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（由申请人提供）：基于实验动物研究，对调节性树突细胞（DCreg）进行临床测试以提高器官移植存活率已经出现了令人信服的理由，重要的是，使用稳健的、临床相关的非人类灵长类动物模型。和最小的免疫抑制，我们已经证明，移植前一周输注 DCreg 可以安全地延长肾同种异体移植物的存活，而没有宿主致敏的证据。这种治疗效果与选择性相关。供体特异性 T 衰减记忆细胞反应是促进长期移植物存活的重要障碍，我们从淘洗的血液单核细胞中产生了 GMP 级人 DCreg，并证明了它们在炎症条件下对成熟的稳定抵抗力以及负调节同种异体反应性 T 细胞反应的能力。基于这些成就，我们还制定了临床测试的发布标准，我们现在计划在成人从头活体肾移植中进行供体来源的 DCreg 的临床试验，这是一种新颖且独特的调节性免疫细胞方法。治疗于该 R34 申请的目的是完成临床试验方案、最终确定 DCreg 生产的放大和生产 SOP、完成机制研究的设计、获得 FDA 和 IRB 的必要批准，并建立器官移植框架。我们努力进行临床试验操作和管理，认为体外产生的供体来源的 DCreg 并前瞻性地给予接受常规免疫抑制治疗的活体供体肾移植受者，将是安全的，并且会引起有利于改善移植物存活的免疫变化。两个具体目标：目标 1：计划在接受新活体肾移植的成人患者中开展一项首次人体、开放标签、单中心剂量递增安全性研究。在移植前一周，他们将接受一次来自供体的 DCreg 与霉酚酸 (MPA) 的联合输注虽然这是一项安全试验，但我们在试验过程中获得的数据可能使我们能够进行一项安全试验。目的 2：计划对 DCreg 受体进行连续免疫学分析，这对于了解研究结果以及输注细胞对同种免疫反应的潜在影响至关重要。