Automated plasma EV-PDL1 analysis for cancer immunotherapy

摘要 挑战有超过4000项临床试验测试抗PD 1/PD-L1免疫检查点抑制剂（ICI）， 单独或与其它疗法联合使用。虽然许多患者受益，但大量患者并没有受益， 相当大的代价。最有效和FDA批准的指导患者选择的生物标志物是通过 组织活检的免疫组织化学（IHC）染色和PD-L1评分（例如肿瘤比例评分， TPS）。不幸的是，TPS是一种不完美的生物标志物：i）它需要手术或图像引导的组织活检， 有时难以执行; ii）组织采集和染色方案的部位和时间可能影响 TPS的准确性; iii）IHC需要几天的时间来处理，延迟治疗; iv）许多TPS阳性患者不需要 对ICI治疗有反应;和v）TPS可以在化疗、靶向和ICI治疗期间改变。 第一阶段的目标。Accure Health建议探索一种替代方法：循环PD-L1生物标志物检测 基于细胞外囊泡（EV）的技术集成磁电传感（TiMES）。 在有希望的临床数据的支持下，我们假设循环EV分析整合PD-L1表达 可以作为一个更全面的标志物。我们提出两个具体目标。目的 1.开发自动化TiMES检测试剂盒，以分析泛EV-PDL 1和细胞类型特异性EV-PDL 1。目标二。 建立TiMES EV-PDL 1评分并与TPS相关。我们设想自动化的TiMES EV-PDL 1测定 并且综合评分可用于测试抗PD 1/PD-L1单一或组合疗法的临床试验。它 可以为评估治疗反应提供更快、更可靠的解决方案， 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.