Nonablative AlloSCT in Refractory Autoimmune Disease

非剥脱异体干细胞移植治疗难治性自身免疫性疾病

• 批准号: 6561595
• 负责人: Mitchell S. Cairo
• 金额: $ 8.18万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-23 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561595
• 关键词: autoimmune disorder; biomarker; chemoprevention; clinical research; combination therapy; flow cytometry; homologous transplantation; human subject; human therapy evaluation; immune tolerance /unresponsiveness; immunopathology chemotherapy; immunosuppressive; lymphocyte; natural killer cells; patient oriented research; prognosis; relapse /recurrence; stem cell transplantation; tissue mosaicism

DESCRIPTION (provided by applicant): Selected patients with medically refractory autoimmune disease (MRAID) have a uniformly dismal prognosis. High dose chemotherapy followed by autologous stem cell transplant (AutoSCT) has induced transient stabilization of disease but has been associated with significant morbidity and mortality and ultimate progression of disease. Recently, reduced intensity (RI) conditioning followed by allogeneic stem cell transplant (AIIoSCT) has resulted in mixed or complete donor chimerism in both malignant and other nonmalignant diseases. We hypothesize that RI chemoimmunotherapy followed by AlloSCT + donor lymphocyte infusion (DLI) will be well tolerated and result in mixed or complete donor chirnerism and stabilization of disease in patients with MRAID. The primary specific aims include: 1) to determine the toxicity of RI conditioning with fludarabine, busulfan and alemtuzumab (FBA) followed by AIIoSCT; 2) to quantitate percent mixed and complete donor chimerism following FBA and AIIoSCT + DLI; 3) to measure immune reconstitution following FBA and AIIoSCT _+DLI; 4) to determine the probability of disease progression and survival following FBA and AlloSCT + DLI; and 5) to determine the incidence and changes of preexisting maternal-fetal derived microchimerism (<1%). The secondary aims include: 6) the toxicity and response rate of DLI following induction of donor tolerance; 7) to measure the changes in humoral and cellular autoimmune markers following FBA and AlloSCT + DLI; 8) to estimate the probability of acute and chronic GVHD following FBA, AIIoSCT and FK506 and mycophenolate mofetil (MMF) prophylaxis; and 9) to determine the quality of life before and after FBA and AlloSCT. The methods to determine the probability of disease progression, survival and acute and chronic GVHD will use the product-limit method (Kaplan Meier); Whole Blood, T-cell and NK chimerism will be performed by flow cytometry sorting and chimerism by short tandem repeats (STR), kinetic PCR and/or variable number tandem repeats (VNTR); immune reconstitution by flow cytometry, TREC, alpha/beta T-cell receptor CDR3 length distribution (spectratyping); and quality of life by standard evaluations. The results of this novel and innovative strategy (if successful and safe) could offer a new strategy for the treatment of patients with very poor risk autoimmune diseases and form the basis for a future multicenter prospective and randomized study comparing this approach to standard of care.

描述（由申请人提供）： 选定的难治性自身免疫性疾病（MRAID）患者的预后普遍不佳。高剂量化疗后自体干细胞移植（AutoSCT）诱导了疾病的短暂稳定，但与显著的发病率和死亡率以及疾病的最终进展相关。最近，降低强度（RI）预处理后，异基因干细胞移植（AIIoSCT）已导致混合或完全供体嵌合体在恶性和其他非恶性疾病。我们假设RI化学免疫疗法后，AlloSCT +供体淋巴细胞输注（DLI）将是耐受良好的，并导致混合或完全供体chirnerism和稳定的疾病患者的MRAID。主要的具体目的包括：1）确定用氟达拉滨、白消安和阿仑单抗（FBA）进行RI预处理，然后进行AlloSCT的毒性; 2）定量FBA和AlloSCT + DLI后的混合和完全供体嵌合体百分比; 3）测量FBA和AlloSCT_+DLI后的免疫重建; 4）确定FBA和AlloSCT + DLI后疾病进展和存活的概率;（5）确定母体-胎儿来源的微嵌合体（<1%）的发生率和变化。次要目标包括：6）诱导供体耐受后DLI的毒性和应答率; 7）测量FBA和AlloSCT + DLI后体液和细胞自身免疫标志物的变化; 8）估计FBA、AlloSCT和FK 506和霉酚酸酯（MMF）预防后急性和慢性GVHD的概率;和9）确定FBA和AlloSCT前后的生活质量。确定疾病进展、生存和急性和慢性GVHD概率的方法将使用乘积极限法（Kaplan Meier）;将通过流式细胞术分选进行全血、T细胞和NK嵌合，并通过短串联重复序列（STR）、动力学PCR和/或可变数目串联重复序列（VNTR）进行嵌合;通过流式细胞术、TREC、α/β T细胞受体CDR 3长度分布（光谱分析）进行的免疫重建;以及通过标准评估进行的生活质量。这种新型创新策略的结果（如果成功且安全）可以为治疗风险极低的自身免疫性疾病患者提供一种新策略，并为未来将这种方法与标准治疗进行比较的多中心前瞻性随机研究奠定基础。