Epigenetic Therapy for Thoracic Malignancies

胸部恶性肿瘤的表观遗传治疗

基本信息

批准号：
10926579
负责人：
DAVID SCHRUMP
金额：
$ 81.17万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10926579
关键词：
Aberrant DNA Methylation Adjuvant Therapy Adoptive Immunotherapy American Association of Cancer Research Antigen Presentation Pathway Antigens Apoptosis Azacitidine Biodistribution Biopsy Cancer Patient Cell Line Cell Separation Cells Chromatin Structure Chronic Clinic Clinical Clinical Protocols Collaborations Cytidine Deaminase Inhibitor DNA Data Decitabine Drug Kinetics Drug Stability Epigenetic Process Evaluation Event Exhibits FDA approved Gene Expression Goals Growth Histone Deacetylase Inhibitor Histone-Lysine N-Methyltransferase Histones Human Immune Immune checkpoint inhibitor Immune response Immunize Immunocompetent Immunosuppression Immunotherapy In Vitro Inhalation Institutional Review Boards Interleukin-12 Interleukin-15 KDM1A gene 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 Modeling Modification Molecular Mus Neoadjuvant Therapy Neoplasms Nivolumab Non-Small-Cell Lung Carcinoma Normal Cell Nucleosomes Operative Surgical Procedures Oral Oral Administration Ovary Patients Pattern Phase Placenta Positioning Attribute Postoperative Period Proteins Protocols documentation Publishing Regimen Series Site Somatic Cell Techniques Testis Tetrahydrouridine Thoracic Neoplasms Thoracic Oncology Toxic effect Translational Research Tumor Antigens Tumor Suppressor Genes United States National Institutes of Health Vaccines Writing aerosolized cancer cell cancer immunotherapy cancer stem cell cancer/testis antigen chemoradiation chromatin remodeling clinical trial protocol cytokine demethylation epigenetic therapy first-in-human immune checkpoint blockade immunogenicity in vivo Model inhibitor laboratory experiment lung sarcoma meetings pembrolizumab pre-clinical research preclinical study prevent programs response systemic toxicity virtual

项目摘要

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.

我们发表的有关实验室实验和相关临床方案的研究清楚地表明，地西他滨和罗米地辛单独或联合使用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反应。我们的目标始终是将表观遗传启动方案与过继性免疫疗法结合起来治疗胸部恶性肿瘤。目前，不良的生物分布和全身毒性阻碍了重新编程胸部恶性肿瘤所需的表观遗传药物的最佳、长期给药。为了克服这些限制，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）用于口服给药。一项针对无法手术的 NSCLC、食道癌或恶性胸膜间皮瘤患者口服 DAC/THU 和派姆单抗的 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、接近完全和持久的反应。为了进一步优化肺部恶性肿瘤的表观遗传启动以进行免疫检查点阻断，同时减少潜在的全身毒性，我们最近启动了临床前研究，以检查通过雾化技术施用的氮胞苷（AZA）的药代动力学和潜在功效。我们使用从高致死性同基因肺癌和肉瘤细胞系中分离的癌症干细胞开发了一种独特的免疫活性小鼠肺转移模型，用于系统、合理地评估 DNA 去甲基化剂、LSD1 抑制剂和 IL-12 等细胞因子。一项 I/II 期临床方案试验目前正在接受 FDA 审查，该试验旨在检查通过吸入技术施用的 AZA 联合 durvalumab 作为诱导治疗对可手术 NSCLC 患者的毒性和潜在疗效。该试验旨在建立评估一系列雾化表观遗传药物单独或与过继免疫疗法联合治疗局部晚期肺部恶性肿瘤的范例。目前世界其他地方还没有开展此类临床工作。我们的临床前和转化研究工作的结果在 2023 年 AACR 年会上作为正式全体会议演讲提出。癌症种系抗原包括一组共享的肿瘤抗原，仅在由体细胞或免疫细胞产生的癌症中表达。特殊部位，如睾丸、卵巢或胎盘。因此，癌症种系抗原已成为癌症免疫治疗极具吸引力的靶标。尽管癌种系抗原在多种人类恶性肿瘤中表达，但由于抗原表达水平低、异质性、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反应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研究表明，胸部恶性肿瘤表现出多种 CTA 表达模式，以及对上调这些蛋白质的表观遗传方案的异质反应。克服这些限制的策略是让患者对一组 CTA 进行免疫，这些 CTA 可能可以通过全身施用染色质重塑剂来上调。在评估癌细胞裂解物疫苗作为原发性胸部恶性肿瘤或肺部转移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，我们编写了两个使用这种裂解物疫苗的新方案（其中是我们实验室开发的）作为肺癌或食道癌患者的辅助治疗。肺癌方案将评估裂解物疫苗与 IL-15 超级激动剂 N-803 联合作为术后辅助治疗，而食道癌方案将评估裂解物疫苗与 HDAC 抑制剂、恩替司他和免疫抑制剂联合使用。检查点抑制剂，化疗放疗+/-手术后的纳武单抗。这两项协议均已获得 FDA 和 NIH IRB 的批准，预计将于 2024 财年第一季度初开放供患者招募。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recognition of NY-ESO-1+ tumor cells by engineered lymphocytes is enhanced by improved vector design and epigenetic modulation of tumor antigen expression.

