Epigenetic Therapy for Thoracic Malignancies

胸部恶性肿瘤的表观遗传治疗

• 批准号: 10487191
• 负责人: DAVID SCHRUMP
• 金额: $ 68.15万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487191
• 关键词: Aberrant DNA Methylation; Address; Adjuvant; Adoptive Immunotherapy; Antigen Presentation Pathway; Antigens; Apoptosis; Biodistribution; Biological Availability; Biopsy; CD14 gene; CTAG1 gene; Cancer Patient; Carbohydrates; Cell Line; Cells; Chest; Chromatin Structure; Chronic; Clinic; Clinical; Collaborations; Cyclophosphamide; Cytidine Deaminase; Cytidine Deaminase Inhibitor; DNA; Data; Decitabine; Disease; Dose-Limiting; Epigenetic Process; Evaluation; Event; Exhibits; Gene Expression; Goals; Growth; H1299; Histone Deacetylase Inhibitor; Histone-Lysine N-Methyltransferase; Histones; Hour; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunize; Immunosuppression; Immunotherapy; In Vitro; Inhalation; Laboratories; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Malignant neoplasm of thorax; Mediating; Metastatic Neoplasm to the Lung; Metastatic to; Modification; Molecular; Neoplasms; Non-Small-Cell Lung Carcinoma; Normal Cell; Oral; Oral Administration; Patients; Pattern; Peripheral; Phase; Phase I/II Trial; Pleural Mesothelioma; Positioning Attribute; Proteins; Publishing; Randomized; Regimen; Regulatory T-Lymphocyte; Second Primary Neoplasms; Series; Serology; Solid Neoplasm; Techniques; Tetrahydrouridine; Thoracic Neoplasms; Thoracic Oncology; Toxic effect; Transforming Growth Factor beta; Treatment-related toxicity; Tumor Cell Derivative Vaccine; Tumor Suppressor Genes; Tumor-Associated Carbohydrate Antigens; Vaccination; Vaccine Therapy; Vaccines; aerosolized; cancer cell; cancer testis antigen; celecoxib; chromatin remodeling; conventional therapy; epigenetic therapy; first-in-human; follow-up; immune checkpoint blockade; immunogenicity; in vivo Model; inhibitor/antagonist; intradermal injection; lung cancer cell; monocyte; pembrolizumab; prevent; primary endpoint; programmed cell death ligand 1; programmed cell death protein 1; response; systemic inflammatory response; systemic toxicity; uptake; virtual

Our published studies pertaining to more than 100 patients with lung and esophageal cancers and pleural mesotheliomas, or pulmonary metastases from non-thoracic malignancies have clearly demonstrated that Decitabine and romidepsin alone or in combination can modulate gene expression in thoracic malignancies and induce immune responses against these neoplasms. Our goal has always been to couple epigenetic priming regimens with adoptive immunotherapy for thoracic malignancies. Presently, poor biodistribution and systemic toxicities prevent optimal, chronic administration of epigenetic agents necessary to reprogram thoracic malignancies. For example, DNA demethylating agents have very limited bioavailability when administered as oral agents and extremely short half-lives (5min) resulting in poor uptake into solid tumors due to cytidine deaminase (CDA) which is present at high levels throughout the body. To overcome these limitations, we formulated DAC and tetrahydrouridine (a potent, non-toxic inhibitor of CDA) for oral administration in collaboration with the Cleveland Clinic. A phase I/II study of oral DAC/THU and pembrolizumab for patients with inoperable NSCLC, esophageal cancers, or malignant pleural mesotheliomas is currently underway. Virtually all patients have exhibited evidence of systemic epigenetic reprogramming, and impressive, near complete and durable (1 yr) responses have been observed in several patients. To further optimize epigenetic priming of pulmonary