Project 2: Analyses of the human GBM microenvironment form clinical trial specimens treated with the oncolytic HSV, rQNestin34v.2

项目 2：分析经溶瘤 HSV rQNestin34v.2 处理的临床试验标本中的人类 GBM 微环境

• 批准号: 10712281
• 负责人: E. Antonio Chiocca
• 金额: $ 40.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-07 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712281
• 关键词: Adenosine; Antigen Presentation; Antitumor Response; B-Cell Antigen Receptor; B-Lymphocytes; Biological; Biological Markers; Biopsy Specimen; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Clinical; Clinical Trials; Data; Development; Down-Regulation; FDA approved; Failure; Funding; Future; Glioblastoma; Glioma; Growth; HLA Antigens; Herpes Simplex Infections; Human; Image; Immune; Immune response; Immunologics; Immunosuppression; Immunotherapy; In Situ; Infection; Infiltration; Japan; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Measures; Mediating; Medical; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Oncolytic; Oncolytic viruses; Patient-Focused Outcomes; Patients; Phase I Clinical Trials; Plasma; Population; Pre-Clinical Model; Proteome; Publishing; Recurrence; Serum; Simplexvirus; Specimen; Stimulus; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Transcript; Tumor Antigens; Tumor Virus Infections; Tumor-Infiltrating Lymphocytes; Viral Antigens; Virus Diseases; Work; Xenograft procedure; antigen binding; cancer infiltrating T cells; chemokine; cytokine; cytotoxic; human subject; imaging biomarker; immune cell infiltrate; immune checkpoint blockade; immunotherapy trials; improved; melanoma; novel; oncolytic herpes simplex virus; oncolytic virotherapy; patient response; peripheral blood; phase I trial; potential biomarker; pre-clinical; programs; rate of change; response; success; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY – PROJECT 2 Glioblastoma (GBM), arguably the deadliest of all cancers, has remained impervious to treatments, including immunotherapies that have seen evidence of success in other cancers. The profound immunosuppressive microenvironment in GBM thwarts immune activating stimuli like immune checkpoint blockade and significantly limits activated T cell tumor infiltration. In fact, GBM has been described as an immune-desert. As part of this Program Project, we plan to analyze the immune infiltration in clinical specimens from human GBMs injected with a novel oncolytic virus (NCT03152318, clinicaltrial.gov). Oncolytic viruses (OV) are a form of immunotherapy being investigated clinically against multiple cancers with one oncolytic Herpes Simplex Virus (oHSV) approved in the USA against melanoma and a different oHSV approved against GBM in Japan. In the previous funding period, we started and finished a phase 1 clinical trial of the novel oHSV, rQNestin34.5v.2, that accrued 50 human subjects with recurrent high-grade gliomas. Preliminary data from tumors after in situ administration of this oHSV shows increased TILs. In addition, we show that elevated T cell and/or B cell receptor (TCR/BCR) transcripts are associated with improved subject survival. Volumetric analyses of MRIs from subjects also show that growth rate changes correlate with increased response in treated patients. These published and preliminary data thus provide a conceptual framework justifying in situ administration of OVs to revert the immunosuppressive microenvironment of GBM into one whose cellular and molecular components become immuno-activating. Based on the above, we hypothesize that in situ oHSV administration profoundly changes the human GBM microenvironment into one that is more favorable for immunotherapy. We plan to utilize clinical GBM specimens obtained from the current clinical trial to validate the hypothesis, via the following Specific Aims: Aim 1. Validate the immune-activating changes in the human GBM microenvironment perturbed by oHSV in situ administration; Aim 2. Investigate subjects’ plasma proteome, serum cytokine/chemokine and MRI volumetrics as potential biomarkers of oHSV response and correlate with TCR/BCR transcript abundance; and Aim 3. Utilize human GBM patient derived cells and xenografts obtained from current clinical trial patients to characterize HLA-immunopeptidomes after oHSV infection. These aims, if successful, will support the development of oHSV-elicited tumor antigens to boost the immune response to oHSV infection and thereby improve patient outcomes. In addition, we will work with Project 4 to develop the studies needed to bring the novel oHSVs to future clinical trials and with Project 1 to add our discovered oHSV-tumor antigens to the preclinical therapeutic models with armed oHSV. With Project 3, we will measure immunosuppressive metabolites in biopsy specimens.

项目摘要--项目2 胶质母细胞瘤(GBM)，可以说是所有癌症中最致命的，仍然对治疗无效，包括 免疫疗法已经在其他癌症中看到了成功的证据。深刻的免疫抑制作用 GBM中的微环境可阻止免疫检查点阻断等免疫激活刺激，并显著 限制活化T细胞肿瘤的侵袭。事实上，GBM被描述为免疫沙漠。作为这项工作的一部分 计划项目，我们计划分析注射人GBM的临床标本中的免疫渗透 与一种新的溶瘤病毒(NCT03152318，Clinicaltrial.gov)。溶瘤病毒(OV)是一种 单纯性溶瘤单纯疱疹病毒免疫治疗多癌的临床研究 (OHSV)在美国被批准用于治疗黑色素瘤，另一种OHSV在日本被批准用于治疗GBM。在 在之前的资助期间，我们开始并完成了新型OHSV rQNestin34.5v.2的第一阶段临床试验， 收集了50名患有复发性高级别胶质瘤的受试者。肿瘤原位术后的初步资料 这种OHSV的给药显示TIL增加。此外，我们发现升高的T细胞和/或B细胞受体 (TCR/BCR)转录本与受试者存活率的提高有关。受试者磁共振成像的体积分析 还表明，生长速度的变化与治疗后患者的反应增加有关。这些已出版和 因此，初步数据提供了一个概念框架，证明原地给药是合理的，以恢复 将GBM的免疫抑制微环境转变为细胞和分子成分 免疫激活剂。在此基础上，我们提出了OHSV原位给药的假设。 将人的GBM微环境改变为更有利于免疫治疗的微环境。我们计划 为了利用从当前临床试验中获得的临床GBM样本来验证假设，通过 以下具体目标：目的1.验证人基底膜的免疫激活变化 OHSV原位注射对微环境的扰动；目的2.调查受试者的血浆 蛋白质组、血清细胞因子/趋化因子和MRI容量测定作为OHSV应答的潜在生物标志物 与TCR/BCR转录丰度相关；以及目标3.利用人GBM患者来源的细胞 和从目前的临床试验患者获得的异种移植来表征人类白细胞抗原免疫肽 OHSV感染。这些目标，如果成功，将支持OHSV诱导的肿瘤抗原的发展 增强对OHSV感染的免疫反应，从而改善患者的预后。此外，我们还将致力于 与项目4合作开发将新型OHSV带入未来临床试验所需的研究，并与项目1合作 将我们发现的OHSV-肿瘤抗原添加到武装OHSV的临床前治疗模型中。使用项目 3、我们将检测活检标本中的免疫抑制代谢物。