hematologic disorders such as the thalassemias and hemoglobinopathies, resulting from absent/reduced or abnormal production of one or more of the globin-molecule subunits, respectively, together constitute the most prevalent group of human monogenic diseases. Strategies which aim to replace the absent or defective globin gene have long been envisioned as potentially curative, and gene transfer strategies targeting hematopoietic stem cells have been central to this goal. Certainly, allogeneic bone marrow transplantation, a form of hematopoietic stem cell based gene transfer accomplished by replacement of the entire diseased organ with that from a donor with a normal genotype, has proven curative, yet procedural toxicities limit application. In order to expand application, we have explored nonmyeloablative transplant regimens which are designed to allow engraftment of allogeneic hematopoietic stem cells without the toxicity of conventional marrow ablative conditioning. Using mobilized peripheral blood stem cells as the source, we demonstrated reliable engraftment in the absence of marrow ablation in patients with metastatic cancer and extended these observations to patients ineligible for conventional myeloablative transplantation due to comorbidities. While clearly establishing the ability to achieve hematopoietic engraftment in humans without marrow ablation, procedural toxicity, mainly in the form of graft-versus-host disease, remained too high for application to nonmalignant disorders. We therefore returned to animal models and have recently developed a low intensity conditioning regimen designed to promote tolerance to the allograft. Based upon a unique mechanism for tolerance induction, we compared the use of immunosuppression with rapamycin to that with conventional immunosuppression with cyclosporine after low dose irradiation in a murine model of mobilized peripheral blood allograft rejection. Only mice treated with rapamycin demonstrated long-term hematopoietic chimerism, and the levels achieved exceeded 75% at greater than 4 months of follow up. In anticipation of moving these observations toward clinical application for adults with sickle cell anemia, we established the safety and feasibility of peripheral blood stem cell mobilization in individuals with sickle cell trait, as these heterozygotes represent approximately half of the sibling donor pool. We initiated a clinical trial for adults with sickle cell anemia and thalassemia and recently reported our results in the first 10 patients. Since that report, accrual has reached over 30, and results are similar with an 86% disease free survival. The protocol has been amended to accrue up to 50, with a number of secondary endpoints such as neurocognitive functioning measured before and yearly with their sibling donor as the control, pain, quality of life, kidney function, lung function, heart function. Additionally, we have begun a planned immunosuppression taper in individuals with >50% CD3+ T cell chimerism, and the majority of subjects are now off immunosuppression with stable mixed chimerism. There has been no acute or chronic graft versus host disease, and the mixed hematopoietic chimerism observed in the absence of long term immunosuppression demonstrates operational tolerance. These results have also now been reported. We have now determined the level of chimerism sufficient to correct the phenotype, modeled it mathematically, and the results are published in Blood. We are almost at our accrual ceiling of 50 successfully transplanted patients, and this will allow us to complete our analysis of secondary outcomes including extensive neuropsychological testing in patients during follow up compared to their sibling donor. The first, cross-sectional analysis of the data has been published this year, and we are now performing the prospective study. Given the limited number of patients with an available HLA-matched sibling donor, we have also moved on to test this approach in the haplo-idendtical setting in a protocol testing escalating doses of post-graft cyclophosphamide. Our first protocol testing this was just published this year and a new protocol is now active. Accrual to the new protocol is now ongoing, and the protocols now being run by a new tenure-track investigator in our group, Dr. Courtney Fitzhugh, and will be reported upon by her.

分别由一种或多种珠蛋白分子亚基的缺失/减少或异常产生引起的血液疾病，例如地中海贫血和血红蛋白病，共同构成了最普遍的人类单基因疾病。长期以来，人们一直认为旨在替换缺失或有缺陷的珠蛋白基因的策略具有潜在的治疗作用，而针对造血干细胞的基因转移策略一直是这一目标的核心。当然，同种异体骨髓移植是一种基于造血干细胞的基因转移形式，通过用具有正常基因型的供体的器官替换整个患病器官来完成，已被证明具有治愈性，但程序毒性限制了应用。 为了扩大应用范围，我们探索了非清髓移植方案，该方案旨在允许异体造血干细胞植入，而没有传统骨髓消融调理的毒性。 使用动员的外周血干细胞作为来源，我们在转移性癌症患者中证明了在没有骨髓消融的情况下可靠的移植，并将这些观察结果扩展到因合并症而无法进行常规清髓移植的患者。 虽然明确建立了在不进行骨髓消融的情况下在人体中实现造血移植的能力，但主要以移植物抗宿主病形式出现的程序毒性对于应用于非恶性疾病来说仍然太高。 因此，我们回到动物模型，最近开发了一种低强度调理方案，旨在促进对同种异体移植物的耐受性。 基于独特的耐受诱导机制，我们在动员外周血同种异体移植排斥的小鼠模型中，将低剂量照射后雷帕霉素免疫抑制的使用与环孢菌素传统免疫抑制的使用进行了比较。只有接受雷帕霉素治疗的小鼠表现出长期的造血嵌合状态，并且在超过 4 个月的随访中达到了超过 75% 的水平。 为了将这些观察结果应用于镰状细胞性贫血成人患者的临床应用，我们确定了镰状细胞性状个体外周血干细胞动员的安全性和可行性，因为这些杂合子约占同胞供体库的一半。我们针对患有镰状细胞性贫血和地中海贫血的成人启动了一项临床试验，并于最近报告了前 10 名患者的结果。 自该报告发布以来，应计人数已超过 30，结果相似，无病生存率为 86%。 该方案已修改为最多可累积 50 个终点，其中包括一些次要终点，例如之前和每年以兄弟供体作为对照进行测量的神经认知功能、疼痛、生活质量、肾功能、肺功能、心脏功能。 此外，我们已经开始对 CD3+ T 细胞嵌合体 > 50% 的个体进行计划的免疫抑制逐渐减少，并且大多数受试者现在已停止免疫抑制，具有稳定的混合嵌合体。 没有出现急性或慢性移植物抗宿主病，并且在没有长期免疫抑制的情况下观察到的混合造血嵌合现象证明了操作耐受性。这些结果现在也已被报道。 我们现在已经确定了足以纠正表型的嵌合水平，并对其进行了数学建模，结果发表在《Blood》上。我们几乎达到了 50 名成功移植患者的应计上限，这将使我们能够完成对次要结果的分析，包括在随访期间对患者与其兄弟捐赠者进行广泛的神经心理学测试。 第一份数据横断面分析已于今年发布，我们现在正在进行前瞻性研究。 鉴于拥有 HLA 匹配同胞供体的患者数量有限，我们还继续在单倍体相同环境中测试这种方法，并在测试移植后环磷酰胺剂量递增的方案中进行测试。 我们的第一个协议测试今年刚刚发布，新协议现已生效。 新协议的计提工作正在进行中，该协议目前由我们小组的一位新的终身教授研究员 Courtney Fitzhugh 博士负责管理，并将由她进行汇报。