Core Clinical Centers for the Blood and Marrow Transplant Clinical Trials Network (UG1)

血液和骨髓移植临床试验网络(BMT CTN)的长期目标是产生 来自多中心II期和III期试验的疗效和安全性数据，并推动 治疗血液疾病的免疫和造血细胞疗法。莫菲特癌症中心已经在 将促进和提供免疫和造血细胞疗法的所有基础设施 稳健的免疫学工作组定位于设计解决方案--符合GMP的细胞疗法 细胞制造和质量控制设施，骨髓移植和免疫和细胞治疗服务，以 为非恶性血液疾病患者提供已建立的和实验性的细胞疗法， 血液系统恶性肿瘤和实体瘤。我们的团队渴望为推动这一领域的发展做出贡献 与BMT CTN合作，完成创新细胞疗法的所有开发步骤。具体目标1是 与BMT CTN合作设计和进行多中心研究，并传播 结果。新的想法始于单一中心的研究团队，但在医学方面取得了重大进展 CARE需要多中心III期随机试验。我们的团队带来了细胞免疫疗法方面的专业知识， GVHD免疫生物学和行为研究。莫菲特癌症中心拥有完善的临床和 转化性研究计划，基础设施不断扩大，以促进40多种细胞疗法和 每年超过400例HSCT，并将继续向我们机构的患者提供BMT CTN试验。我们 带来独特的科学、临床试验设计经验、临床专业知识和数量，以及我们对 通过极具价值的BMT CTN网络积极追求这些进步。具体目标2是测试 在骨髓移植CTN进行的III期多中心试验中，ustekinumab预防GVHD的疗效。BMT 研究已经认识到Th17和Th1细胞在GVHD中都是重要的效应者 啮齿动物和人类移植，与IL-12和IL-23共有的p40亚单位与GVHD有关 发病机制。我们提供了一项安慰剂对照的原则验证临床试验的初步数据 Ustekinumab(StelaraTM)是一种抗人p40的抗体，它使T细胞极化为Th2，同时抑制Th1 同种异基因造血干细胞移植后Th17的表达。临床数据还表明，Ustekinumab有缓解疾病的潜力 包括急性和慢性移植物抗宿主病，并在不破坏移植物抗白血病反应的情况下提高存活率。我们的 提出的最终多中心试验的概念解决了重大的未得到满足的需求，以预防急性和 慢性移植物抗宿主病，积极的结果将对未来的临床研究产生持续、强大的影响 预防和扩大异基因造血干细胞移植的应用。

The long term goal of the Blood and Marrow Transplant Clinical Trial Network (BMT CTN) is to generate efficacy and safety data from multicenter Phase II and III trials, and advance the science and technology of immune and hematopoietic cellular therapies for the cure of blood disorders. The Moffitt Cancer Center has in place all the infrastructures for promoting and delivering immune and hematopoietic cellular therapies, with a robust Immunology Working Group properly positioned to design solutions, a GMP-compliant Cellular Therapy Facility for cell manufacturing and quality control, the BMT and the Immune and Cellular Therapy services to deliver established and experimental cellular therapies to patients with nonmalignant blood disorders, hematological malignancies and solid tumors. Our team is eager to contributing moving the field forward by collaborating with the BMT CTN for all the development steps of innovative cellular therapies. Specific Aim 1 is to collaborate with the BMT CTN in the design and conduct of multicenter studies and the dissemination of the results. Novel ideas start from teams of investigators at a single center, but significant advances in medical care require multicenter phase III randomized trials. Our team brings expertise in cellular immunotherapy, GVHD immunobiology, and behavioral studies. Moffitt Cancer Center has a fully established clinical and translational research program with a growing infrastructure to facilitate over 40 cellular therapy treatments and over 400 HSCT per year, and will continue to make BMT CTN trials available to patients in our institution. We bring unique science, clinical trial design experience, clinical expertise and volume, and our commitment to aggressively pursue these advances through the highly valuable BMT CTN network. Specific Aim 2 is to test the efficacy of ustekinumab for GVHD prophylaxis in a phase III multicenter trial by the BMT CTN. The BMT research program has recognized that Th17 are important effectors in GVHD alongside Th1 cells both in rodents and human transplants, and that the p40 subunit shared with IL-12 and IL-23 is relevant to GVHD pathogenesis. We present preliminary data from a placebo-controlled proof-of-principle clinical trial that ustekinumab (StelaraTM), an antibody against the human p40, polarizes T cells to Th2 while dampening Th1 and Th17 after allogenic HSCT. The clinical data also suggest that ustekinumab has the potential for mitigating both acute and chronic GVHD, and improving survival without disrupting graft-vs-leukemia responses. Our proposed concept for a definitive multicenter trial addresses the significant unmet need to prevent acute and chronic GVHD, and positive results will exert a sustained, powerful influence on the future clinical research in GVHD prevention and expand utilization of allogeneic HSCT.