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

描述（由申请人提供）：本K23提案中概述的职业发展活动将在Sung Choi博士的几个新领域的指导经验下提供教学和体验式培训。她将获得临床研究特定领域的生物统计学技能和知识，学习新的实验室技术，并制定进行人类受试者研究必不可少的伦理原则和研究诚信。因此，全面的课程将补充她现有的技能，新的和先进的技术和方法，目标是发展一个独立的，以患者为导向的研究事业，作为骨髓移植（BMT）领域的转化研究者。在K23的支持下，崔博士将根据她的培训活动和整体职业目标，开展一项以患者为导向的指导研究项目。同种异体骨髓移植是许多非血液病和血液病的潜在治疗方法。移植物抗宿主病（GVHD）仍然是异体骨髓移植后发病和死亡的主要原因，并阻碍了这种治疗性治疗的广泛应用。目前用于GVHD预防和治疗的药物主要针对GVHD的基本效应，供体T细胞。GVHD的其他关键效应物，因此是潜在的治疗靶点，是抗原提呈细胞（APCs）。因此，靶向apc异位刺激功能的药物可能是GVH过程中的一种创新治疗潜力。组蛋白去乙酰化酶（HDAC）抑制剂是一种新型的抗肿瘤药物，在人体临床试验中表现出良好的耐受性。然而，迄今为止，它们的免疫调节作用在很大程度上尚未被认识到。在Choi博士的导师Reddy博士的实验室中产生的临床前数据构成了该建议的基本原理。Choi博士将在一项创新的II期临床试验中验证HDAC抑制将通过抑制人类apc （GVHD的关键介质）的功能来降低GVHD严重程度的中心假设。这些研究可能允许开发一类新的免疫调节药物来减轻GVHD。该临床试验的具体目的是：1)在标准免疫抑制的基础上使用伏立诺他进行II期试验，以预防相关供体低强度调节（RIC） BMT的GVHD。2)测定相关供体RIC BMT术后给予伏立诺他后去乙酰酶抑制炎症的细胞和血浆标志物。总之，这个K23将为Choi博士提供时间和资源：1)执行一项新的临床试验，并在一个明确定义的指导结构中进行稳健的相关研究；2)接受临床研究设计和统计分析方面的正规培训；3)提高她的研究效率；4)发展稿件和拨款准备的技能；然后演变成一名独立调查员。同种异体骨髓移植是一种治疗许多恶性和非恶性疾病的潜在治疗方法，但由于其最严重的并发症移植物抗宿主病（GVHD）的发展，其适用性受到阻碍。一种减轻GVHD的新型预防策略将允许更好地利用这种有效的治疗方式。

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.