Regulatory Dendritic Cell Therapy in Live Donor Renal Transplant Recipients

项目概要/摘要 基于临床前研究，已经出现了一个令人信服的理由，用于调节性树突状细胞的临床测试。 细胞（DCreg），以提高器官移植存活率。重要的是，使用一个强大的，临床相关的，非人类 灵长类动物模型和最小的免疫抑制，我们已经表明，输注DCreg，一周前， 移植，可以安全地延长肾移植物的生存，没有宿主致敏的证据。这种治疗 效应与供体特异性T记忆细胞应答的选择性衰减有关， 促进移植物的长期存活。我们已经从淘析的血液中产生了GMP级人DCreg 单核细胞，并证明了它们在体外炎症条件下对成熟的稳定抗性 以及它们负调节同种异体反应性T细胞应答的能力。我们还制定了放行标准 用于临床试验。基于这些成就并在R34临床试验计划的支持下， 我们已经与DAIT项目官员一起完成了临床试验方案。我们还 最终确定了DCreg生产的规模扩大生产SOP，完成了机理研究的设计， 获得FDA的必要批准（IND），建立了临床试验操作框架， 管理、统计考虑和分析计划。因此，我们已做好充分准备， 开展拟定的临床试验。这是一种新的和独特的方法，调节免疫细胞治疗， 器官移植 我们假设供体来源的DCreg，体外产生并前瞻性地给予活体供体， 肾移植受者接受常规免疫抑制治疗，将是安全的， 有利于提高移植物存活率的免疫学变化。我们的两个具体目标是：目标1： 在成人初治接受者中进行的首次人体、开放标签、单中心、I期剂量递增安全性研究， 活体肾脏移植患者将接受标准治疗免疫抑制。前一周 然而，在移植后，他们将接受单次输注供体来源的DCreg， 霉酚酸虽然这是一项安全性和可行性试验，但我们在试验过程中获得的数据 可以让我们对疗效进行初步检验目的2：进行序贯免疫学研究 对DCreg接收者的分析。我们将进行详细的机械研究，这对理解 研究结果和输注细胞对同种免疫应答的潜在影响。

Project Summary/Abstract Based on pre-clinical studies, a compelling rationale has emerged for clinical testing of regulatory dendritic cells (DCreg) to improve organ transplant survival. Importantly, using a robust, clinically-relevant, non-human primate model and minimal immunosuppression, we have shown that infusion of DCreg, one week before transplant, can safely prolong renal allograft survival, without evidence of host sensitization. This therapeutic effect is associated with selective attenuation of donor-specific T memory cell responses, an important barrier to promotion of long-term graft survival. We have generated GMP grade human DCreg from elutriated blood monocytes and demonstrated both their stable resistance to maturation under inflammatory conditions in vitro and their ability to negatively regulate alloreactive T cell responses. We have also established release criteria for clinical testing. Based on these accomplishments and with the support of an R34 clinical trial planning grant, we have, in conjunction with DAIT program officers, completed the clinical trial protocol. We have also finalized scale-up manufacturing SOPs for DCreg production, completed design of the mechanistic studies, obtained the requisite approval (IND) from the FDA, established the framework for clinical trial operation and management, and the statistical considerations and analytical plan. We are thus well-prepared and ready to conduct the proposed clinical trial. This is a novel and unique approach to regulatory immune cell therapy in organ transplantation. We hypothesize that donor-derived DCreg, generated ex vivo and administered prospectively to live donor renal transplant recipients treated with conventional immunosuppression, will be safe and induce immunological changes conducive to improved graft survival. Our two Specific Aims are: Aim 1: To conduct a first-in-human, open-label, single center phase 1 dose escalation safety study in adult recipients of de novo, live donor renal transplants. Patients will receive standard-of-care immunosuppression. One week before transplantation, however, they will receive a single infusion of donor-derived DCreg in combination with mycophenolic acid. While this is a safety and feasibility trial, data that we acquire during the course of the trial may enable us to conduct a preliminary examination of efficacy. Aim 2: To conduct sequential immunological analyses of the DCreg recipients. We will perform detailed mechanistic studies critical to understanding the outcome of the study and potential effects of the infused cells on the alloimmune response.