malignancies for immune checkpoint blockade while decreasing potential systemic toxicities, we have recently initiated a phase I/II trial to examine the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with M7824, a dual immune checkpoint inhibitor-TGF-beta trap in patients with locally advanced pulmonary metastases. No similar efforts are currently underway elsewhere in the world; this trial is intended to establish the paradigm for evaluation of a series of aerosolized epigenetic agents alone or in combination with adoptive immunotherapy for the treatment of locally advanced pulmonary malignancies. Whereas cancer-testis antigens are expressed in a variety of human malignancies, immune responses to these proteins are uncommon in thoracic oncology patients due to low level, heterogeneous antigen expression, deficient antigen processing/presentation, and local as well as systemic immunosuppression. Our published studies from cell lines and patient biopsies have demonstrated that thoracic malignancies exhibit diverse patterns of CTA expression and heterogeneous responses to epigenetic regimens that up-regulate CTAs. A strategy to overcome these limitations is to immunize patients against a panel of CTAs that potentially can be up-regulated by systemic administration of chromatin remodeling agents. To address this issue, we conducted a phase 2.5 First-in-Human trial to ascertain if a tumor lysate vaccine can induce broad immunity to CTA and determine if metronomic oral cyclophosphamide and celecoxib (cy/cel) enhances vaccine-induced immune responses. Briefly, 21 patients with primary thoracic malignancies or extra-thoracic neoplasms metastatic to the chest rendered NED by conventional therapies were randomized to receive H1299 lung cancer cell lysates with Iscomatrix adjuvant via deep intradermal injection q month x 6 +/- daily cy/cel. The primary endpoint was serologic response to purified CTA 1 month after the 6th vaccination. Exploratory objectives included analysis of serologic reactivity to carbohydrate antigens and assessment of peripheral immune subsets before and after vaccine therapy. All patients exhibited local and systemic inflammatory responses lasting 72-96 hours following vaccinations. There were no dose limiting treatment related toxicities. 14 patients (67%) completed all six vaccinations. With a median follow-up of 64.6 months (range 58.8-68.4), 12 patients are alive and NED; 2 patients are alive with controlled, second malignancies. 11 of 14 surviving patients (79%) received six vaccinations compared to 3 of 7 patients (42%) who succumbed to their malignancies. Seven of 10 patients randomized to vaccine with cy/cel received all six vaccinations; 3 of these 7 patients (43%) died of disease. Seven of 11 patients randomized to vaccine alone completed six vaccinations; none (0%) of these 7 patients have died. 8 patients (57%) exhibited serologic responses to NY-ESO-1. Additional reactivities were observed against GAGE7, XAGE, and MAGE-C2. Reactivities against tumor-associated carbohydrate antigens were uncommon. Vaccine therapy decreased percent Tregs (p=0.067*), PD-1 expression on Tregs (p=0.023*), and PD-L1 expression on CD14+ monocytes (p=0.0089*), classical monocytes (p=0.0159*), and intermediate monocytes (p= 0.0031*). Cy/cel did not impact immune responses or vaccine-induced alterations in peripheral immune subsets. Laboratory metrics of response did not appear to correlate with patient survival. Results of this positive trial have recently been published online and support further vaccination efforts in patients with thoracic malignancies.

