Epigenetic Therapy for Thoracic Malignancies

我们发表的关于实验室实验和我们相关临床方案的研究已经清楚地证明，地西他滨和罗米地辛单独或联合可以调节胸部恶性肿瘤的基因表达，并诱导针对这些肿瘤的免疫应答。我们的目标一直是夫妇表观遗传引发方案过继免疫治疗胸部恶性肿瘤。目前，不良的生物分布和全身毒性阻止了重新编程胸部恶性肿瘤所需的表观遗传剂的最佳长期施用。为了克服这些局限性，我们与克利夫兰诊所合作，配制了DAC和四氢尿苷（一种有效的、无毒的胞苷脱氨酶抑制剂）口服给药。口服DAC/THU和pembrolizumab治疗不可手术的NSCLC、食管癌或恶性胸膜间皮瘤患者的I/II期研究于2017年底启动，但由于药物稳定性问题于今年关闭。这是不幸的，因为几乎所有患者都表现出系统性表观遗传重编程的证据，并且在几名患者中观察到令人印象深刻的、接近完全和持久的反应。为了进一步优化肺恶性肿瘤的免疫检查点阻断的表观遗传引发，同时降低潜在的全身毒性，我们最近启动了临床前研究，以检查通过雾化技术给予的氮杂胞苷（AZA）的药代动力学和潜在疗效。我们已经开发了一种独特的免疫活性小鼠肺转移模型，使用从高致死性同系肺癌和肉瘤细胞系中分离的癌症干细胞，用于DNA去甲基化剂、LSD 1抑制剂和细胞因子（如IL-12）的系统、合理评价。一项I/II期临床方案试验正在接受FDA审查，该试验旨在检查通过吸入技术给予的AZA与durvalumab联合作为可手术NSCLC患者诱导治疗的毒性和潜在疗效。本试验旨在建立评价一系列雾化表观遗传药物单独或联合过继免疫治疗治疗局部晚期肺恶性肿瘤的范例。目前世界上其他地方还没有这样的临床研究。我们的临床前和转化研究成果在2023年AACR年会上作为正式的全体会议演讲发表。癌症生殖系抗原包括一组共享的肿瘤抗原，其仅在由体细胞或免疫豁免位点（例如睾丸、卵巢或胎盘）产生的癌症中表达。因此，癌症生殖系抗原已成为癌症免疫治疗的高度有吸引力的靶标。尽管癌胚系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、抗原加工/呈递缺陷以及局部和全身免疫抑制，对这些蛋白质的免疫应答在胸部肿瘤患者中并不常见。我们发表的细胞系和患者活检的研究表明，胸部恶性肿瘤表现出不同的CTA表达模式和对上调这些蛋白质的表观遗传方案的异质性反应。克服这些局限性的策略是使患者对一组CTA免疫，所述CTA可能通过染色质重塑剂的全身施用而上调。在评估使用癌细胞裂解物疫苗作为原发性胸部恶性肿瘤或转移到肺部的肿瘤患者的辅助治疗的2.5期首次人体试验的积极结果之后，我们已经编写了两个新的方案，使用这种裂解物疫苗（在我们的实验室开发）作为肺癌或食管癌患者的辅助治疗。肺癌方案将评估裂解物疫苗与IL-15超级激动剂N-803组合作为术后辅助治疗，而食管癌方案将评估裂解物与HDAC抑制剂恩替诺特和免疫检查点抑制剂纳武单抗在化疗-放射+/-手术后的组合。这两项方案均已获得FDA和NIH IRB的批准，预计将于2024财年第1季度初开放供患者招募。

Our published studies pertaining to laboratory experiments and our related clinical protocols 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. To overcome these limitations, we formulated DAC and tetrahydrouridine (a potent, non-toxic inhibitor of cytidine deaminase) 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 was initialed in late 2017, but was closed this year due to drug stability issues. This was unfortunate as virtually all patients had exhibited evidence of systemic epigenetic reprogramming, and impressive, near complete and durable responses were observed in several patients. To further optimize epigenetic priming of pulmonary malignancies for immune checkpoint blockade while decreasing potential systemic toxicities, we recently initiated preclinical studies to examine the pharmacokinetics and potential efficacy of azacytidine (AZA) administered by aerosolization techniques. We have developed a unique immunocompetent murine pulmonary metastasis model using cancer stem cells isolated from highly lethal syngeneic lung cancer and sarcoma cell lines for systematic, rational evaluation of DNA demethylating agents, LSD1 inhibitors, and cytokines such as IL-12. A phase I/II clinical protocol trial to examine the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with durvalumab as induction therapy for patients with operable NSCLC is presently undergoing FDA review. 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. No such clinical efforts are currently underway elsewhere in the world. Results of our preclinical and translational research efforts were presented as a formal plenary session talk at the Annual Meeting of the AACR in 2023. Cancer-germline antigens comprise a group of shared tumor antigens that are only expressed in cancers arising from somatic cells or immune-privileged sites such as testes, ovary, or placenta. As such, cancer-germline antigens have emerged as highly attractive targets for cancer immunotherapy. Although cancer-germline 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 these proteins. A strategy to overcome these limitations is to immunize patients against a panel of CTAs that potentially can be upregulated by systemic administration of chromatin remodeling agents. Following positive results of a phase 2.5 First-in-Human trial evaluating the use of a cancer cell lysate vaccine as adjuvant therapy in patients with primary thoracic malignancies or tumors metastatic to the lungs, we have written two new protocols using this lysate vaccine (which was developed in our lab) as adjuvant therapy for patients with lung or esophageal cancers. The lung cancer protocol will evaluate the lysate vaccine in combination with the IL-15 super-agonist N-803 as post-operative adjuvant therapy, while the esophageal cancer protocol will evaluate the lysate in combination with the HDAC inhibitor, entinostat, and the immune checkpoint inhibitor, nivolumab following chemo-radiation +/- surgery. Both protocols have been approved by the FDA and NIH IRB and are expected to be open for patient accrual in early Q1 of FY24.