Induction of Donor Tolerance in Renal Transplants

描述：肾移植是终末器官衰竭的首选治疗方法。然而，长期使用免疫抑制剂对预防排斥反应至关重要。这些药物价格昂贵（15,000-25,000美元/年），并且具有明显的毒性，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。诱导供体特异性耐受将解决这些限制。骨髓嵌合诱导对移植器官的耐受性。然而，与传统造血干细胞移植（HSCT）相关的毒性和并发症，主要是移植物抗宿主病（GVHD）和对匹配供体的需求，限制了HSCT在诱导耐受方面的治疗应用。我们已经确定了一种新的CD8+/TCR-促进细胞（FC）的耐受性骨髓细胞群，并获得了专利，该细胞群可以增强不匹配受体中干细胞的植入，而不会引起GVHD。FC的发现为采用HSCT作为一种可行的基于细胞的耐受性诱导方法打开了大门。该产品FCRx解决了阻碍HSCT广泛应用于耐受性诱导的主要挑战。FCRx是一种生物工程骨髓产品，包括造血干细胞（HSC）和FC，但在不匹配的受体中避免了GVHD。在该方案的I期，我们实现了我们所提出的里程碑，证明我们可以可靠地生产和运输FCRx，并安全地将其注入非清髓条件肾移植受者。我们证明了专有的FCRx程序可以常规地产生具有定义的12-TCR+ T细胞组成的移植物，并富集HSC和增强移植物的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200 cGy TBI/氟达拉滨/环磷酰胺/MMF/方案的非清髓调节方案，以避免调节的毒性。自I期完成以来，我们解决了审稿人对我们招募受试者的能力所表达的主要担忧，目前已经成功移植了6例活体供体肾脏患者，所有患者在移植后一个月均表现出供体嵌合。收集、运输和制备FCRx的方法也得到了FDA的批准。三名患者显示出供体特异性耐受性的实验室证据，免疫抑制正在断奶。其余受试者处于早期随访阶段。FCRx工艺的可重复性和质量保证将导致其成功的商业发射。在II期，我们将增加移植的速度，并证明FCRx在非清髓条件肾移植受者中持续实现HLA错配的HSC移植，诱导供者特异性耐受性而不引起显著的GVHD，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分类为II期，这是另一个将加强商业化的里程碑。

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.