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：
10396484
负责人：
Angus W Thomson
金额：
$ 71.23万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396484
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 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 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 evaluation efficacy trial feasibility trial first-in-human graft dysfunction 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.

项目摘要/摘要基于临床前研究，出现了令人信服的理由，用于调节树突状的临床测试细胞（DCREG）改善器官移植存活率。重要的是，使用坚固的，临床上的非人类灵长类动物模型和最少的免疫抑制，我们已经表明了DCREG的输注，一周前移植，可以安全地延长同种异体移植的生存，而无需宿主致敏的证据。这种治疗性效果与供体特异性T记忆细胞反应的选择性衰减有关，这是一个重要的障碍促进长期移植生存。我们已经从洗脱的血液中产生了GMP级人类DCREG 单核细胞表现出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T细胞反应的能力。我们还建立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格兰特（Grant），我们与DAIT计划官员一起完成了临床试验方案。我们也有最终确定的扩大制造SOP用于DCREG生产，完成的机械研究设计，获得了FDA的必要批准（IND），建立了临床试验的框架和管理以及统计考虑和分析计划。因此，我们已经准备好了，准备好了进行拟议的临床试验。这是一种新颖而独特的调节性免疫细胞疗法的方法器官移植。我们假设捐赠者衍生的DCREG产生了离体并前瞻性管理以实现捐助者接受常规免疫抑制治疗的肾移植接受者将是安全的，并诱发免疫学变化有助于改善移植物存活率。我们的两个具体目标是：目标1：进行首先是人类，开放标签，单中心1剂量升级安全研究，成年人的成人接受者活供体肾移植。患者将接受护理标准的免疫抑制。一周前但是，移植将收到单一的注入供体衍生的DCREG，并结合使用霉酚酸。虽然这是一个安全性和可行性试验，但我们在试验过程中获取的数据可以使我们能够对疗效进行初步检查。目标2：进行顺序免疫学 DCREG收件人的分析。我们将进行详细的机械研究，至关重要研究结果以及注入细胞对同种免疫反应的潜在影响。