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: 10929110
• 负责人: John Tisdale
• 金额: $ 179.22万
• 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/10929110
• 关键词: Ablation; Acute; Adult; Age; Allogeneic Bone Marrow Transplantation; Allogenic; Allografting; Amendment; Animal Model; Antibodies; Blood; CD3 Antigens; Child; Chimerism; Clinical Protocols; Clinical Trials; Cross-Sectional Studies; Cyclosporine; Data Analyses; Disease; Disease-Free Survival; Disseminated Malignant Neoplasm; Dose; Engraftment; Frequencies; Gene Transfer; Genes; Genotype; Globin; Goals; Hematological Disease; Hematopoiesis; 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; Proto-Oncogene Protein c-kit; Protocols documentation; Publishing; Quality of life; Regimen; Renal function; Reporting; Risk; Second Primary Cancers; 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; chronic graft versus host disease; clinical application; comorbidity; conditioning; curative treatments; design; follow-up; graft vs host disease; heart function; hematopoietic engraftment; hydroxyurea; improved; irradiation; mortality; mouse model; peripheral blood; programs; pulmonary function; safety and feasibility; secondary analysis; secondary endpoint; secondary outcome; synergism; vaso-occlusive crisis

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 have completed accrual to our 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 studies. A new protocol testing the ability of an additional antibody to c-Kit to reduce the proportion of patients with mixed donor chimerism is now been developed and accrual has begun this year. Early results in patients are encouraging, yet the accrual is still low and the follow up brief.

由于一个或多个珠蛋白分子亚单位的缺失/减少或异常产生而导致的血液病，如地中海贫血和血红蛋白病，共同构成了人类最常见的单基因疾病组。长期以来，人们一直认为，旨在取代缺失或有缺陷的珠蛋白基因的策略具有潜在的疗效，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，异基因骨髓移植已经被证明是有效的，但程序性毒性限制了应用。异基因骨髓移植是一种基于造血干细胞的基因转移，通过用正常基因的捐赠者替换整个患病器官来完成。为了扩大应用范围，我们探索了非清髓性移植方案，这些方案旨在允许移植异基因造血干细胞，而不会出现传统骨髓清除性条件处理的毒性。使用动员的外周血干细胞作为来源，我们证明了在没有骨髓切除的情况下，转移性癌症患者可以可靠地植入，并将这些观察扩展到因合并疾病而不符合常规清髓移植条件的患者。虽然清楚地确定了在不去除骨髓的情况下在人类身上实现造血植入的能力，但程序性毒性，主要是移植物抗宿主病，仍然太高，不适用于非恶性疾病。因此，我们回到了动物模型，最近开发了一种低强度的调节方案，旨在促进对同种异体移植的耐受性。基于诱导耐受的独特机制，我们在动员外周血异基因移植排斥反应的小鼠模型中，比较了小剂量照射后雷帕霉素和环孢素的免疫抑制作用。只有接受雷帕霉素治疗的小鼠表现出长期的造血细胞嵌合体，在4个月以上的随访中达到了75%以上。为了将这些观察结果应用于成人镰状细胞性贫血，我们确定了在具有镰状细胞特征的个体中动员外周血干细胞的安全性和可行性，因为这些杂合子代表了兄弟姐妹捐赠者池的大约一半。我们启动了一项针对成人镰状细胞性贫血和地中海贫血的临床试验，最近报告了我们在前10名患者中的结果。自那份报告以来，累计值已超过30，结果与86%的无病存活率相似。该方案已被修改，以积累多达50个，一些次要终点，如神经认知功能，在兄弟姐妹捐赠者之前和每年进行测量，作为对照，疼痛，生活质量，肾功能，肺功能，心功能。此外，我们已经开始计划在CD3+T细胞嵌合体为50%的患者中逐步减少免疫抑制，大多数受试者现在已经停止了免疫抑制，混合嵌合体稳定。没有急性或慢性移植物抗宿主病，在没有长期免疫抑制的情况下观察到的混合造血细胞嵌合体表明了手术耐受性。这些结果现在也被报道了。我们现在已经确定了足以纠正表型的嵌合体水平，并对其进行了数学建模，结果发表在《血液》杂志上。我们已经完成了50名成功移植患者的上限，这将使我们能够完成对次要结果的分析，包括对患者在随访期间与其兄弟姐妹捐赠者进行广泛的神经心理测试。对数据的第一次横断面分析已于今年发表，我们现在正在进行前瞻性研究。现在已经开发了一种新的方案，测试额外的c-Kit抗体降低混合供者嵌合体患者比例的能力，并于今年开始累积。患者的早期结果令人鼓舞，但收益仍然很低，随访时间也很短。

项目成果

Allogenic hematopoietic stem cell transplantation in sickle cell disease.

镰状细胞病的同种异体造血干细胞移植。

• DOI: 10.1016/j.transci.2021.103057
• 发表时间: 2021
• 期刊: Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis
• 作者: Furstenau,DanaK;Tisdale,JohnF
• 通讯作者: Tisdale,JohnF

Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres.

• DOI: 10.1111/bjh.17311
• 发表时间: 2021-03
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Alzahrani M;Damlaj M;Jeffries N;Alahmari B;Singh A;Rondelli D;Tisdale JF;Saraf SL;Hsieh MM
• 通讯作者: Hsieh MM

Public titles of clinical trials should have ethics review.

临床试验公开名称应当进行伦理审查。

• DOI: 10.1016/j.jclinepi.2014.05.016
• 发表时间: 2015
• 期刊: Journal of clinical epidemiology
• 影响因子: 7.2
• 作者: Saenz,Carla;Reveiz,Ludovic;Tisdale,JohnF
• 通讯作者: Tisdale,JohnF

Neurocognitive functioning in symptomatic adults with sickle cell disease: A description and comparison with unaffected siblings.

• DOI: 10.1080/09602011.2019.1598876
• 发表时间: 2020-10
• 期刊: Neuropsychological rehabilitation
• 影响因子: 2.7
• 作者: Martin S;Roderick MC;Abel C;Wolters P;Toledo-Tamula MA;Fitzhugh C;Hsieh M;Tisdale J
• 通讯作者: Tisdale J

Optimizing haematopoietic stem and progenitor cell apheresis collection from plerixafor-mobilized patients with sickle cell disease.

优化来自普乐沙福动员的镰状细胞病患者的造血干细胞和祖细胞单采采集。

• DOI: 10.1111/bjh.18311
• 发表时间: 2022
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Sharma,Akshay;Leonard,Alexis;West,Kamille;Gossett,JeffreyM;Uchida,Naoya;Panch,Sandhya;Stroncek,David;Poston,Leigh;Akel,Salem;Hankins,JaneS;Fitzhugh,Courtney;Hsieh,MatthewM;Kang,Guolian;Tisdale,JohnF;Weiss,MitchellJ;Zheng
• 通讯作者: Zheng