Induction of Donor Tolerance in Renal Transplants

描述：肾移植是终末性器官衰竭的首选治疗方法。然而，长期使用免疫抑制剂是预防排斥反应的关键。这些药物价格昂贵(15,000-25,000美元/年)，并有显著的毒性，包括机会性感染、恶性肿瘤发生率增加、肾毒性和其他终端器官损害。诱导特定于供者的耐受将解决这些限制。骨髓嵌合体诱导对移植器官的耐受。然而，传统的造血干细胞移植(HSCT)的毒性和并发症，主要是移植物抗宿主病(GVHD)和需要匹配的供者，限制了HSCT在诱导耐受方面的治疗应用。我们已经鉴定并申请了一种新的耐受性骨髓细胞群CD8+/TCR促进细胞(FC)，该细胞可在不引起GVHD的情况下增强不相合受者的干细胞植入。Fc的发现为使用HSCT作为一种可行的基于细胞的耐受诱导方法打开了大门。该产品FCRx解决了阻碍HSCT广泛用于耐受诱导的主要挑战。FCRx是一种生物工程骨髓产品，包括造血干细胞(HSC)和FC，但避免了不相合受者的GVHD。在这项建议的第一阶段，我们实现了我们提出的里程碑，表明我们可以可靠地生产和运输FCRx，并将其安全地注入非清髓条件下的肾移植受者。我们证明，专利的FCRx程序可以常规地产生具有明确的12-TCR+T细胞组成的移植物，并富含HSC和植入性增强的FC。最终目标是诱导免疫耐受，消除或减少对昂贵和有害的免疫抑制药物的需求。我们开发了一种非清髓性的预适应方案，包括200cGyTBI/氟达拉滨/环磷酰胺/MMF/Prograf，以避免预适应的毒性。自完成第一阶段以来，我们已经解决了审查者对我们招募受试者的能力表达的主要担忧，现在已经成功地移植了6名活体供肾患者，他们在移植后一个月都表现出供者嵌合体。收集、运输和FCRx制备的方法也已获得FDA的批准。三名患者显示出供者特异性耐受性的实验室证据，免疫抑制正在断奶。其余受试者还在早期随访中。FCRx进程的可重复性和质量保证将导致其成功的商业发射。在第二阶段，我们将加快移植的速度，并证明FCRx始终能够在非清髓条件下的肾移植受者中植入不匹配的HSC，在不引起显著GVHD的情况下诱导供者特异性耐受，并减少或消除长期免疫抑制的需要。最近与FDA的一次会议将我们的产品归类为第二阶段，这将是加强商业化的另一个里程碑。 公共卫生相关性：实体器官移植后，终身免疫抑制治疗是必要的。这些药物价格昂贵，而且有很大的毒性，包括机会性感染、癌症发病率增加和肾衰竭。造血干细胞移植(HSCT)诱导对移植器官和组织的耐受，消除了终身免疫抑制治疗的需要。如果成功，这项被提议商业化的过程被称为FCRx，将产生一种生物工程HSCT，它将促进细胞和干细胞的移植，从而安全地诱导耐受，从而消除对免疫抑制治疗的需要，以及与金钱和健康相关的高昂成本。

DESCRIPTION: Renal transplantation is the preferred therapeutic approach for end organ failure. However, the chronic use of immunosuppressive agents is critical to prevent rejection. The drugs are costly ($15,000-25,000/year) and have significant toxicities including opportunistic infection, an increased rate of malignancy, nephrotoxicity, and other end organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism induces tolerance to transplanted organs. However, the toxicity and complications associated with conventional hematopoietic stem cell transplants (HSCT), primarily graft-versus-host disease (GVHD) and the need for a matched donor, has limited the therapeutic application of HSCT to tolerance induction. We have identified and patented a novel tolerogenic bone marrow cell population of CD8+/TCR- facilitating cells (FC) that enhances engraftment of stem cells in mismatched recipients without causing GVHD. The discovery of FC opens the door to employing HSCT as a viable cell-based approach for tolerance induction. The product, FCRx, addresses the major challenges preventing the widespread use of HSCT for tolerance induction. FCRx is a bioengineered bone marrow product that includes hematopoietic stem cells (HSC) and FC, but avoids GVHD in mismatched recipients. In phase I of this proposal, we achieved our proposed milestones, demonstrating that we could reliably produce and transport FCRx and safely infuse it into nonmyeloablatively conditioned renal transplant recipients. We demonstrated that the proprietary FCRx procedure can routinely produce a graft with defined 12-TCR+ T cell composition and enriched for HSC and engraftment-enhancing FC. The ultimate goal is the induction of immune tolerance and the elimination of or reduction in the need for expensive and harmful immunosuppressive drugs. We have developed a nonmyeloablative conditioning regimen with 200 cGy TBI/fludarabine/cyclophosphamide/MMF/prograf to avoid the toxicity of conditioning. Since completing Phase I, we have addressed a major concern expressed by the reviewers regarding our ability to enroll subjects and have now successfully transplanted 6 living donor kidney patients, all of whom demonstrated donor chimerism at one month post-transplant. The approaches for collection, shipping, and FCRx preparation have also been approved by the FDA. Three patients show laboratory evidence of donor-specific tolerance, and immunosuppression is being weaned. The remaining subjects are early in follow-up. The reproducibility and quality assurance of the FCRx process will lead to its successful commercial launch. In phase II we will increase the pace of transplants and demonstrate that FCRx consistently achieves engraftment of HLA mismatched HSC in nonmyeloablatively conditioned kidney transplant recipients, induces donor-specific tolerance without causing significant GVHD, and reduces or eliminates the need for long-term immunosuppression. A recent meeting with FDA classified our product as Phase II, another milestone that will enhance commercialization. PUBLIC HEALTH RELEVANCE: Life-long immunosuppressive therapy is necessary following solid organ transplant. These drugs are expensive and have significant toxicities including opportunistic infection, an increased rate of cancer, and kidney failure. Hematopoietic stem cell transplantation (HSCT) induces tolerance to transplanted organs and tissue, eliminating the need for life-long immunosuppressive therapy. If successful, the process proposed for commercialization, called FCRx, will produce a bioengineered HSCT graft-enriched for facilitating cells and stem cells that will safely induce tolerance, eliminating the need for immunosuppressive therapy along with its high monetary and health-related cost.