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

• 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
• 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

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，调节性树突状细胞的临床测试已经出现了一个令人信服的理由 细胞(DCreg)以提高器官移植的存活率。重要的是，使用健壮的、与临床相关的、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，可以安全地延长移植肾的存活，没有证据表明宿主致敏。这是一种治疗 这种效应与供者特异性T记忆细胞反应的选择性减弱有关，这是一种重要的障碍 以促进移植物的长期存活。我们已经从淘洗的血液中产生了GMP级的人DCreg 单核细胞在体外表现出对炎症条件下成熟的稳定抵抗 以及它们负向调节同种异体反应性T细胞反应的能力。我们还建立了发布标准 用于临床测试。在这些成就的基础上，在R34临床试验计划的支持下 格兰特，我们已经与DAIT项目官员一起完成了临床试验方案。我们还有 最终确定DCreg生产的规模化生产标准操作规程，完成机械研究的设计， 获得FDA必要的批准(IND)，建立临床试验运行框架和 管理，以及统计方面的考虑和分析计划。因此，我们已做好充分准备，并准备好 进行拟议的临床试验。这是一种新的和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，并预期用于活体供体 接受常规免疫抑制治疗的肾移植受者将是安全和诱导的。 免疫学改变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 新药成人接受者的首例人类、开放标签、单中心1期剂量递增安全性研究， 活体供体肾移植。患者将接受标准护理的免疫抑制。一周前 然而，移植后，他们将接受一次供体来源的DCreg联合 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 可能会使我们能够对疗效进行初步检查。目标2：进行序贯免疫学 对DCreg接受者的分析。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异体免疫反应的潜在影响。