Epigenetic Therapy for Thoracic Malignanceis

胸部恶性肿瘤的表观遗传学治疗

• 批准号: 9556779
• 负责人: DAVID SCHRUMP
• 金额: $ 38.67万
• 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/9556779
• 关键词: Aberrant DNA Methylation; Adoptive Transfer; Aftercare; Allogenic; American College of Surgeons; Antigens; Apoptosis; Autologous; Biodistribution; Biopsy; CD14 gene; CTAG1 gene; Cancer Patient; Cell Line; Cells; Chest; Chromatin Structure; Clinic; Clinical; Clinical Protocols; Clinical Trials; Congresses; Cytidine; Cytometry; DNA; DNA Methylation; Data; Decitabine; Depsipeptides; Disease; Dose; Endogenous Retroviruses; Epigenetic Process; Evaluation; Event; Exhibits; Formulation; Freezing; Future; Gene Expression; Genes; Genomic Instability; Genomics; Germ Cells; Goals; Growth; H1299; Half-Life; Histone Deacetylase Inhibitor; Histones; Hour; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunocompetent; Inflammatory Response; Infusion procedures; Intravenous; Investigation; K-562; Laboratories; Lasers; MAGEA3 gene; Malignant - descriptor; Malignant neoplasm of lung; Malignant neoplasm of testis; Malignant neoplasm of thorax; Manuscripts; Mediating; Methylation; Modeling; Modification; Molecular; Mus; Neoplasm Circulating Cells; Non-Small-Cell Lung Carcinoma; Oral; PDCD1LG1 gene; Patients; Peripheral; Phase; Polycomb; Positioning Attribute; Proteins; Protocols documentation; Publications; Publishing; Randomized; Recurrence; Regimen; Regulatory T-Lymphocyte; Repression; Series; Serological; Sickle Cell Anemia; Site; Structure of respiratory epithelium; T-Lymphocyte; Tetrahydrouridine; Thoracic Oncology; Toxic effect; Treatment-related toxicity; Tumor Antigens; Tumor Immunity; Tumor Suppressor Genes; Tumor Tissue; United States National Institutes of Health; Universities; Vaccination; Vaccine Therapy; Vaccines; X Chromosome; bronchial epithelium; cancer cell; cancer genome; cancer immunotherapy; cancer stem cell; chromatin remodeling; conventional therapy; demethylation; gene induction; genetic signature; genome-wide; immunogenicity; immunological intervention; imprint; in vivo; intradermal injection; monocyte; neoplastic cell; next generation sequencing; nonhuman primate; novel; oncology; phase II trial; pre-clinical; response; tumor; tumor DNA

More than 100 patients with thoracic malignancies have been treated on a series of clinical protocols examining toxicities and clinical responses following infusions of DNA demethylating agents (Decitabine; DAC), and HDAC inhibitors, such as romidepsin (DP) alone or in combination with other investigational agents. Collectively these trials demonstrated no objective clinical regressions, although prolonged stabilization of disease (4 - 12months) was observed in approximately 10% of patients. Nearly one quarter of all patients receiving DAC infusions exhibited increased expression of p16, MAGE-3, or NY-ESO-1 in tumor tissues. Serologic responses to NY-ESO-1 were observed in several patients receiving DAC for more than six months. Approximately 50% of patients receiving DP infusions exhibited increased intratumoral levels of H3Ac and p21. In addition, several patients exhibited enhanced expression of NY-ESO-1 and MAGE-A3 in tumor biopsies following DP infusions. Micro-array analysis of laser captured tumor cells from pre and post treatment biopsies from patients receiving DAC, DP or sequential DAC/DP infusions revealed a shift from a lung cancer gene signature to one observed in normal respiratory epithelia. These early trials provided proof of concept for the use of epigenetic regimens in combination with immunologic interventions for the treatment of thoracic malignancies. Because CT-X antigens appear to be preferentially expressed in pluripotent tumor cells, it is conceivable that autologous epigenetically modified tumor cells may be