(PQ #8) Biomarkers of efficacy and adverse events due to treatment with immune checkpoint inhibitors

（PQ

• 批准号: 10001451
• 负责人: Michael Benjamin Atkins
• 金额: $ 53.33万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001451
• 关键词: Adverse effects; Adverse event; Affect; Aftercare; Antibodies; Antineoplastic Agents; Autoimmune Process; BRAF gene; Biological Markers; Blood Circulation; Blood specimen; CTLA4 gene; Cancer Patient; Cells; Clinical; Clinical Trials; Combined Modality Therapy; DNA; DNA Repair Disorder; DNA analysis; Data; Development; Disease Progression; Endocrine Glands; Exposure to; FDA approved; Gastrointestinal tract structure; Hodgkin Disease; Immune; Immune checkpoint inhibitor; Immune system; Immunomodulators; Immunosuppression; In complete remission; Inflammatory; Institution; Lead; Liver; Lung; Malignant Neoplasms; Molecular; Monitor; Mutation; Nivolumab; Normal tissue morphology; Organ; PD-1 blockade; PD-1 pathway; Pathway interactions; Patients; Pattern; Regimen; Self Tolerance; Skin; Steroids; Survival Rate; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Treatment Efficacy; Tumor Burden; anti-CTLA4; anti-PD-1; anti-PD1 therapy; anti-cancer; body system; cancer therapy; cell free DNA; checkpoint inhibition; checkpoint therapy; immune checkpoint; immune checkpoint blockade; immune self tolerance; immune-related adverse events; immunomodulatory therapies; injured; kidney cell; melanoma; mutant; neoplastic cell; novel strategies; partial response; predictive marker; real time monitoring; responders and non-responders; response; tissue injury; treatment response; tumor; tumor DNA

Tumor cells escape recognition by the immune system by multiple mechanisms that include activation of inhibitory immune checkpoint pathways. Therapeutic inhibition of these immune checkpoints has demonstrated striking efficacy in a number of cancers and is a promising new approach to cancer treatment in combination with other anti-cancer regimens. Antibodies against the PD-1 pathway have in particular revolutionized the treatment of patients with advanced melanoma and produce tumor responses in >40% of patients. Combinations of anti-PD-1 with anti-CTLA-4 produces tumor responses in approximately 60% of patients. However, immune checkpoint blockade frequently causes inflammatory and immune-related Adverse Events (irAEs) due to the disruption of self-tolerance protection of normal tissues. These irAEs can be severe, lead to discontinuation of immune checkpoint inhibitor therapy and can require immunosuppressive treatment. Any tissue can be injured with the most frequent occurrences in the skin, gastro-intestinal tract, endocrine glands, liver, and lungs. Combined anti-PD-1 and CTLA-4 has significantly higher toxicity than monotherapy and requires more frequent and aggressive management. Although treatment with steroids and other immune modulators can reverse these irAEs, immunosuppression may compromise the anti-tumor activity of the checkpoint blockade. Thus, there is an unmet need for availability of clinically validated, non-invasive biomarkers for real time monitoring and prediction of on- or post-treatment irAEs and therapeutic efficacy to allow for proper management of cancer patients exposed to immune checkpoint inhibitors. Here we propose to monitor anti-tumor efficacy (Aim 1) as well as organ-specific irAEs (Aim 2) using cell-free DNA analysis from serial blood samples obtained before and at regular intervals during and after treatment. Under Aim 1 we propose to monitor changes in circulating cell-free mutant tumor DNA (ctDNA) patterns as a readout of anti- tumor treatment efficacy. Under Aim 2 we propose to assess autoimmune organ damage by monitoring changes in the abundance of circulating cell-free, tissue-specific methylated DNA (cmeDNA). We are currently leading a national cooperative group trial (EA6134) that involves combination anti-CTLA-4 and anti-PD-1 treatment of patients with BRAF mutant melanoma. Serially collected blood samples from patients on this trial will be analyzed as they respond to treatment, develop irAEs, require immunosuppressive therapy or discontinuation of treatment. We will compare the ctDNA and cmeDNA biomarker readouts with clinical observations of efficacy and adverse events in the trial to establish their utility.

肿瘤细胞通过多种机制逃脱免疫系统的识别，包括激活 抑制性免疫检查点途径。这些免疫检查点的治疗抑制已证明 许多癌症中的效果引人注目，是一种结合癌症治疗的新方法 与其他抗癌方案。针对PD-1途径的抗体尤其彻底改变了 > 40％的患者治疗晚期黑色素瘤患者并产生肿瘤反应。 抗PD-1与抗CTLA-4的组合在大约60％的患者中会产生肿瘤反应。 但是，免疫检查点封锁经常引起炎症和免疫相关事件 （IRAE）由于对正常组织的自我耐受保护而破坏。这些伊拉斯可能很严重，导致 中止免疫检查点抑制剂治疗，可能需要免疫抑制治疗。任何 在皮肤，胃肠道，内分泌腺体中最常见的情况下，组织可能受伤 肝脏和肺。抗PD-1和CTLA-4组合的毒性明显高于单一疗法和 需要更频繁和积极的管理。尽管类固醇和其他免疫治疗 调节剂可以扭转这些伊拉斯，免疫抑制可能损害 检查点封锁。因此，未满足临床验证的无创侵入性的需求 实时监测和预测现场或治疗后伊拉斯的生物标志物以及治疗功效 允许适当管理暴露于免疫检查点抑制剂的癌症患者。在这里我们建议 使用来自无细胞的DNA分析，监测抗肿瘤功效（AIM 1）和器官特异性IRAE（AI​​M 2） 在治疗期间和之后定期获得的连续血样。在目标1下我们 建议监测循环无细胞突变肿瘤DNA（CTDNA）模式的变化 肿瘤治疗功效。在AIM 2下，我们建议通过监视评估自身免疫器官损伤 无循环细胞，组织特异性甲基化DNA（CMEDNA）的丰度变化。我们目前 领导国家合作小组试验（EA6134），该试验涉及抗CTLA-4和抗PD-1 Braf突变黑色素瘤患者的治疗。该试验中的患者的连续收集的血液样本 将在对治疗，发展伊拉斯，需要免疫抑制治疗或 中断治疗。我们将比较CTDNA和CMEDNA生物标志物读数与临床 在试验中对效力和不良事件的观察以建立其效用。