Type 1 Diabetes-A Proposal for Prevention & Intervention

描述（由申请人提供）：明尼苏达大学是美国最初的 14 个 TrialNet 中心之一。迄今为止，我们已经实施了 8 项协议。我们的独特优势是预防和干预试验的招募，在这些试验中我们是排名第一的招募者。然而，我们在自然历史研究 (NHS) 中的招募情况却很平均。为了改进这一点，我们开始与密歇根大学家庭医学和社区健康系研究主任兼明尼苏达州家庭医师学院研究网络主任 Kevin Peterson 博士开展新的合作。我们预计将立即为 1000 多名 T1D 患者提供服务，并且随着该网络的发展，未来的访问量也会增加。 在此应用中，我们建议使用自体调节性细胞 (Treg) 进行治疗。之前的方案尝试用药物增加内源性 Treg 数量。此前，Treg 本身的数量还不足以用于临床。我们课题组率先开发出一种临床适用的选择和培养方法，用于从外周血中大量生产Tregs。动物模型和人类白血病患者的初步数据表明该产品是安全的。 这是一项单中心、单组 1 期剂量递增试验。最近（3-12 个月）发病的 T1D 和持续 C 肽分泌的成年受试者将使用 UM 分子和细胞治疗 cGMP 设施开发的新方法接受自体外周血来源的 Tregs（CD4 / CD25 / FoxP3 ）输注。细胞将通过白细胞去除术收集并在培养物中扩增长达 35 天，然后冷冻保存。白细胞去除术后，受试者将立即接受一个疗程的胸腺球蛋白治疗，1 周内 4 剂。解冻的自体 Tregs 将在大约 2 个月后被输注，此时循环中没有可检测到的残留兔抗体。安全性和免疫学数据以及 C 肽分泌将被跟踪 2 年。长期目标是收集初步数据，以预期外周血来源的自体 CD4 /CD25 /FoxP3 治疗新发 T1D 的干预试验。

DESCRIPTION (provided by applicant): The University of Minnesota is one of the original 14 US TrialNet centers. We have implemented 8 protocols to date. Our particular strength has been enrollment in prevention and intervention trials, where we are the number 1 overall recruiter. Our recruitment in the Natural History Study (NHS), however, has been average. In order to improve this, we have embarked on a new collaboration with Dr. Kevin Peterson, Director of Research for the UM Department of Family Medicine and Community Health and Director of the Minnesota Academy of Family Physicians Research Network. We anticipate access immediately to more than 1000 patients with T1D, with increased future access as this network grows. In this application we are proposing therapy with autologous Tregulatory cells (Tregs). Previous protocols have attempted to increase endogenous Treg numbers with drugs. Tregs themselves have not previously been available in sufficient numbers for clinical use. Our group is the first to develop a clinically applicable selection and culture method for manufacturing large numbers of Tregs from peripheral blood. Preliminary data in animal models and in humans with leukemia suggest that this product is safe. This is a single site, single arm phase 1 dose escalation trial. Adult subjects with recent (3-12 months) onset T1D and persistent C-peptide secretion will receive an infusion of autologous peripheral blood- derived Tregs (CD4+/CD25+/FoxP3+) using new methodology developed at the UM Molecular and Cellular Therapeutics cGMP Facility. Cells will be collected by leukapheresis and expanded in culture for up to 35 days and then cryopreserved. Immediately following leukapheresis, subjects will receive a course of thymoglobulin, 4 doses over 1 week. Thawed, autologous Tregs will be infused approximately 2 months later, at a time when there is no residual detectable rabbit antibody in the circulation. Safety and immunologic data and C-peptide secretion will be followed for 2 years. The long-term goal is to gather preliminary data in anticipation of an intervention trial of peripheral-blood derived autologous CD4+/CD25+/FoxP3+ treatment of new onset T1D.