Ph2 of T-Cell Depl Familial Haploidentical SCT for tx Hi-Risk Sickle Cell Anemia

项目摘要 镰状细胞病（SCD）是一种孤儿病（在美国有75 - 85，000例），患者具有高风险特征， 包括有脑血管病和/或肺和/或肺血管病史的患者 并发症预示着预后不良，具有严重慢性病的高趋势， 过早死亡唯一的治愈和器官稳定的治疗方法是异基因干细胞移植 （AlloSCT）来自未受影响的HLA匹配的同胞供体。然而，只有大约15%的SCD患者 有这样的捐助者。替代的同种异体供体来源包括未受影响的家族性单倍体相合（FHI） 捐助者。这种供体来源的使用受到GVHD和/或移植失败风险增加的限制。但这些 通过CD34+造血细胞的阳性选择，使用T细胞耗竭（TCD）可以最大限度地降低风险。 干细胞，然后是最小的T细胞回加。FHI TCD利用CD34+造血干细胞的AlloSCT 已证明阳性选择在高危血液病患者中是成功的。 恶性肿瘤。目前，该器械/手术尚无FDA适应症用于非恶性肿瘤 疾病，例如SCD。我们假设，适当的宿主骨髓免疫抑制（MIC）后，FHI TCD AlloSCT通过对CD34+造血干细胞阳性的高危SCD患者进行选择，将是安全的， 导致持续的供体嵌合，迅速的造血植入，及时的供体免疫重建， 稳定神经和肺功能，从而全面改善与健康相关生活质量 （HRQL），并导致FDA批准的孤儿病SCD适应症。的具体目标 包括：1）确定MIC后FHI TCD AlloSCT在高危患者中安全性和可行性 与SCD; 2）持续的供体全血和RBC嵌合体; 3）免疫细胞的质量和数量 重建和功能; 4）神经和神经认知后遗症的变化; 5） 肺和肺血管功能; 6）HRQL的变化。这些方法包括（简要）： 通过Kaplan Meier统计的EFS、OS、造血重建和AGVHD/CGVHD的概率; STR法检测供者嵌合体;定性和定量T、B、NK细胞免疫 通过流式细胞术、细胞因子内染色、供者特异性HLA抗体检测重建和功能 使用微阵列，调理作用和细胞毒性研究;神经血管病变和认知功能， 脑MRI/MRA和神经认知测试;肺功能和肺血管功能 功能测试，超声心动图和多普勒; HQRL使用CHRIs-一般和-HSCT问卷， 收件人和家长。首要的长期目标包括确定安全性和可行性，长期 长期EFS和器官稳定性遵循这一实验设计，组建了一个多学科研究团队， 建立和集中关键核心，并导致FDA批准这种孤儿病SCD的适应症。

PROJECT SUMMARY Sickle cell disease (SCD) is an orphan disease (75-85,000 in USA) and patients with high-risk features, including those with a history of cerebral vasculopathy and/or pulmonary and/or pulmonary vascular complications portend to have a poor prognosis with a high tendency toward serious chronic morbidities and premature death. The only curative and organ stabilizing therapy is allogeneic stem cell transplantation (AlloSCT) from unaffected HLA matched sibling donors. However, only approximately 15% of SCD patients have such donors. An alternate allogeneic donor source includes unaffected familial haploidentical (FHI) donors. The use of this donor source is limited by increased risks of GVHD and/or graft failure. However, these risks can be minimized by the use of T cell depletion (TCD) through positive selection of CD34+ hematopoietic stem cells followed by minimal T cell addback. FHI TCD AlloSCT utilizing CD34+ hematopoietic stem cell positive selection has been demonstrated to be successful in patients with high-risk hematological malignancies. Currently there is no FDA indication for this device/procedure for non-malignant diseases, such as SCD. We hypothesize that adequate host myeloimmunsuppression (MIC) followed by FHI TCD AlloSCT by positive CD34+ hematopoietic stem cell selection in patients with high-risk SCD, will be safe, result in sustained donor chimerism, prompt hematopoietic engraftment, timely donor immune reconstitution, stabilization of neurological and pulmonary function, result in overall improved health-related quality of life (HRQL) and lead to an approved FDA indication in the orphan disease, SCD. The specific objectives include (Brief): 1) to determine safety and feasibility of MIC followed by FHI TCD AlloSCT in high-risk patients with SCD; 2) sustained donor whole blood and RBC chimerism; 3) quality and quantity of immune cell reconstitution and function; 4) changes in neurological and neurocognitive sequelae; 5) differences in pulmonary and pulmonary vascular function; and 6) changes in HRQL. The methodologies include (Brief): Probability of EFS, OS, hematopoietic reconstitution and AGVHD/CGVHD by Kaplan Meier statistics; measurement of donor chimerism by STR methodology; qualitative and quantitative T, B, NK cell immune reconstitution and function by flow cytometry, intracytokine staining, detection of donor-specific HLA antibodies using micro-arrays, opsonization and cytotoxicity studies; neurovasculopathy and cognitive functioning by cerebral MRI/MRA and neurocognitive testing; pulmonary and pulmonary vascular function by pulmonary function tests, echocardiogram and Doppler; and HQRL using CHRIs-General and -HSCT questionnaires in recipients and parents. The overarching long-term objectives include determining safety and feasibility, long- term EFS and organ stability following this experimental design, assemble a multidisciplinary research team, establish and centralize critical cores and lead to an FDA approved indication in this orphan disease, SCD.