Automated plasma EV-PDL1 analysis for cancer immunotherapy

摘要 挑战。有4000多项临床试验测试抗PD1/PD-L1免疫检查点抑制物(ICI)， 可以单独使用，也可以与其他疗法联合使用。虽然许多患者受益，但大量患者根本没有受益 这是一笔可观的费用。指导患者选择的最有效和FDA批准的生物标志物是通过 免疫组织化学(IHC)染色和组织活检PD-L1评分(例如，肿瘤比例评分， TPS)。不幸的是，TPS不是一个完美的生物标志物：i)它需要手术或图像引导的组织活检， 有时很难执行；ii)组织采集的位置和时间以及染色方案可能会影响 TPS的准确性；iii)IHC需要几天的时间来处理，延误了治疗；iv)许多TPS阳性的患者不 对ICI治疗有反应；以及v)TPS在化疗、靶向和ICI治疗过程中会发生变化。 第一阶段目标。Accuve Health建议探索另一种方法：循环PD-L1生物标记物检测 基于技术集成的细胞外小泡的磁电传感(TIME)。 在有希望的临床数据支持下，我们假设循环EV分析整合了PD-L1的表达 从原发灶和转移灶可以作为更全面的标记物。我们提出了两个具体目标。目标 1.建立了一种检测PAN EV-PDL1和细胞类型特异性EV-PDL1的自动时间分析方法。目标2. 建立次数EV-PDL1评分并与TPS相关。我们设想EV-PDL1检测的自动化时代 综合评分可用于测试抗PD1/PD-L1单一疗法或联合疗法的临床试验。它 可以为评估治疗反应提供更快、更可靠的解决方案，并有助于加快 监管决策。

ABSTRACT Challenges. There are over 4000 clinical trials testing anti-PD1/PD-L1 immune checkpoint inhibitors (ICI), either alone or in combination with other therapies. While many patients benefit, the vast amount do not, all at a considerable cost. The most validated and FDA-approved biomarker to guide patient selection is through immunohistochemical (IHC) staining and scoring of tissue biopsies for PD-L1 (e.g. Tumor Proportion Score, TPS). Unfortunately, TPS is an imperfect biomarker: i) it requires surgical or image guided tissue biopsy which is sometimes difficult to perform; ii) the site and timing of tissue acquisition and staining protocols can influence the accuracy of TPS; iii) IHC takes days to process, delaying treatment; iv) many TPS-positive patients do not respond to ICI treatment; and v) TPS can change during chemo, targeted and ICI therapies. Phase I goals. Accure Health proposes to explore an alternative approach: circulating PD-L1 biomarker assay based on Technology-integrated magneto-electronic sensing (TiMES) of extracellular vesicles (EVs). Supported by promising clinical data, we hypothesize that circulating EV analysis integrating PD-L1 expression from primary and metastatic lesions can be a more comprehensive marker. We propose two specific aims. Aim 1. Develop an automated TiMES assay to analyze pan EV-PDL1 and cell type-specific EV-PDL1. Aim 2. Establish TiMES EV-PDL1 scores and correlate with TPS. We envision the automated TiMES EV-PDL1 assay and integrated scores can be utilized in clinical trials testing anti-PD1/PD-L1 mono- or combination therapies. It can provide a faster and more reliable solution for evaluating treatment response, and help accelerate regulatory decision-making.