Phase I Serum-free cultured thymus transplantation in DiGeorge anomaly, IND9836,

DiGeorge 异常的 I 期无血清培养胸腺移植，IND9836，

• 批准号: 7565124
• 负责人: M. Louise MARKERT
• 金额: $ 20万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565124
• 关键词: Phase; Serum; free; cultured; thymus

DESCRIPTION (provided by applicant): This application proposes a Phase 1 clinical trial of thymus transplantation involving 8 subjects with complete DiGeorge anomaly. The objective of this study is to determine if thymus tissue cultured in a serum free medium is comparable in its ability to support thymopoiesis and thymus (T) cell reconstitution as thymus tissue cultured in media containing fetal bovine serum. The use of serum free medium would reduce the concerns of exposure of animal products including the potential for exposure to bovine spongiform encephalopathy (BSE). Though in vitro studies of cultured thymus tissue indicate serum free and serum containing media are comparable, there are no in vitro or animal studies that recapitulate the thymus engraftment and T cell reconstitution in athymic infants. The composition of the medium for thymus tissue culture must be finalized prior to initiation of a pivotal trial for thymus transplantation. Results of the pivotal trial will be submitted for a Biologic License Application. Though the lack of na¿ve T cells results in a fatal immunodeficiency, 73% of 49 infants treated with thymus transplantation survive and all over 2 years after transplantation have good T cell reconstitution. Eight infants with complete DiGeorge anomaly (<50/mm3 na¿ve T cells) will be transplanted with thymus tissue cultured in serum free medium. Four subjects will have "typical" complete DiGeorge anomaly (no rash) and four with have "atypical" complete DiGeorge anomaly with rash and circulating oligoclonal T cells. The initial two typical and two atypical subjects will receive thymus cultured in serum containing medium and also, in a separate site, thymus cultured in serum free medium. The remaining subjects will receive only thymus cultured in serum free medium. The primary clinical safety outcomes will be survival at 1 year after transplantation and absence of graft versus host disease within the first year after transplantation. The secondary safety outcome measure is the incidence of autoimmune disease at 2 years after transplantation. Other secondary outcomes are the number of na¿ve cluster of differentiation (CD4) T cells at one year, the number of CD4 T cells at one year, the T cell proliferative response to the mitogen phytohemagglutinin (PHA) at one year, and the diversity of the CD4 T cell receptor beta variable chain (TCRBV) at one year. Criteria based on the primary and secondary outcomes are included in the protocol which will allow for acceptance or rejection of the serum free medium for use in the pivotal trial. Lastly in a descriptive analysis using immunohistochemistry and real time polymerase chain reaction (PCR), the allograft biopsies obtained at 2 months after transplantation of tissue cultured in serum free medium will be compared with biopsies in which serum was used in the culture medium. The focus of these experiments is the development of thymopoiesis and normal presentation of promiscuously expressed antigens in the thymus.

描述（由申请人提供）： 本申请提出了一项胸腺移植的I期临床试验，涉及8例完全DiGeorge异常受试者。本研究的目的是确定在无血清培养基中培养的胸腺组织在支持胸腺生成和胸腺（T）细胞重建方面是否与在含胎牛血清培养基中培养的胸腺组织相当。使用无血清培养基将减少动物产品暴露的担忧，包括暴露于牛海绵状脑病（BSE）的可能性。尽管培养胸腺组织的体外研究表明无血清和含血清培养基相当，但没有体外或动物研究概括无胸腺婴儿的胸腺植入和T细胞重建。胸腺组织培养的培养基组成必须在胸腺移植关键试验开始前确定。关键试验的结果将提交生物许可证申请。虽然缺乏Na？由于T细胞缺乏导致致命的免疫缺陷，49例接受胸腺移植治疗的婴儿中有73%存活，移植后2年以上都有良好的T细胞重建。8名患有完全DiGeorge异常（<50/mm 3幼稚T细胞）的婴儿将移植在无血清培养基中培养的胸腺组织。四名受试者将具有“典型的”完全DiGeorge异常（无皮疹），四名具有“非典型的”完全DiGeorge异常，具有皮疹和循环寡克隆T细胞。最初的2例典型受试者和2例非典型受试者将接受在含血清培养基中培养的胸腺，并在单独的研究中心接受在无血清培养基中培养的胸腺。其余受试者将仅接受在无血清培养基中培养的胸腺。主要临床安全性结局将是移植后1年的生存率和移植后第一年内无移植物抗宿主病。次要安全性结局指标是移植后2年自身免疫性疾病的发生率。其他次要结果是1年时幼稚分化簇（CD 4）T细胞的数量，1年时CD 4 T细胞的数量，1年时T细胞对有丝分裂原植物血凝素（PHA）的增殖反应，以及1年时CD 4 T细胞受体β可变链（TCRBV）的多样性。方案中包含基于主要和次要结局的标准，允许接受或拒绝关键试验中使用的无血清培养基。最后，在使用免疫组织化学和真实的时间聚合酶链反应（PCR）的描述性分析中，将在无血清培养基中培养的组织移植后2个月获得的同种异体移植物活检与在培养基中使用血清的活检进行比较。这些实验的重点是胸腺生成的发展和胸腺中混杂表达抗原的正常呈递。