Neoadjuvant anti-PD-1 immunotherapy and Stereotactic Radiation in Patients with Recurrent Glioblastoma

复发性胶质母细胞瘤患者的新辅助抗 PD-1 免疫治疗和立体定向放射治疗

基本信息

批准号：
10356681
负责人：
Chirag Gadkary Patil
金额：
$ 19.52万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-08 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356681
关键词：
Address Adjuvant Adult Aftercare Antigen Presentation Biological Assay Biopsy CD8-Positive T-Lymphocytes Clinical Clinical Research Clinical Trials Clonal Expansion Combined Modality Therapy Complex Cytotoxic T-Lymphocytes DNA Sequence Alteration Disease Progression Dose Enrollment Evaluation Excision Future Genes Genomics Glioblastoma Glioma Heterogeneity Immune Immune response Immunologic Markers Immunooncology Immunosuppression Immunotherapy Inflammatory Knowledge Lead Malignant Neoplasms Malignant neoplasm of brain Measures Mediator of activation protein Neoadjuvant Study Neoadjuvant Therapy Operative Surgical Procedures PD-1 blockade PTPRC gene Pathologic Pathway interactions Patient Selection Patients Phase Phenotype Population Prognosis Radiation Radiation therapy Recurrence Research Design Resistance STAT3 gene Safety Survival Rate T cell clonality T cell receptor repertoire sequencing T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Tissues Tumor-infiltrating immune cells Up-Regulation Work anti-PD-1 anti-tumor immune response arm combinatorial design early phase clinical trial experience immune activation immune resistance innovation mRNA Expression macrophage malignant breast neoplasm novel pembrolizumab primary outcome programmed cell death ligand 1 programmed cell death protein 1 recruit responders and non-responders response single-cell RNA sequencing standard of care targeted treatment transcriptome treatment strategy tumor tumor heterogeneity tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Project Summary/Abstract Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and has a dismal prognosis. Tumor heterogeneity and immune suppression (via the PD-1/PDL-1 mechanism) are likely reasons why GBMs almost always recur after treatment. Neo-adjuvant anti-PD-1 immunotherapy has recently been shown to have a modest benefit. Radiation therapy promotes a pro-inflammatory tumor microenvironment and can work synergistically with immunotherapy. Therefore, we propose an early phase clinical trial to compare the anti-tumor immune response before and after the novel combination of neoadjuvant anti-PD-1 immunotherapy and stereotactic radiation (SRT). Ten adult subjects with pathologically confirmed WHO Grade IV, recurrent glioblastoma multiforme that are planning to undergo surgical resection will be recruited. All subjects will have pre-treatment biopsy tissue available. Patients will be administered a single dose of anti-PD-1 immunotherapy followed by SRT followed by surgical resection and then continue on anti-PD-1 until disease progression. In our first aim, we propose to measure the changes in the T cell response against GBM following treatment. We hypothesize that the pre-surgical administration of anti-PD-1 combined with SRT will lead to an increase in the anti-tumor immune response. The primary immune biomarkers will be T cell receptor clonality and CD8+ T cell activation. We will perform single-cell RNA sequencing to study the changes in the T cell and macrophage populations after treatment and interrogate their functional phenotypes. In our second aim, we will assess the changes in intra-tumoral heterogeneity following treatment and identify genomic correlates of immune resistance. Our hypothesis is that treatment will reduce the number of distinct GBM clones as assessed by single cell RNA sequencing. We will also compare the expression profiles of cancer pathways between immune responders versus non-responders using differential enrichment analysis. This will allow us to identify the little-known genomic correlates of anti-PD-1 immune resistance in GBM. Knowledge of these correlates can assist in better selection of GBM patients that are likely to benefit from PD-1 blockade as well as inform us on future combinatorial treatment strategies. Successful completion of our specific aims will deepen our understanding of the changes in the immune response and GBM heterogeneity. Encouraging findings from our study would lead us to pursue a phase II RCT of neoadjuvant anti-PD-1 immunotherapy plus SRT versus best available standard of care.

项目概要/摘要多形性胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤，其发病率令人沮丧预后。肿瘤异质性和免疫抑制（通过 PD-1/PDL-1 机制）可能是原因为什么 GBM 在治疗后几乎总是复发。最近，新辅助抗PD-1免疫治疗显示有一定的好处。放射治疗促进促炎性肿瘤微环境可以与免疫疗法协同作用。因此，我们建议进行早期临床试验来比较新辅助抗PD-1免疫疗法联合治疗前后的抗肿瘤免疫反应和立体定向辐射（SRT）。 10 名经病理证实为 WHO IV 级、复发的成人受试者将招募计划接受手术切除的多形性胶质母细胞瘤。所有科目都会有可获得治疗前的活检组织。患者将接受单剂抗 PD-1 免疫疗法随后进行 SRT，随后进行手术切除，然后继续抗 PD-1 治疗直至疾病进展。在我们的第一个目标是，我们建议测量治疗后 T 细胞对 GBM 反应的变化。我们假设术前给予抗 PD-1 联合 SRT 将导致抗肿瘤免疫反应。主要免疫生物标志物是 T 细胞受体克隆和 CD8+ T 细胞激活。我们将进行单细胞RNA测序来研究T细胞和巨噬细胞的变化治疗后的人群并询问其功能表型。在我们的第二个目标中，我们将评估治疗后肿瘤内异质性的变化并确定免疫抵抗的基因组相关性。我们的假设是，根据单细胞 RNA 评估，治疗将减少不同 GBM 克隆的数量测序。我们还将比较免疫反应者之间癌症途径的表达谱使用差异富集分析与无应答者进行比较。这将使我们能够识别鲜为人知的 GBM 中抗 PD-1 免疫抵抗的基因组相关性。了解这些相关性可以帮助我们更好地选择可能受益于 PD-1 阻断的 GBM 患者，并告知我们未来的情况组合治疗策略。成功完成我们的具体目标将加深我们对免疫反应和 GBM 异质性的变化。我们的研究令人鼓舞的结果将导致我们将进行新辅助抗 PD-1 免疫疗法加 SRT 与最佳可用标准的 II 期随机对照试验的照顾。