Dendritic Cell (DCreg) Therapy in Live Donor Renal Transplant Recipients

活体肾移植受者的树突状细胞 (DCreg) 治疗

基本信息

批准号：
9067561
负责人：
Angus W Thomson
金额：
$ 23.12万
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：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9067561
关键词：
Acute Adoptive Transfer Adult Adverse effects Allografting Animals Antigens Biopsy Calcineurin Cardiovascular system Cell Therapy Cells Chronic Clinical Clinical Trials Clinical trial protocol document Consultations Data Dendritic Cells Dependence Dose Functional disorder Goals Graft Rejection Graft Survival Hematopoietic Stem Cell Transplantation Human Immune Immunity Immunologics Immunosuppression Immunosuppressive Agents Incidence Inflammatory Infusion procedures Institutional Review Boards Isoantibodies Kidney Kidney Transplantation Leukocytes Living Donors Modeling Monitor Morbidity - disease rate Mycophenolic Acid National Institute of Allergy and Infectious Disease Neoadjuvant Therapy Organ Transplantation Outcome Study Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Production Property Reaction Regulation Regulatory T-Lymphocyte Research Personnel Resistance Rodent Safety Severities Steroids T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Tacrolimus Therapeutic Agents Therapeutic Effect Time Transplant Recipients Transplantation Withdrawal adaptive immunity attenuation base clinically relevant design falls graft failure graft function improved kidney allograft manufacturing scale-up monocyte mortality neoplastic nonhuman primate novel open label operation peripheral blood prevent public health relevance research clinical testing response safety study standard of care

项目摘要

DESCRIPTION (provided by applicant): Based on experimental animal studies, a compelling rationale has emerged for the 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 the 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 and their ability to negatively regulate alloreactive T cell responses. We have also established release criteria for clinical testing. Based on these accomplishments, we will now plan to conduct a clinical trial of donor-derived DCreg in adult, de novo live donor renal transplantation. This is a novel and unique approach to regulatory immune cell therapy in organ transplantation. The purpose of this R34 application is to complete the clinical trial protocol, finalize scale-up and manufacturing SOPs for DCreg production, complete design of the mechanistic studies, obtain the requisite approvals from the FDA and IRB, and establish the framework for clinical trial operation and management. 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. We have two Specific Aims: Aim 1: To plan 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, they will receive a single infusion of donor-derived DCreg in combination with Mycophenolic Acid (MPA). While this is a safety trial, data that we acquire during the course of the trial may enable us to conduct a preliminary examination of efficacy. Aim 2: To plan sequential immunological analyses of the DCreg recipients. We will plan to conduct detailed mechanistic studies critical to understanding the outcome of the study and the potential effects of the infused cells on the alloimmune response.

描述（由适用提供）：根据实验动物研究，出现了引人注目的基本原理，用于调节性树突状细胞（DCREG）的临床测试，以改善器官移植存活率。重要的是，使用强大的，临床上的，非人类的私有模型和最小的免疫抑制，我们已经表明，在移植前一周的DCREG可以安全地延长肾脏同种异体移植的存活，而无需宿主敏化的证据。这种治疗作用与供体特异性T的选择性衰减有关记忆细胞反应，这是促进长期移植生存的重要障碍。我们已经从流行的血液单核细胞中产生了GMP级人类DCREG，并证明了它们在炎症条件下对成熟的稳定抗性，又证明了它们对同种反应性T细胞反应负调节的能力。基于这些成就，我们现在计划在成人，从头活供体肾移植中对供体衍生的DCREG进行临床试验。这是一种新型且独特的方法，用于器官移植中的调节性免疫细胞疗法。该R34应用的目的是完成临床试验方案，最终确定DCREG生产的扩大规模和制造SOP，对机械研究的完整设计，从FDA和IRB获得所需的批准，并为临床试验操作和管理建立框架。我们假设供体衍生的DCREG产生了离体和前瞻性给予的，以实用的供体肾移植受者接受常规免疫抑制处理，将是安全的，并且会导致免疫学变化，以改善移植物存活率。我们有两个具体的目标：目标1：在从头开始的成人肾脏肾移植物中计划首个人类，开放标签，单中心1剂量升级安全研究。患者将接受护理标准的免疫抑制。移植前一周，他们将与麦角苯甲酸（MPA）联合使用供体衍生的DCREG。尽管这是一项安全试验，但我们在试验过程中获得的数据可能使我们能够对有效性进行初步检查。目标2：计划DCREG受体的顺序免疫学分析。我们计划进行详细的机械研究，对于了解研究结果以及感染细胞对同种免疫反应的潜在影响至关重要。