Monitoring Immunotherapy Response via Gene Silencing Landscapes in Cell-Free DNA

摘要： 免疫治疗在非小细胞肺癌患者亚群中产生显著的长期应答 癌症，但不幸的是，大多数患者对这种治疗没有反应。目前的生物标志物来预测 患者将受益的准确性有限，继续或暂停治疗的决定主要取决于 监测肿瘤大小的放射学变化。然而，不寻常的免疫相关反应模式，如 因为假进展、混合反应和延迟反应可能会使扫描难以解释。循环 肿瘤DNA（ctDNA）已经成为用于监测免疫治疗功效的非常有前途的生物标志物。 涉及各种免疫治疗剂和多种类型癌症的几项研究表明， 治疗期间ctDNA水平的早期降低可预测肿瘤反应和改善的存活率 结果。然而，通过探测常见的体细胞突变来测量ctDNA的现有技术， 那些肿瘤缺乏这些突变的患者会失败。通过创建自定义的 基于患者特异性肿瘤突变谱的分析;但这种方法复杂、昂贵且缓慢。 我们已经开发了一种ctDNA测定技术，该技术基于对表观遗传特征的检测，这些表观遗传特征在 几乎所有的癌细胞基因组。初步数据表明，我们的方法具有广泛的患者覆盖范围， 可以应用于多种类型的癌症，而不需要肿瘤分析和测定定制。作为证据 在概念上，我们的目标是建立我们的检测技术用于监测肺癌免疫治疗的效用 反应在本阶段I SBIR应用中，我们将评估分析和基线临床性能 分析技术的特征，并计划在II期进行更大规模的后续临床实用性研究。的 分析确认和基线临床性能指标将根据现有商业 基于突变的ctDNA分析，以证明我们的技术的进一步开发和商业化。

ABSTRACT: Immunotherapies produce remarkable, long-term responses in subsets of patients with non-small cell lung cancer, but unfortunately, most patients do not respond to such treatment. Current biomarkers to predict which patients will benefit have limited accuracy, and decisions to continue or suspend treatment are mainly guided by monitoring of radiographic changes in tumor size. However, unusual immune-related response patterns such as pseudo-progression, mixed response, and delayed response can make scans difficult to interpret. Circulating tumor DNA (ctDNA) has emerged as a highly promising biomarker for monitoring immunotherapy efficacy. Several studies involving various immunotherapy agents and multiple types of cancer have demonstrated that early reduction in ctDNA levels during treatment are predictive of tumor response and improved survival outcomes. However, existing technologies that measure ctDNA by probing for common somatic mutations will fail patients whose tumors lack these mutations. This limitation is being addressed by creating customized assays based on patient-specific tumor mutation profiles; but this approach is complex, expensive, and slow. We have developed a ctDNA assay technology based on detection of epigenetic features that are found in virtually all cancer cell genomes. Preliminary data indicate that our approach has broad patient coverage and can be applied to multiple types of cancer without requiring tumor profiling and assay customization. As proof of concept, we aim to establish the utility of our assay technology for monitoring of lung cancer immunotherapy response. In this Phase I SBIR application, we will evaluate the analytical and baseline clinical performance characteristics of the assay technology, with a plan for a larger follow-on clinical utility study in Phase II. The analytical validation and baseline clinical performance metrics will be benchmarked against existing commercial mutation-based ctDNA assays to justify further development and commercialization of our technology.