Selective histone deacetylase inhibition with entinostat to enhance the anti-tumor immune response to immune checkpoint inhibition in urothelial cancer

摘要： 尿路上皮癌（UC）的全身治疗在过去几年中取得了进展， 免疫检查点抑制剂用于治疗转移性疾病。虽然在许多情况下很有帮助， 大多数患者对免疫检查点抑制剂治疗没有反应。这些患者的肿瘤有或 获得抑制主动免疫应答的能力，尽管免疫检查点抑制。因此 关键是开发能够调节抗肿瘤免疫应答的药物， 并且可以与免疫检查点抑制剂组合联合收割机以进行更有效的治疗。Entinostat 是一种选择性I类组蛋白脱乙酰酶（HDAC）抑制剂，可导致组蛋白超乙酰化，染色质 重塑和基因表达改变。我们有初步的数据表明恩替司他可以增加免疫 基因签名表达，改变预测的新抗原表达，并与免疫检查点协同作用 在UC的鼠模型中的抑制。基于这些发现，一项评估恩替司他 促进人UC组织中的抗肿瘤免疫应答是必要的。具体而言，该提案将使用 恩替司他在肌肉浸润性UC患者中的机会窗研究，以检验以下假设： 恩替司他可以增强由单独的免疫检查点抑制诱导的抗原驱动的免疫应答。 这一假设将通过表征免疫基因表达、肿瘤新抗原和T 与接受恩替司他+派姆单抗治疗的患者相比，接受恩替司他+派姆单抗治疗的患者的细胞受体谱系 pembrolizumab单药治疗，并与未治疗的患者进行比较。本文提出的研究战略将 同时评估恩替司他作为一种有前途新药在UC的发展，并实现我的短菌 我的职业目标是加强我在免疫基因组学研究方法方面的科学训练。完成后 这个建议，我将很好地定位研究独立，以实现我的长期职业目标， 成为泌尿生殖肿瘤学的领导者，专注于新的基于机制的转化研究。 使用表观遗传和免疫调节剂的组合与免疫疗法组合。

Abstract: The systemic treatment of urothelial cancer (UC) has advanced over the last several years to include the use of immune checkpoint inhibitors for the treatment of metastatic disease. While helpful in many cases, the majority of patients do not respond to immune checkpoint inhibitor treatment. These patients’ tumors have or acquire the ability to suppress an active immune response despite immune checkpoint inhibition. Therefore, it is critical to develop agents that can modulate the anti-tumor immune response toward a less suppressive microenvironment and can combine with immune checkpoint inhibitors for more effective treatment. Entinostat is a selective class I histone deacetylase (HDAC) inhibitor that leads to histone hyperacetylation, chromatin remodeling, and gene expression alterations. We have preliminary data that entinostat can increase immune gene signature expression, alter predicted neoantigen expression, and synergize with immune checkpoint inhibition in murine models of UC. Based on these findings, a study evaluating the ability of entinostat to promote an anti-tumor immune response in human UC tissues is warranted. Specifically, this proposal will use a window of opportunity study of entinostat in patients with muscle-invasive UC to test the hypothesis that entinostat can augment the antigen-driven immune response induced by immune checkpoint inhibition alone. This hypothesis will be tested through characterization of immune gene expression, tumor neoantigens, and T cell receptor repertoires in patients treated with entinostat plus pembrolizumab compared to patients treated with pembrolizumab alone and compared to untreated patients. The research strategy proposed herein will simultaneously evaluate entinostat as a promising new agent in development for UC and fulfill my short-germ career goal of strengthening my scientific training in immunogenomic research methods. After completion of this proposal, I will be well positioned for research independence to achieve my long-term career goal to become a leader in genitourinary oncology with a focus on mechanism-based translational studies of novel combinations using epigenetic and immunomodulatory agents in combination with immunotherapy.