Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France; Inserm U932 Research Unit - Immunite et cancer, Paris, France.
Unicancer, Paris, France.
ESMO Open. 2021 Jun;6(3):100106. doi: 10.1016/j.esmoop.2021.100106. Epub 2021 Apr 14.
Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patients experience a durable response with immunotherapy. Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. We herein review the preclinical and the clinical rationale for combining immunotherapy with an epidrug, and detail the design of PEVOsq, a basket clinical trial combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, in patients with SCCs of different locations. Sequential blood and tumor sampling will be collected in order to identify predictive and pharmacodynamics biomarkers of efficacy of the combination. We also present how clinical and biological data will be managed with the aim to enable the development of a prospective integrative platform to allow secure and controlled access to the project data as well as further exploitations.
鳞状细胞癌（SCCs）是人类最常见的实体肿瘤之一。与人类乳头瘤病毒相关或不相关的 SCCs 具有共同的分子特征。免疫疗法，特别是免疫检查点抑制剂，已被证明可改善多种癌症类型的总生存率，包括 SCCs。然而，只有少数患者对免疫疗法有持久的反应。表观遗传调控在逃避肿瘤免疫监视方面起着重要作用，并赋予对免疫检查点抑制剂的耐药性。临床前证据表明，调节表观基因组可能会提高免疫疗法的疗效。本文综述了联合免疫疗法和表皮生长因子治疗 SCC 的临床前和临床理论基础，并详细介绍了在不同部位 SCC 患者中联合使用 pembrolizumab 和 vorinostat（一种组蛋白去乙酰化酶抑制剂）的 PEVOsq 篮子临床试验的设计。为了确定联合治疗的疗效预测和药效动力学生物标志物，将连续采集血液和肿瘤样本。我们还介绍了如何管理临床和生物学数据，旨在建立一个前瞻性的综合平台，允许安全和受控地访问项目数据以及进一步的开发利用。
