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

摘要 免疫检查点抑制剂最近成为癌症护理的一场革命， 为众多癌症患者提供持久缓解和改善生存率的潜力 多种癌症类型。然而，只有10-20%的患者接受检查点治疗， 抑制剂在大多数癌症类型中有反应，需要生物标志物测定， 可靠和准确地识别那些可能有反应的患者。最近，令人信服的证据 支持微卫星不稳定性（MSI）的临床效用作为一个预测标志物， 免疫治疗反应，达到总生存率>64%，而微卫星组为11%。 稳定（MSS）肿瘤。MSI高的肿瘤在组织病理学上与MSS不同 对应物，显示肿瘤浸润淋巴细胞的显著流入，并表达高水平的 免疫检查点抑制剂水平，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， 被提议作为对患者人群进行分层的生物标志物。支持这一观点， FDA刚刚批准了Keytrudaestine（PD-1抑制剂）补充申请的优先审查 在既往接受过治疗的MSI-H肿瘤中，基于5项开放标签I/II期试验， 肿瘤类型目前的MSI筛查是使用可变的、非特异性的方法对肿瘤活检进行的。 标准化的基于PCR和IHC的实验室开发的测试（LDT），创造了对 标准化的、准确的、非侵入性的测定，其可以分散以告知临床 管理患者进行免疫疗法治疗。无细胞肿瘤特异性遗传 在≥80%的癌症患者血浆中可检测到循环肿瘤DNA（ctDNA）的改变 转移性疾病患者。可靠地检测血浆中肿瘤特异性改变可以 有助于对靶向治疗的患者进行分层， 通过传统的分子方法。该提案的目标是开发一个独立的 分子诊断测定以确定癌症患者血浆的MSI状态（称为 CancerPROGRESSMSI），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.