EBNA1 Inhibitor for Treatment of EBV-positive DLBCL

项目摘要 EB病毒（EBV）每年在全球范围内造成约20万例新发癌症病例。 其中，EBV+弥漫性大B细胞淋巴瘤（DLBCL）是患者中的紧急全球癌症威胁 没有明显的免疫抑制，无论年龄大小，代表了日益增长的未满足的医疗需求。新 需要治疗EBV+ DLBCL的治疗方法。只有一种病毒编码的蛋白质EBNA 1， 在所有已知的EBV相关恶性肿瘤中一致表达，是抑制EBV的有效靶点。 依赖性转化和致癌作用。 Wistar研究所的研究人员开发了VK-2019，这是一种一流的EBNA 1抑制剂， 代理，选择它从超过2500候选抑制剂化合物在命中铅和铅优化 阶段。VK-2019符合或超过行业公认的效价、选择性、代谢稳定性、药物 适用性、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EBNA 1的人类直系同源物。基于临床前证据和首次人体试验 在晚期鼻咽癌（NPC）患者中进行的I期临床研究，VK-2019符合所有安全性， 耐受性和药代动力学终点，记录的不良事件（AE）或重度不良事件很少 事件（SAE）。在这项早期研究中，我们观察到超过三分之一的患者病情稳定， 在超过一半的患者中，EBV血浆水平，一种已知的NPC进展的生物标志物， 与药代动力学接触。我们认为，这项I期研究的数据在这两方面都令人鼓舞。 目标效应和临床获益，并支持在EBV阳性患者中进行的后续概念验证研究。 DLBCL。 该补助金的目的是资助每日口服VK-2019的Ib期临床试验，以（1）进一步 在晚期EBV+ DLBCL患者中确认安全性特征并确定任何剂量限制性毒性（DLT） （2）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 表达和（3）研究治疗对肿瘤微环境和免疫应答的影响。 Sidney Kimmel已具备开展本研究所需的临床试验基础设施 托马斯杰斐逊大学癌症中心。这项临床试验将提供关于安全性的关键信息， 在EBV+ DLBCL患者人群中，VK-2019的耐受性和初步疗效。该应用程序带来了 将基础和转化研究人员聚集在一起，以了解EBNA 1抑制剂是否可以作为治疗药物， 潜伏性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.