A Phase I/II Clinical Trial to Investigate Fucosylated Tregs in Prevention of GVHD

 描述(申请人提供)：异基因造血干细胞移植具有治愈各种血液系统恶性肿瘤和遗传性疾病的潜力，但受到治疗相关死亡率的限制，在大多数情况下，这与移植物抗宿主病(GVHD)直接相关。目前对GVHD的治疗包括使用钙调神经磷酸酶抑制剂，如环孢素和他克莫司，延长免疫抑制时间。然而，长期的免疫抑制本身会导致免疫功能延迟，导致感染并发症以及移植后淋巴增生性疾病的风险。因此，显然需要其他办法来减轻GVHD的有害影响，无论是急性的还是慢性的。随着概念验证临床前研究的完成，我们正在申请资金，以支持一项试验性的两阶段I/IIa阶段安全性和初步疗效临床试验，调查一种基于细胞的创新方法，以预防双脐血移植环境中的移植物抗宿主病。我们提出的方法是新颖的，因为它利用了系统管理的调节性T细胞(Tregs)和TZ101体外治疗后增强的归巢/植入相结合的有益和公认的抗炎效果。TZ101由α1，3岩藻糖基转移酶(FTVI1，3岩藻糖基转移酶)及其底物鸟苷二磷酸岩藻糖组成，当与细胞孵育时，导致岩藻糖与细胞表面糖蛋白的定位和立体特异性加成。许多不同的研究人员已经证明了这一点，以增强不同类型细胞的选择介导的结合。最值得注意的是，这种相互作用是干细胞/祖细胞归巢到选择素水平上调的部位的基础，选择素水平上调是炎症组织的标志。在临床试验网站gov上搜索“调节性T细胞”，可以找到400多项临床试验，证明了对这一免疫群体进行管理的重要性和安全性。此外，T-regs具有多种特征，可以清楚地解决广泛患者群体中的GVHD问题，例如：同种异体反应性T细胞缺乏增殖反应的刺激，体外树突状细胞、T细胞和自然杀伤细胞细胞因子分泌谱的改变，促炎症细胞因子的分泌受到抑制，抑制性细胞因子的表达增加。我们提出了四个具体目标：1)生产cGMP TZ101试剂(FTVI和GDP-岩藻糖)2)第一阶段：检查剂量水平1的安全性：以1x106/公斤患者体重计算的新T-Regs。我们将使用三个共同的主要结果来衡量安全性：1)严重输液毒性的时间，2)3级，4 GVHD和3)死亡。3)IIa期：单次剂量岩藻糖化T-regss 1x107个/kg患者体重的初步疗效检查。我们将使用主要结果T=严重(3级或4级)GVH死亡的时间，在同种异体移植后的前100天内监测疗效。 体外和体内研究追求岩藻糖基化Tregs的作用机制，以及体内结果与正在进行的临床结果的相关性。这些拟议研究的结果将为我们提供足够的信息，以评估将这一基于细胞的方法应用于GVHD进入IIb期多中心试验的优点。如果最终成功，岩藻糖基化Tregs的可获得性将为移植物抗宿主病的临床治疗提供更多的选择，以更好地恢复患者和改善生活质量。此外，它还将促进对这种有前景的新细胞治疗方法的探索，将其应用于自身免疫和其他疾病。

 DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplant has the potential to cure various hematological malignancies and inherited disorders but is limited by treatment-related mortality, which in a majority of cases is directly related to Graft-versus-Host Disease (GVHD). Current therapy for GVHD involves prolonged immunosuppression with calcineurin inhibitors such as cyclosporine and tacrolimus. However, in itself prolonged immunosuppression results in delayed immune function leading to infectious complications as well as a risk of post-transplant lymphoproliferative disorders. Thus, there is a clear need for alternative approaches to mitigate the deleterious effects of GVHD whether acute or chronic. With proof-of-concept preclinical studies completed, we are requesting funding to support a pilot two- stage Phase I/IIa safety and preliminary efficacy clinical trial investigating an innovative cell-based approach for prevention of GVHD in a dual cord blood transplant setting. Our proposed approach is novel in that it capitalizes on the beneficial and well-established anti-inflammatory effects of systemically administered regulatory T cells (Tregs) combined with enhanced homing/engraftment following their ex vivo treatment with TZ101. TZ101 is comprised of the enzyme α 1, 3 fucosyltransferase (FTVI) and its substrate, guanosine diphosphate-fucose which, when incubated with cells, leads to site and stereospecific addition of fucose to cell surface glycoproteins. This has been shown by a number of different Investigators to enhance selecting- mediated binding for varying cell types. Most notably, this interaction underlies the homing of stem/progenitor cells to sites of upregulated levels of selectins which is a hallmark of inflamed tissue. A search on clinical trials.gov for "regulatory T cells" reveals over 400 clinica trials, demonstrating the importance and safety of administration of this immune population. Furthermore, T-regs are endowed with multiple features that can clearly address GVHD across a broad patient population, such as: lack of stimulation of a proliferative response from alloreactive T-cells, alteration of cytokine secretion profile of dendritic cells, T cells and natual killer cells in vitro, inhibition of secretion of proinflammatory cytokines and increased expressio of suppressive cytokines. We are proposing four specific aims: 1) Production of cGMP TZ101 reagents (FTVI and GDP-fucose) 2) Phase I: examination of the safety of dose level 1: fuocsylated T-regs at 1x106 /kg patient weight. We will use three co-primary outcomes measures for safety: 1) time to severe infusional toxicity, 2) grade 3, 4 GVHD and 3) death. 3) Phase IIa: examination of preliminary efficacy at a single dose of fucosylated T-regss at 1x107 cells/kg patient weight. We will use the primary outcome T = the time to severe (grade 3 or 4) GVH to death, monitored over the first 100 days post allotransplant for efficacy 4) Preclinical in vitro and in vivo studies pursuing the mechanism of action of fucosylated Tregs along with correlating in vivo outcome measures with ongoing clinical results The results from these proposed studies will provide us with sufficient information to assess the merits of advancing this cell-based approach for GVHD into a Phase IIb multicenter trial. If ultimately successful, availability of fucosylated Tregs will provide additional options in the clinical management of GVHD for better patient recovery and improved quality of life. Furthermore, it will stimulate exploration of this promising new cell therapeutic approach for application with autoimmune and other diseases.