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

研究岩藻糖基化 Tregs 预防 GVHD 的 I/II 期临床试验

• 批准号: 9134660
• 负责人: JoAnn Flaim
• 金额: $ 46.71万
• 依托单位: TARGAZYME, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134660
• 关键词: Acute; Address; Affect; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Process; Binding; CD44 gene; Calcineurin inhibitor; Cancer Center; Cells; Cessation of life; Chronic; Clinic; Clinical; Clinical Management; Clinical Research; Clinical Trials; Collaborations; Contracts; Cyclic GMP; Cyclosporine; Dendritic Cells; Disease; Dose; E-Selectin; Economic Burden; Engraftment; Enrollment; Enzymes; Florida; Fucose; Funding; Future; Glycoproteins; Grant; Guanosine Diphosphate Fucose; Health; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Home environment; Homing; Immune; Immunosuppression; In Vitro; Inborn Genetic Diseases; Incubated; Infusion procedures; Killer Cells; Lead; Ligands; Lymphoproliferative Disorders; Mediating; Membrane Glycoproteins; Minnesota; Monitor; Multicenter Trials; Outcome Measure; P-Selectin; Patients; Phase; Population; Pre-Clinical Model; Prevention; Prevention approach; Quality of life; Reagent; Recovery; Regulatory T-Lymphocyte; Research Personnel; Risk; Safety; Selectins; Series; Site; Staging; Stem cells; T-Lymphocyte; Tacrolimus; Therapeutic; Time; TimeLine; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation; Umbilical Cord Blood; Universities; Up-Regulation; Weight; allotransplant; base; cGMP production; cell type; chronic graft versus host disease; cytokine; follow-up; galactoside 3-fucosyltransferase; graft vs host disease; immune function; improved; improved outcome; in vivo; innovation; mortality; novel; novel strategies; open label; patient population; phase I trial; pre-clinical; preclinical study; primary outcome; response; safety study; stem; sugar; treatment planning

 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.

 描述（由申请人提供）：异基因造血干细胞移植具有治愈各种血液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，治疗相关死亡率与移植物抗宿主病（GVHD）直接相关。目前GVHD的治疗涉及用钙调磷酸酶抑制剂如环孢霉素和他克莫司进行长期免疫抑制。然而，长期的免疫抑制本身会导致免疫功能延迟，从而导致感染性并发症以及移植后淋巴组织增生性疾病的风险。因此，显然需要替代方法来减轻急性或慢性GVHD的有害影响。 随着概念验证临床前研究的完成，我们正在申请资金支持一项试点两阶段I/IIa期安全性和初步疗效临床试验，研究一种创新的基于细胞的方法，用于预防双重脐带血移植环境中的GVHD。我们提出的方法是新颖的，因为它利用了全身施用的调节性T细胞（TCFs）的有益的和公认的抗炎作用，并在用TZ 101离体治疗后增强归巢/植入。TZ 101由酶α 1，3岩藻糖基转移酶（FTVI）及其底物鸟苷二磷酸岩藻糖组成，鸟苷二磷酸岩藻糖与细胞孵育时，导致岩藻糖向细胞表面糖蛋白的位点和立体特异性加成。许多不同的研究者已经表明，这增强了不同细胞类型的选择介导的结合。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位点的基础，选择素水平上调是炎症组织的标志。 在临床trials.gov上搜索“调节性T细胞”，发现了400多个临床试验，证明了这种免疫群体的重要性和安全性。此外，T-T细胞被赋予多种特征，这些特征可以清楚地解决广泛患者群体中的GVHD，例如：缺乏来自同种异体反应性T细胞的增殖反应的刺激，体外树突状细胞、T细胞和自然杀伤细胞的细胞因子分泌谱的改变，促炎细胞因子分泌的抑制和抑制性细胞因子表达的增加。我们提出了四个具体目标：1）cGMP TZ 101试剂（FTVI和GDP-岩藻糖）的生产2）I期：检查剂量水平1的安全性：1 × 106/kg患者体重的氟糖基化T-TZ 101。我们将使用三个共同主要结局指标来评估安全性：1）至严重输注毒性的时间，2）3级，4 GVHD和3）死亡。3)IIa期：以1x 107个细胞/kg患者体重单次给予岩藻糖基化T-regss的初步疗效检查。我们将使用主要结果T =从严重（3级或4级）GVH到死亡的时间，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THEB的作用机制，沿着相关的体内结果测量与正在进行的临床结果这些提议的研究的结果将为我们提供足够的信息来评估将这种基于细胞的GVHD方法推进到IIb期多中心试验的优点。如果最终获得成功，岩藻糖基化THBG的可用性将为GVHD的临床管理提供额外的选择，以改善患者的恢复和生活质量。此外，它将刺激探索这种有前途的新细胞治疗方法，用于自身免疫性疾病和其他疾病。

项目成果

Third party, umbilical cord blood derived regulatory T-cells for prevention of graft versus host disease in allogeneic hematopoietic stem cell transplantation: feasibility, safety and immune reconstitution.

• DOI: 10.18632/oncotarget.26242
• 发表时间: 2018-11-02
• 期刊: Oncotarget
• 作者: Kellner JN;Delemarre EM;Yvon E;Nierkens S;Boelens JJ;McNiece I;Olson A;Nieto Y;Ciurea S;Popat U;Ahmed S;Champlin R;Ramos J;Nishimoto M;Ma H;Ke Z;Thall P;Khoury JD;Negrin R;Andersson B;Parmar S
• 通讯作者: Parmar S