Regulatory Dendritic Cell Therapy in Live Donor Renal Transplant Recipients

活体肾移植受者的调节性树突状细胞治疗

基本信息

批准号：
9924470
负责人：
Angus W Thomson
金额：
$ 95.08万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924470
关键词：
Acute Adult Allografting Biopsy Blood Calcineurin Cardiovascular system Cell Therapy Cells Cellular immunotherapy Chronic Clinical Clinical Trials Clinical trial protocol document Control Groups Data Dendritic Cell Therapy Dendritic Cells Dependence Dose Feasibility Studies Functional disorder Future Goals Graft Rejection Graft Survival Grant Hematopoietic Stem Cell Transplantation Human Immune Immunity Immunologics Immunosuppression Immunosuppressive Agents In Vitro Incidence Inflammatory Infusion procedures Kidney Kidney Transplantation Leukocytes Maintenance Modeling Monitor Morbidity - disease rate Mycophenolic Acid National Institute of Allergy and Infectious Disease Neoadjuvant Therapy Organ Transplantation Outcome Outcome Study Patients Pharmaceutical Preparations Phase Production Property Regimen Research Design Research Personnel Resistance Rodent Safety Severities Steroids T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Tacrolimus Technology Testing Therapeutic Agents Therapeutic Effect Time Transplant Recipients Transplantation U-Series Cooperative Agreements Withdrawal adaptive immune response antigen-specific T cells attenuation base clinically relevant design efficacy trial feasibility trial first-in-human graft failure graft function healthy volunteer immunoreaction immunoregulation improved kidney allograft manufacturing scale-up monocyte mortality neoplastic nonhuman primate novel open label operation phase 2 study phase I trial post-transplant preclinical study prevent programs prospective research clinical testing response safety and feasibility safety study scale up side effect standard of care

项目摘要

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.

项目概要/摘要基于临床前研究，监管树突临床测试出现了令人信服的理由细胞（DCreg）以提高器官移植存活率。重要的是，使用强大的、临床相关的、非人类的灵长类动物模型和最小免疫抑制，我们已经证明，在一周前输注 DCreg 移植，可以安全地延长肾同种异体移植物的存活，且没有宿主致敏的证据。这种治疗效应与供体特异性 T 记忆细胞反应的选择性减弱有关，这是一个重要的障碍以促进移植物的长期成活。我们从淘洗血液中生成了 GMP 级人类 DCreg 单核细胞，并在体外证明了它们在炎症条件下对成熟的稳定抵抗力以及它们负向调节同种异体反应性 T 细胞反应的能力。我们还制定了发布标准用于临床测试。基于这些成就并在R34临床试验计划的支持下拨款后，我们与 DAIT 项目官员一起完成了临床试验方案。我们还有最终确定了 DCreg 生产的放大制造 SOP，完成了机械研究的设计，获得FDA必要的批准（IND），建立临床试验运作框架管理、统计考虑和分析计划。因此，我们已做好充分准备进行拟议的临床试验。这是一种新颖且独特的调节性免疫细胞治疗方法器官移植。我们假设供体来源的 DCreg 在体外产生并前瞻性地给予活体供体接受常规免疫抑制治疗的肾移植受者将是安全的并可诱导免疫变化有利于提高移植物存活率。我们的两个具体目标是：目标 1：开展在成人接受 de novo 的患者中进行首次人体、开放标签、单中心 1 期剂量递增安全性研究，活体肾移植。患者将接受标准免疫抑制治疗。一星期前然而，移植时，他们将接受单次输注供体来源的 DCreg 并结合霉酚酸。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使我们对功效进行初步检查。目标2：进行序贯免疫学 DCreg 接收者的分析。我们将进行详细的机制研究，这对于理解研究结果以及输注细胞对同种免疫反应的潜在影响。