Development of a Novel, Plasma-Based Microsatellite Instability Diagnostic for Guiding Immunotherapy

摘要 免疫检查点抑制剂最近作为癌症治疗的一场革命而出现，提供了 全球众多癌症患者的持久反应和改善生存的潜力 多种癌症类型。然而，接受检查站治疗的患者中只有10%-20% 抑制剂在大多数癌症类型中都有反应，需要进行生物标记物分析，以 可靠、准确地识别可能有反应的患者。最近令人信服的证据 支持微卫星不稳定性(MSI)作为一种预测标记物的临床应用 免疫治疗反应，达到的总体存活率为11%，而微卫星的存活率为11% 稳定型(MSS)肿瘤。MSI高的肿瘤在组织病理学上与其MSS不同 相应的，显示明显的肿瘤浸润性淋巴细胞的流入并高表达 免疫检查点抑制剂的水平，包括PD-1。这种独特的免疫微环境 支持MSI高的肿瘤对免疫疗法更敏感的假设，并 已被建议作为患者群体分层的生物标志物。支持这一概念的是 FDA刚刚批准了Keytruda(PD-1抑制剂)的补充应用优先审查 在先前治疗的MSI-H肿瘤中，基于多个多个开放标签I/II期试验 肿瘤类型。目前的MSI筛查是在肿瘤活检组织上使用可变的、非 标准化的基于聚合酶链式反应和IHC实验室开发的测试(LDT)，创造了对 标准化的、准确的、非侵入性的检测，可分散用于通知临床 对接受免疫疗法治疗的患者进行管理。无细胞肿瘤特异性基因 在80%的癌症患者的血浆中都可以检测到循环肿瘤dna(Ctdna)的变化。≥ 患有转移性疾病的患者。血浆中肿瘤特异性改变的可靠检测 帮助患者分层进行靶向治疗并克服对肿瘤组织的需求 通过传统的分子方法。这项提议的目标是开发一个独立的 用于确定癌症患者血浆中MSI状态的分子诊断方法(称为 以指导多种适应症的免疫治疗。

Abstract Immune checkpoint inhibitors have recently emerged as a revolution in cancer care, providing the potential for durable response and improved survival for numerous cancer patients across multiple cancer types. However, only 10-20% of patients who are treated with checkpoint inhibitors have responded in most cancer types, necessitating biomarker assays that can reliably and accurately identify those patients likely to respond. Recent, compelling evidence supports the clinical utility of microsatellite instability (MSI) as a predictive marker of immunotherapy response, reaching overall survival rates of >64% versus 11% in microsatellite stable (MSS) tumors. MSI-high tumors are histopathologically distinct from their MSS counterparts, displaying a marked influx of tumor-infiltrating lymphocytes and express high levels of immune checkpoint inhibitors, including PD-1. This unique immune microenvironment supports the hypothesis that MSI-high tumors more susceptible to immunotherapies, and has been proposed as a biomarker for stratifying patient populations. Supporting this notion, The FDA just granted priority review for a supplemental application of KeytrudaÒ (a PD-1 inhibitor) in previously treated MSI-H tumors on the basis of 5 open-label Phase I/II trials across multiple tumor types. Current MSI screening is conducted on tumor biopsies using variable, non- standardized PCR-based and IHC laboratory developed tests (LDTs), creating the need for a standardized, accurate, non-invasive assay that may be decentralized to inform the clinical management of patients for treatment with immunotherapies. Cell-free tumor-specific genetic alterations, or circulating tumor DNA (ctDNA), are detectable in the plasma of ≥80% of cancer patients with metastatic disease. Reliable detection of tumor specific alterations in plasma can aid in the stratification of patients for targeted therapies and overcome the need for tumor tissue by traditional molecular approaches. The goal of this proposal is to develop a stand-alone molecular diagnostic assay to determine MSI status from plasma in cancer patients (known as CancerPROÔ MSI) to guide immunotherapy for multiple indications.