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

（PQ

基本信息

批准号：
10462570
负责人：
Michael Benjamin Atkins
金额：
$ 52.27万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-17 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462570
关键词：
Adverse effects Adverse event Affect Aftercare Antibodies Antineoplastic Agents Autoimmune 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 Immunosuppressive Agents 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 ipilimumab kidney cell melanoma mutant neoplastic cell novel strategies partial response pembrolizumab predictive marker real time monitoring responders and non-responders response tissue injury treatment response tumor tumor DNA

项目摘要

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避免疫系统的识别，包括激活抑制性免疫检查点途径。这些免疫检查点的治疗性抑制已被证明对多种癌症具有显着疗效，是一种很有前景的癌症联合治疗新方法与其他抗癌疗法一起使用。针对 PD-1 通路的抗体尤其彻底改变了治疗晚期黑色素瘤患者并在 > 40% 的患者中产生肿瘤反应。抗 PD-1 与抗 CTLA-4 的组合在大约 60% 的患者中产生肿瘤反应。然而，免疫检查点阻断经常导致炎症和免疫相关的不良事件（irAE）由于正常组织的自我耐受保护破坏而导致。这些 irAE 可能很严重，导致停止免疫检查点抑制剂治疗并可能需要免疫抑制治疗。任何组织可能受到损伤，最常发生在皮肤、胃肠道、内分泌腺、肝脏和肺。抗PD-1和CTLA-4联合治疗的毒性明显高于单药治疗需要更频繁、更积极的管理。尽管使用类固醇和其他免疫治疗调节剂可以逆转这些 irAE，免疫抑制可能会损害其抗肿瘤活性检查站封锁。因此，对经过临床验证的非侵入性方法的需求尚未得到满足。用于实时监测和预测治疗中或治疗后 irAE 以及治疗效果的生物标志物允许对暴露于免疫检查点抑制剂的癌症患者进行适当的管理。在此我们建议使用无细胞 DNA 分析监测抗肿瘤功效（目标 1）以及器官特异性 irAE（目标 2）在治疗前以及治疗期间和治疗后定期采集的系列血样。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，作为抗- 肿瘤治疗功效。在目标 2 下，我们建议通过监测来评估自身免疫器官损伤循环游离细胞、组织特异性甲基化 DNA (cmeDNA) 丰度的变化。我们目前领导一项涉及抗 CTLA-4 和抗 PD-1 组合的国家合作小组试验 (EA6134) BRAF突变黑色素瘤患者的治疗。从本试验中连续收集患者的血液样本将在他们对治疗有反应、出现 irAE、需要免疫抑制治疗或停止治疗。我们将 ctDNA 和 cmeDNA 生物标志物读数与临床进行比较观察试验中的疗效和不良事件以确定其效用。