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

通过游离 DNA 中的基因沉默景观监测免疫治疗反应

基本信息

批准号：
10760450
负责人：
Michael T Barrett
金额：
$ 39.8万
依托单位：
BINARY GENOMICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10760450
关键词：
Address Benchmarking Biological Assay Biological Markers Biological Specimen Banks Blood Blood Tests Budgets Cancer Patient Characteristics Circulation Clinical Clinical Sensitivity Clinical Trials Complex DNA Probes Data Detection Development Epigenetic Process Gene Silencing Genome Genomic Segment Genomics Goals Hypermethylation Immune Immune checkpoint inhibitor Immunotherapeutic agent Immunotherapy Kinetics Malignant Neoplasms Malignant neoplasm of lung Measurement Measures Methods Methylation Monitor Mutation Non-Small-Cell Lung Carcinoma Outcome Paper Patients Pattern Performance Phase Plasma Prediction of Response to Therapy Publishing Reproducibility Scanning Screening for cancer Sensitivity and Specificity Signal Transduction Small Business Innovation Research Grant Somatic Mutation Specific qualifier value Specificity Surveys Technology Therapeutic Therapeutic Equivalency Treatment Efficacy Tumor Tissue Universities Validation Work cancer genome cancer immunotherapy cancer type cell free DNA checkpoint therapy chemotherapy clinical practice clinical predictors commercialization density disorder control effective therapy exome sequencing immune cell infiltrate improved ineffective therapies liquid biopsy mutant patient subsets promoter radiological imaging responders and non-responders response serial imaging side effect survival outcome tumor tumor DNA validation studies virtual

项目摘要

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.

抽象的：免疫疗法在非小细胞肺患者的子集中产生显着的长期反应癌症，但不幸的是，大多数患者对这种治疗没有反应。当前的生物标志物可以预测哪个患者将受益的准确性有限，而继续或暂停治疗的决定主要由监测肿瘤大小的放射学变化。但是，异常的免疫相关反应模式此类作为伪产生，混合反应和延迟的响应可能会使扫描难以解释。循环肿瘤DNA（CTDNA）已成为一种高度有希望的生物标志物，用于监测免疫疗法的功效。几项涉及各种免疫疗法和多种癌症的研究表明治疗期间ctDNA水平的早期降低是预测肿瘤反应和改善的生存率结果。但是，通过探测常见的体细胞突变测量ctDNA的现有技术将肿瘤缺乏这些突变的失败患者。通过创建自定义来解决此限制基于患者特异性肿瘤突变特征的测定；但是这种方法很复杂，昂贵且缓慢。我们基于对表观遗传特征的检测而开发了CTDNA测定技术几乎所有癌细胞基因组。初步数据表明我们的方法具有广泛的患者覆盖范围，并且可以将其应用于多种类型的癌症，而无需肿瘤分析和测定定制。作为证明从概念上讲，我们旨在建立我们的测定技术来监测肺癌免疫疗法的实用性回复。在此阶段I SBIR应用中，我们将评估分析和基线临床性能测定技术的特征，并在II期进行更大的后续临床实用性研究计划。这分析验证和基线临床性能指标将针对现有商业的基准测试基于突变的CTDNA分析，以证明我们技术的进一步发展和商业化是合理的。