unique, personalized vaccines to induce immune responses to cancer stem cells. Difficulties regarding reliable establishment of primary cell lines limited our ability to formally evaluate this issue in the clinic, and these protocols were closed. In an attempt to circumvent these problems, we have examined if vaccines produced from allogeneic cancer cells can induce broad immunity to CT-X antigens that potentially can be up-regulated in thoracic malignancies by gene induction regimens. In a recent phase II trial, we have evaluated the immunogenicity of a freeze thaw lysate of H1299 lung cancer cells. This NSCLC line was established at the NCI and exhibits high level expression of numerous relevant CT-X gene expression relative to K562-GM due to amplification of the X chromosome. In an ongoing first-in- humans trial, 21 patients with thoracic malignancies rendered NED by conventional therapy were randomized to receive freeze-thaw lysates from H1299 lung cancer cells exhibiting high-level CTA expression with Iscomatrix via intradermal injection q month x 6 +/- oral metronomic cy/cel. The primary endpoint was serologic response to purified tumor antigens one month after the 6th vaccination. All patients exhibited local and systemic inflammatory responses lasting 72-96 hours following vaccinations. There were no treatment related toxicities. 14 patients (67%) completed all six vaccinations; 7 patients were removed from study early due to disease recurrence. 8 patients (57%) exhibited serologic responses to NY-ESO-1. Additional responses were observed against GAGE7, XAGE and MAGE-C2. Vaccine therapy also decreased percent Tregs (p=0.0067) and PD-1 expression on Tregs (p=0.0023), as well as PD-L1 expression on CD14+ monocytes (p=0.0089), classical monocytes (p=0.0159), and intermediate monocytes (p= 0.0031). Cy/cel did not increase immune responses or enhance vaccine-induced alterations in peripheral immune subsets.H1299 lysate vaccines induce immune responses to CTAs, and modulate peripheral immune subsets in a manner that may enhance antitumor immunity. These findings support evaluation of this lysate in combination with immune checkpoint inhibitors in thoracic oncology patients. Results of this trial have been selected for oral presentation at the American College of Surgeons Annual Clinical Congress, and a manuscript pertaining to these findings will be submitted for publication in the near future. A major limitation regarding the use of DNA demethylating agents in cancer immunotherapy regimens pertains to the short half-life (5min) and poor biodistribution due to cytidine deminase (CDA) which is present at high levels throughout the body. Recent studies in non-human primates and a clinical trial in patients with sickle cell disease, have demonstrated that an oral formulation of tetrahydrouridine (THU)- a compound that has been previously administered intravenously to hundreds of cancer patients with no toxicities can markedly increase Cmax (50nM)and T1/2 ( 4 hours) of oral Decitabine. These findings have provided the rationale for a phase II trial evaluation oral DAC/THU and the immune checkpoint inhibitor Nivolumab as second line therapy for patients with NSCLC, as well as a phase I/II dose escalation study of oral DAC/THU and pembrolizumab as first line therapy for patients with inoperable NSCLC exhibiting high level PDL1 expression. Comprehensive state of the art translational analyses of PD endpoints including multiplex quantitative IHC, multiparametric mass cytometry (CyTOF) and next-gen sequencing will be conducted in the Translational Imuno-Oncology Laboratory at Yale University. Additional studies including analysis of immune subsets, circulating tumor cells and methylation status of circulating tumor DNA will be performed at the NIH Clinical Center.