DOI：
10.1007/s00262-008-0562-x
发表时间：
2009-03
期刊：
CANCER IMMUNOLOGY IMMUNOTHERAPY
影响因子：
5.8
作者：
Wargo, Jennifer A.;Robbins, Paul F.;Li, Yong;Zhao, Yangbing;El-Gamil, Mona;Caragacianu, Diana;Zheng, Zhili;Hong, Julie A.;Downey, Stephanie;Schrump, David S.;Rosenberg, Steven A.;Morgan, Richard A.
通讯作者：
Morgan, Richard A.

Analysis of circulating tumor DNA: The next paradigm shift in detection and treatment of lung cancer.

循环肿瘤 DNA 分析：肺癌检测和治疗的下一个范式转变。

DOI：
10.1016/j.jtcvs.2018.01.060
发表时间：
2018
期刊：
The Journal of thoracic and cardiovascular surgery
影响因子：
0
作者：
Schrump,DavidS;Hong,JulieA
通讯作者：
Hong,JulieA

Polycomb repressor complex-2 is a novel target for mesothelioma therapy.

DOI：
10.1158/1078-0432.ccr-11-0962
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Kemp CD;Rao M;Xi S;Inchauste S;Mani H;Fetsch P;Filie A;Zhang M;Hong JA;Walker RL;Zhu YJ;Ripley RT;Mathur A;Liu F;Yang M;Meltzer PA;Marquez VE;De Rienzo A;Bueno R;Schrump DS
通讯作者：
Schrump DS

Extended Resections of Non-small Cell Lung Cancers Invading the Aorta, Pulmonary Artery, Left Atrium, or Esophagus: Can They Be Justified?

DOI：
10.1016/j.thorsurg.2014.07.012
发表时间：
2014-11-01
期刊：
THORACIC SURGERY CLINICS
影响因子：
2.1
作者：
Reardon, Emily S.;Schrump, David S.
通讯作者：
Schrump, David S.

Definition of a new blood cell count score for early survival prediction for non-small cell lung cancer patients treated with atezolizumab: Integrated analysis of four multicenter clinical trials.

DOI：
10.3389/fimmu.2022.961926
发表时间：
2022
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Zhou, Jian-Guo;Wong, Ada Hang-Heng;Wang, Haitao;Jin, Su-Han;Tan, Fangya;Chen, Yu-Zhong;He, Si-Si;Shen, Gang;Frey, Benjamin;Fietkau, Rainer;Hecht, Markus;Carr, Shamus R.;Wang, Ruihong;Shen, Bo;Schrump, David S.;Ma, Hu;Gaipl, Udo S.
通讯作者：
Gaipl, Udo S.