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

摘要： 免疫疗法在非小细胞肺患者亚群中产生显著的长期反应 癌症，但不幸的是，大多数患者对这种治疗没有反应。目前预测哪些生物标记物 患者将受益的准确性有限，决定继续或暂停治疗主要受以下因素的指导 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 假性进展、混合反应和延迟反应会使扫描难以解释。流通中 肿瘤DNA(CtDNA)已成为监测免疫治疗疗效的一种极具前景的生物标志物。 几项涉及各种免疫治疗药物和多种癌症的研究表明， 治疗期间早期ctDNA水平降低可预测肿瘤反应和改善生存期 结果。然而，现有的通过探测常见体细胞突变来测量ctDNA的技术将 那些肿瘤缺乏这些突变的患者失败了。通过创建自定义的 根据患者特定的肿瘤突变图谱进行分析；但这种方法复杂、昂贵且速度慢。 我们开发了一种基于对表观遗传特征的检测的ctDNA检测技术，这些特征在 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面和 可以应用于多种类型的癌症，而不需要肿瘤特征分析和分析定制。作为证据 的概念，我们的目标是建立我们的检测技术在监测肺癌免疫治疗方面的效用。 回应。在这个第一阶段的SBIR应用中，我们将评估分析和基线临床表现 分析技术的特点，并计划在第二阶段进行更大规模的临床实用研究。 分析验证和基线临床性能指标将以现有的商业 基于突变的ctDNA检测证明我们的技术进一步开发和商业化是合理的。

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.