在一系列临床方案中，已经对100多名胸腔恶性肿瘤患者进行了治疗，这些临床方案检查了DNA脱甲基化剂（Decitabine; DAC）和HDAC抑制剂（例如Romidepsin（DP）（DP）（DP）（DP）（DP）（DP）或与其他研究人员的结合，毒性和临床反应。尽管在大约10％的患者中观察到疾病的稳定延长（4-12个月），但这些试验总共表现出没有客观的临床回归。在所有接受DAC输注的患者中，将近四分之一的患者表现出肿瘤组织中p16，Mage-3或NY-ESO-1的表达增加。在接受DAC的几名患者中观察到了对NY-ESO-1的血清学反应超过六个月。接受DP输注的患者中约有50％表现出肿瘤内H3AC和P21的升高。此外，在DP输注后，几名患者在肿瘤活检中表现出增强的NY-ESO-1和MAGE-A3的表达。对激光的微阵列分析从接受DAC，DP或顺序DAC/DP输注的患者的治疗前和治疗后活检中捕获的肿瘤细胞表明，从肺癌基因的签名转移到正常呼吸性上皮elia中观察到的肿瘤细胞。这些早期试验为使用表观遗传方案与免疫学干预措施相结合的治疗胸腔恶性肿瘤提供了概念证明。由于CT-X抗原似乎在多能肿瘤细胞中优先表达，因此可以想象，自体遗传遗传修饰的肿瘤细胞可能是独特的个性化疫苗，可以诱导对癌症干细胞的免疫反应。关于可靠建立原始细胞系的困难限制了我们在诊所正式评估此问题的能力，并且这些方案已关闭。为了解决这些问题，我们检查了同种异体癌细胞产生的疫苗是否可以诱导对CT-X抗原的广泛免疫力，这些免疫力可能通过基因诱导方案在胸腔恶性肿瘤中上调。在最近的II期试验中，我们评估了H1299肺癌细胞的冻结裂解物的免疫原性。该NSCLC线在NCI上建立，由于X染色体的扩增，相对于K562-GM的许多相关CT-X基因表达的高水平表达。在正在进行的第一人类试验中，随机分配了21例由常规疗法引起的胸腔恶性肿瘤患者，以接收来自H1299 H1299肺癌细胞的冻融裂解物，这些肺癌细胞通过ISCOMATRIX通过ISCOMATRIX通过内部静脉内部X +月份x 6 +/-口服X 6 +/-口服Metral metral cy/cel/cel cy/cel cy/cy/cy/cel/cel cyccomatrix表达高级CTA表达。主要终点是第六次疫苗接种后一个月对纯化的肿瘤抗原的血清学反应。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。没有治疗相关的毒性。 14例患者（67％）完成了所有六项疫苗接种；由于疾病复发，提早将7例患者从研究中移除。 8例患者（57％）对NY-ESO-1表现出血清学反应。观察到针对GAGE7，XAGE和MAGE-C2的其他响应。疫苗疗法还降低了Treg的Treg百分比（P = 0.0067）和PD-1表达（P = 0.0023），以及CD14+单核细胞（P = 0.0089）的PD-L1表达（PD-L1），经典的单核细胞（P = 0.0159）（p = 0.0159），以及中间的单核细胞和中间单核细胞（P = 0.0031）。 CY/CEL不会增加免疫反应或增强疫苗诱导的外周免疫亚群的改变。H1299裂解物疫苗可诱导对CTA的免疫反应，并以可能增强抗肿瘤免疫力的方式调节外周种免疫亚群。这些发现支持对该裂解物的评估，并结合胸部肿瘤患者的免疫检查点抑制剂。该试验的结果已在美国外科医生学院年度临床大会上进行口头介绍，与这些发现有关的手稿将在不久的将来提交出版。在癌症免疫疗法方案中使用DNA脱甲基剂的主要局限性与短期寿命（5分钟）和由于胞苷脱氨酸酶（CDA）引起的生物分布不佳，这是整个体内高水平的。最近在非人类灵长类动物和镰状细胞病患者的临床试验中进行的研究表明，四氢胺（THU）的口服配方（THU）先前已静脉内对数百名无毒性癌症患者静脉内服用的化合物可以显着增加CMAX（50nm）（50nm）和T1/2（4小时（4小时））。 These findings have provided the rationale for a phase II trial evaluation oral DAC/THU and the immune checkpoint inhibitor Nivolumab as second line therapy for patients with NSCLC, as well as a phase I/II dose escalation study of oral DAC/THU and pembrolizumab as first line therapy for patients with inoperable NSCLC exhibiting high level PDL1 expression.耶鲁大学的转化Imuno-Concology实验室将进行PD终点的最新转化分析，包括多重定量IHC，多参数质量细胞仪（CYTOF）和下一代测序。其他研究将在NIH临床中心进行，包括对免疫亚群，循环肿瘤细胞和循环肿瘤DNA的甲基化状态。