我们发表的研究与100多名肺和食管癌和胸膜间皮瘤患者有关，或来自非胸腔恶性肿瘤的肺转移酶，清楚地表明，单独或单独的romidebine和romidepsin和romidepsin或合并中可以调节基因表达，以抗免疫反应和抗免疫反应。我们的目标一直是将表观遗传启动方案与胸腔恶性肿瘤的收养免疫疗法。目前，生物分布不良和全身毒性可预防最佳，长期给予重编程胸腔恶性肿瘤所必需的表观遗传因子。例如，当作为口服剂和极短的半衰期（5分钟）给药时，DNA去甲基化剂的生物利用度非常有限，导致由于胞苷脱氨酶（CDA）的摄取量较差，该蛋白酶脱氨酶（CDA）在整个人体中的水平很高。为了克服这些局限性，我们与克利夫兰诊所合作制定了DAC和四氢胺（一种有效的，无毒的CDA抑制剂）。目前正在进行一项针对无法手术NSCLC，食管癌或恶性胸膜间皮瘤患者的口服DAC/THU和Pembrolizumab的I/II期研究。实际上，所有患者均表现出全身表观遗传重编程的证据，并且在几名患者中都观察到了令人印象深刻的几乎完整且耐用（1年）的反应。 To further optimize epigenetic priming of pulmonary malignancies for immune checkpoint blockade while decreasing potential systemic toxicities, we have recently initiated a phase I/II trial to examine the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with M7824, a dual immune checkpoint inhibitor-TGF-beta trap in patients with locally advanced pulmonary metastases.目前在世界其他地方没有类似的努力。该试验旨在建立单独评估一系列雾化表观遗传剂的范例，或与收养免疫疗法结合使用，以治疗局部晚期肺部恶性肿瘤。尽管癌症测试抗原在多种人类恶性肿瘤中表达，但由于低水平，异质性抗原表达，不足的抗原加工/表现，以及局部以及全身免疫抑制，对这些蛋白质的免疫反应在胸部肿瘤学患者中并不常见。我们从细胞系和患者活检中发表的研究表明，胸腔恶性肿瘤表现出对表观遗传方案的CTA表达和异质反应的不同模式，这些模式上调了CTA。克服这些局限性的一种策略是使患者免疫一组CTA，该小组可能会通过系统性地施用染色质重塑剂来上调。为了解决这个问题，我们进行了2.5阶段的人类试验，以确定肿瘤裂解物疫苗是否可以诱导广泛的CTA免疫力，并确定水平口腔环磷酰胺和CELECOXIB（CY/CEL/CEL）是否增强了疫苗诱导的免疫反应。简而言之，有21例原发性胸腔恶性肿瘤或胸外肿瘤转移到胸部通过常规疗法渲染的胸部转移，随机分配了通过深层内部注入Q Q 6 +/-每日cy/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cel/cy299 H1299通过深层辅助辅助通过深度内部辅助辅助物质辅助Q月6日+/-每日cy/cel/cel/cel/cel/cel/cel/cel/cel。主要终点是在第六次疫苗接种后1个月对纯化CTA的血清学反应。探索性目标包括分析对碳水化合物抗原的血清学反应性以及疫苗治疗前后周围免疫亚群的评估。所有患者均表现出疫苗接种后持续72-96小时的局部和全身性炎症反应。没有剂量限制治疗相关的毒性。 14例患者（67％）完成了所有六项疫苗接种。中位随访时间为64.6个月（范围为58.8-68.4），有12例还活着和NED。 2例患者有控制，第二次恶性肿瘤。在14例幸存的患者中，有11例（79％）接受了6次疫苗接种，而屈服于恶性肿瘤的7例患者中有3例（42％）接受了疫苗接种。 10例随机疫苗的患者中有7名接受CY/CEL的疫苗接种；这7例患者中有3例（43％）死于疾病。单独疫苗的11例患者中有7例完成了6次疫苗接种；这7名患者中没有（0％）死亡。 8例患者（57％）对NY-ESO-1表现出血清学反应。针对GAGE7，XAGE和MAGE-C2观察到了其他反应率。针对肿瘤相关的碳水化合物抗原的反应率并不常见。疫苗疗法降低了Treg的百分比（P = 0.067*），Tregs上的PD-1表达（P = 0.023*）和CD14+单核细胞上的PD-L1表达（P = 0.0089*），经典的单核细胞（P = 0.0159*）（p = 0.0159*），以及中间的单核细胞（P = 0.0031）。 CY/CEL不会影响外周免疫亚群的免疫反应或疫苗诱导的改变。反应的实验室指标似乎与患者存活无关。该积极试验的结果最近在网上发表，并支持胸腔恶性肿瘤患者的进一步疫苗接种工作。