Phase II Trial of Vorinostat plus Tacrolimus and Mycophenolate to Prevent GVHD

描述(由申请人提供)：这份K23提案中概述的职业发展活动将在宋财博士的几个新领域提供指导性和体验式培训。她将获得特定临床研究领域的生物统计学技能和知识，学习新的实验室技术，并制定进行人类主题研究所必需的伦理原则和研究完整性。因此，综合课程将用新的和先进的技术和方法补充她现有的技能，目标是发展独立的、以患者为导向的研究生涯，成为骨髓移植(BMT)领域的翻译研究员。在K23的支持下，崔博士将根据她的培训活动和总体职业目标进行一个以患者为导向的指导研究项目。异基因骨髓移植是一种潜在的治疗许多非血液病和血液病的方法。移植物抗宿主病(GVHD)仍然是异基因骨髓移植后发病率和死亡率的主要原因，阻碍了这种根治疗法的广泛应用。目前预防和治疗移植物抗宿主病的药物主要针对移植物抗宿主病的重要效应因子--供体T细胞。GVHD的其他关键效应细胞是抗原提呈细胞(APC)，因此也是潜在的治疗靶点。因此，靶向APC同种异体刺激功能的药物在GVH过程中可能是一种创新的治疗潜力。组蛋白脱乙酰酶(HDAC)抑制剂是一种新型的抗肿瘤药物，在人体临床试验中似乎耐受性良好。然而，到目前为止，它们的免疫调节作用在很大程度上还没有被认识到。崔博士的导师雷迪博士的实验室产生的临床前数据构成了这一提议的理论基础。崔博士将在一项创新的第二阶段临床试验中验证核心假设，即抑制HDAC将通过抑制人类APC的功能来降低GVHD的严重程度。这些研究可以开发一类新型的免疫调节药物来减轻移植物抗宿主病。这项临床试验的具体目标是：1)在标准免疫抑制的基础上，使用伏立诺他定进行第二阶段试验，以预防相关供者减少强度调节(RIC)骨髓移植中的移植物抗宿主病。2)检测去乙酰化酶抑制相关供体RIC骨髓移植后细胞和血浆炎症反应的细胞和血浆标志物。总之，K23将为崔博士提供时间和资源：1)在定义明确的指导结构内执行新的临床试验和进行强有力的相关研究；2)获得临床研究设计和统计分析方面的正式培训；3)提高她的研究效率；4)发展手稿和拨款准备技能；5)发展成为一名独立的研究人员。异基因骨髓移植是许多恶性和非恶性疾病的潜在治疗方法，但其最严重的并发症-移植物抗宿主病(GVHD)的发展阻碍了其应用。缓解移植物抗宿主病的新的预防策略将允许更好地利用这一有效的治疗方式。

DESCRIPTION (provided by applicant): The career development activities outlined in this K23 proposal will provide didactic and experiential training under a mentored experience in several areas new to Dr. Sung Choi. She will acquire biostatistical skills and knowledge in specific areas of clinical research, learn new laboratory techniques, and develop ethical principles and research integrity essential for the conduct of human subject research. Thus, the comprehensive curriculum will complement her existing skills with new and advanced techniques and approaches with the goal of developing an independent, patient-oriented research career as a translational investigator in the field of bone marrow transplantation (BMT). With support of the K23, Dr. Choi will conduct a mentored patient-oriented research project in alignment with her training activities and overall career goals. Allogeneic BMT is a potentially curative therapy for many non-hematologic and hematologic diseases. Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic BMT and prevents this curative therapy from wider application. Current pharmacologic agents for GVHD prevention and treatment primarily target an essential effector for GVHD, donor T cells. Other key effectors for GVHD, and therefore potential therapeutic targets, are antigen presenting cells (APCs). Therefore, agents that target the allostimulatory functions of APCs may be an innovative therapeutic potential in the GVH process. Histone deacetylase (HDAC) inhibitors are novel anti-tumor agents that appear to be well-tolerated in human clinical trials. However, their immunomodulatory effects have thus far been largely unrecognized. Pre-clinical data generated in the laboratory of Dr. Reddy, Dr. Choi's mentor, form the rationale for this proposal. Dr. Choi will test the central hypothesis that HDAC inhibition will reduce the severity of GVHD by suppressing the functions of human APCs, the key mediators of GVHD, in an innovative Phase II clinical trial. These studies could allow for the development of a novel class of immunomodulatory drugs for attenuating GVHD. The specific aims of the clinical trial are: 1) To conduct a Phase II trial using vorinostat in addition to standard immunosuppression to prevent GVHD in related donor reduced intensity conditioning (RIC) BMT. 2) To determine the cellular and plasma markers of deacetylase inhibition on inflammation after vorinostat administration following related donor RIC BMT. In summary, this K23 will provide Dr. Choi with the time and resources to: 1) execute a novel clinical trial and perform robust correlative studies within a well-defined mentoring structure; 2) obtain formal training in clinical research design and statistical analyses; 3) increase her research productivity; 4) develop skills in manuscript and grant preparation; and 5) evolve into an independent investigator. Allogeneic bone marrow transplantation is a potentially curative therapy for many malignant and nonmalignant conditions whose applicability has been impeded by the development of its most serious complication, graft-versus-host disease (GVHD). A novel preventive strategy to mitigate GVHD will allow for better harnessing of this effective therapeutic modality.