EBNA1 Inhibitor for Treatment of EBV-positive DLBCL

项目总结 爱泼斯坦-巴尔病毒(EBV)每年导致全球约20万新的癌症病例。 其中，EBV弥漫性大B细胞淋巴瘤(DLBCL)是患者面临的一个紧急的全球性癌症威胁 没有明显的免疫抑制，不分年龄，代表着日益增长的未得到满足的医疗需求。新的 EBV DLBCL的治疗需要多种治疗方法。只有一种病毒编码的蛋白质EBNA1是 在所有已知的EBV相关恶性肿瘤中持续表达，是抑制EBV-1的有效靶点。 依赖性转化与致癌。 Wistar研究所的研究人员开发出VK-2019，一种一流的EBNA1抑制剂，用于治疗 试剂，在点击到领先和领先优化过程中从2500多种候选抑制剂化合物中选择 阶段。VK-2019在效力、选择性、代谢稳定性、药物等方面达到或超过行业认可的标准 适合性、药物安全性、毒理学和生物利用度。我们预计VK-2019将具有良好的安全性 因为没有EBNA1的人类同源基因。基于临床前证据和人类首例 晚期鼻咽癌患者的I期临床研究，VK-2019满足所有安全性， 耐受性和药代动力学终点，记录的不良事件(AEs)或严重不良反应很少 事件(SAE)。在这项早期研究中，我们观察到三分之一以上的人病情稳定，而且病情显著下降。 在超过一半的患者中，EBV血浆水平，一个已知的鼻咽癌进展的生物标志物，与 有药代动力学暴露。我们相信，这项第一阶段研究的数据在两个方面都是令人鼓舞的 关于靶效应和临床益处，并支持对EBV阳性患者进行后续概念验证研究 DLBCL。 这笔赠款的目的是资助一项每日口服VK-2019的Ib期临床试验，以进一步 确认晚期EBV DLBCL患者的安全性并确定任何剂量限制毒性(DLT) 了解治疗对EBV特异性生物标志物的影响，包括EBV和细胞基因 研究治疗对肿瘤微环境和免疫反应的影响。 进行这项研究所需的临床试验基础设施已经在Sidney Kimmel就位 托马斯·杰斐逊大学癌症中心。这项临床试验将提供有关安全性的关键信息， VK-2019在EBV DLBCL患者人群中的耐受性和初步疗效。这个应用程序带来了 联合基础研究人员和翻译研究人员了解EBNA1抑制剂是否具有治疗作用 潜在的EBV感染和癌症的选择，并检查其作用机制。

PROJECT SUMMARY The Epstein-Barr Virus (EBV) is responsible for approximately 200,000 new cancer cases each year worldwide. Among these, EBV+ Diffuse Large B-Cell Lymphoma (DLBCL) is an emergent global cancer threat in patients without overt immunosuppression, irrespective of age, and represents a growing unmet medical need. New therapeutic approaches are needed to treat EBV+ DLBCL. Only one viral-encoded protein, EBNA1, is consistently expressed in all known EBV-associated malignancies and is a validated target for inhibition of EBV- dependent transformation and carcinogenesis. Investigators at the Wistar Institute have developed VK-2019, a first-in-class EBNA1 inhibitor as a therapeutic agent, selecting it from over 2500 candidate inhibitor compounds during the hit-to-lead and lead optimization phases. VK-2019 meets or exceeds industry-accepted criteria for potency, selectivity, metabolic stability, drug suitability, drug safety, toxicology and bioavailability. We anticipated that VK-2019 would have a favorable safety profile because there are no human orthologs of EBNA1. Based on preclinical evidence and a first-in-human Phase I clinical study in patients with advanced nasopharyngeal carcinoma (NPC), VK-2019 met all safety, tolerability and pharmacokinetic endpoints with few documented adverse events (AEs) or Severe Adverse Events (SAEs). In this early study, we observed stable disease in more than a third and a significant decrease in EBV plasma levels, a known biomarker of NPC progression, in more than half of the patients, that correlated with pharmacokinetic exposure. We believe that data from this Phase I study are encouraging in terms of both on target effect and clinical benefit, and supports a follow-on proof-of-concept study in patients with EBV-positive DLBCL. The purpose of this grant is to fund a phase Ib clinical trial of daily oral administration of VK-2019 to (1) further confirm the safety profile and determine any dose-limiting toxicities (DLT) in advanced EBV+ DLBCL patient populations; (2) understand the effects of treatment on EBV-specific biomarkers, including EBV and cellular gene expression and (3) study the effects of treatment on the tumor microenvironment and immune response. The clinical trial infrastructure necessary for the conduct of this study is already in place at the Sidney Kimmel Cancer Center at Thomas Jefferson University. This clinical trial will provide critical information on the safety, tolerability, and preliminary efficacy of VK-2019 in a EBV+ DLBCL patient population. This application brings together basic and translational investigators to understand whether EBNA1 inhibitors can be a therapeutic option for latent EBV infection and cancer and examines the mechanism of action.