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: 6663657
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663657
• 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)患者的预后一致很差。大剂量化疗后的自体干细胞移植(AutoSCT)可导致疾病的一过性稳定，但也与显著的发病率、死亡率和疾病的最终进展有关。最近，在异基因干细胞移植(AIIoSCT)之后，降低强度(RI)的预适应导致了恶性和其他非恶性疾病的混合或完全供者嵌合。我们推测，RI化学免疫治疗后的allSCT+供体淋巴细胞输注(DLI)将是耐受性良好的，并导致混合或完全供体手性和疾病稳定的MRAID患者。主要的特异性目标包括：1)确定用氟达拉滨、白花丹和阿仑珠单抗(FBA)进行RI预适应后AIIoSCT的毒性；2)定量FBA和AIIoSCT+DLI后混合供者嵌合体和完全供者嵌合体的百分比；3)测量FBA和AIIoSCT+DLI后的免疫重建；4)确定FBA和allSCT+DLI后疾病进展和存活的可能性；以及5)确定先前存在的母胎来源微嵌合体的发生率和变化(&lt；1%)。次要目标包括：6)诱导供者耐受后DLI的毒性和应答率；7)测量FBA和allSCT+DLI后体液和细胞自身免疫标志物的变化；8)估计FBA、AIIoSCT和FK506以及霉酚酸酯(MMF)预防后急性和慢性GVHD的可能性；9)确定FBA和allSCT治疗前后的生活质量。确定疾病进展、存活和急慢性GVHD的方法将使用限量法(Kaplan Meier)；全血、T细胞和NK嵌合体将通过流式细胞仪分选进行，嵌合体将通过短串联重复序列(STR)、动态PCR和/或可变数目串联重复序列(VNTR)进行；免疫重建将通过流式细胞仪、TREC、T细胞受体CDR3长度分布(光谱分型)进行；以及通过标准评估进行生活质量评估。这一新的和创新的策略(如果成功和安全)的结果可能为治疗风险非常低的自身免疫性疾病的患者提供一种新的策略，并为未来将这种方法与护理标准进行比较的多中心前瞻性随机研究奠定基础。

项目成果

A pilot phase II study of alternate day ganciclovir and foscarnet in preventing cytomegalovirus (CMV) infections in at-risk pediatric and adolescent allogeneic stem cell transplant recipients.

一项关于隔日更昔洛韦和膦甲酸预防高危儿科和青少年同种异体干细胞移植受者巨细胞病毒 (CMV) 感染的试点 II 期研究。

• DOI: 10.1002/pbc.21043
• 发表时间: 2007
• 期刊: Pediatric blood & cancer
• 影响因子: 3.2
• 作者: Shereck,EvanB;Cooney,Erin;vandeVen,Carmella;Della-Lotta,Phyllis;Cairo,MitchellS
• 通讯作者: Cairo,MitchellS

The pharmacokinetics and safety of twice daily i.v. BU during conditioning in pediatric allo-SCT recipients.

每日两次静脉注射的药代动力学和安全性

• DOI: 10.1038/bmt.2012.105
• 发表时间: 2013
• 期刊: Bone marrow transplantation
• 影响因子: 4.8
• 作者: LeGall,JB;Milone,MC;Waxman,IM;Shaw,LM;Harrison,L;Duffy,D;vandeVen,C;Militano,O;Geyer,MB;Morris,E;Bhatia,M;Satwani,P;George,D;Garvin,JH;Bradley,MB;Schwartz,J;Baxter-Lowe,LA;Cairo,MS
• 通讯作者: Cairo,MS