Neoadjuvant checkpoint blockade for recurrent glioblastoma

新辅助检查点阻断治疗复发性胶质母细胞瘤

基本信息

批准号：
10661485
负责人：
Robert M Prins
金额：
$ 48.36万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661485
关键词：
Address Adjuvant Adjuvant Therapy Adverse event Aftercare Antibodies Antitumor Response Biological Blood Blood Cells Brain Brain Neoplasms CD8B1 gene CTLA4 blockade CTLA4 gene Cell Cycle Cell Cycle Regulation Cells Cephalic Clinical Clinical Data Clinical Trials Clone Cells Combined Modality Therapy Data Diagnosis Disease Down-Regulation Educational process of instructing Excision Gene Expression Genetic Transcription Glioblastoma Human Image Immune Immune response ImmunoPET Immunofluorescence Immunologic Immunologic Monitoring Immunologics Immunotherapy Infiltration Interferon Type II Long-Term Survivors Magnetic Resonance Imaging Malignant Neoplasms Monitor Monoclonal Antibodies Neoadjuvant Therapy Nivolumab Operative Surgical Procedures PD-1 blockade Patients Positron-Emission Tomography Productivity Progression-Free Survivals Publishing Radiation therapy Recurrence Research Personnel Resistance Resistance development Sampling Scanning T cell infiltration T cell regulation T-Lymphocyte Testing Toxic effect Tumor Cell Invasion Tumor Expansion Tumor Tissue Up-Regulation Work anti-PD1 antibodies anti-tumor immune response chemotherapy cohort density design early detection biomarkers hazard immune checkpoint blockade immunogenicity ipilimumab lymph nodes lymphoid neoplasm lymphoid organ neoplastic cell non-invasive imaging novel patient population peripheral blood phase III trial pre-clinical primary endpoint programmed cell death protein 1 randomized trial randomized, clinical trials refractory cancer response response biomarker secondary endpoint transcriptome sequencing treatment group tumor tumor microenvironment tumor-immune system interactions uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma is one of the most lethal of human cancers, with very few long-term survivors and no definitive cures for this disease. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells. Although immunotherapies, such as checkpoint blockade, have revolutionized the treatment of several cancers, its benefit in GBM has been limited to small randomized trials in the neoadjuvant setting, and limited benefit in Phase III trials in the adjuvant setting. Recently, we published a surgical trial of neoadjuvant PD-1 antibody blockade, to address the immunologic effects of this agent in recurrent glioblastoma. While it was a small, randomized clinical trial, the median overall survival of the neoadjuvant treatment cohort was 417 d (13.7 months) from registration date, while that of the adjuvant treatment cohort was 228 d (7.5 months; hazard ratio 0.39). Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor than traditional treatment in the adjuvant setting. While provocative, the benefit was restricted to patients whose T cell infiltration and IFN-γ signature was elevated. Our hypothesis is that the combination of CTLA-4 and PD-1 blockade in the neoadjuvant setting will significantly increase the tumor-specific T cell infiltration, allowing for PD-1 blockade to be more effective. To test this hypothesis, we will utilize our unique access to samples and patient data from an ongoing investigator-initiated clinical trial with PD-1 +/- CTLA-4 antibody blockade in the neoadjuvant setting for patients with recurrent GBM. The Specific Aims of this project are: • Aim #1: To evaluate the immunogenicity, toxicity, and clinical benefit for the combination of neoadjuvant CTLA-4 + PD-1 antibody blockade in recurrent GBM patients. • Aim #2: To evaluate how PD-1 and CTLA-4 mAb blockade independently modify the tumor microenvironment and the expansion of tumor-specific T cells following neoadjuvant checkpoint blockade in recurrent GBM patients. • Aim #3: To develop non-invasive imaging biomarkers of response or adaptive resistance in recurrent GBM patients treated with combinations of neoadjuvant CTLA-4 +/- PD-1 antibody blockade. This project could potentially be transformative, as a better understanding of how neoadjuvant immunotherapy alters immune responses within the tumor could teach us important lessons about the critical requirements for productive anti-tumor responses in glioblastoma and how adaptive resistance occurs in this disease.

项目概要/摘要胶质母细胞瘤是最致命的人类癌症之一，长期存活者很少，并且没有明确的治疗方法由于免疫细胞的潜在能力，免疫疗法是治疗这种疾病的一种有吸引力的策略。尽管免疫疗法（例如检查点封锁）已经发挥了作用。彻底改变了多种癌症的治疗方法，但其对 GBM 的益处仅限于小型随机试验新辅助治疗，以及辅助治疗 III 期试验的有限获益最近，我们发表了一篇文章。新辅助 PD-1 抗体阻断的外科试验，以解决该药物在复发性病例中的免疫学影响虽然这是一项小型随机临床试验，但新辅助治疗的中位总生存期。治疗队列从登记日期起为 417 天（13.7 个月），而辅助治疗队列为 228 天（7.5 个月；风险比 0.39）。新辅助 PD-1 阻断与 T 细胞上调相关。和干扰素-γ相关基因表达，但细胞周期相关基因表达下调肿瘤，在单独接受辅助治疗的患者中未观察到。这些发现表明， PD-1 阻断的新辅助给药可增强局部和全身抗肿瘤免疫反应可能代表了一种比传统疗法更有效的治疗这种致命性脑肿瘤的方法辅助治疗中的传统治疗虽然具有挑战性，但其益处仅限于具有 T 细胞的患者。我们的假设是 CTLA-4 和 PD-1 的组合导致浸润和 IFN-γ 信号升高。新辅助治疗中的阻断将显着增加肿瘤特异性 T 细胞浸润，从而允许为了验证这一假设，我们将利用我们独特的样本获取途径来更有效地阻断 PD-1。来自正在进行的研究者发起的 PD-1 +/- CTLA-4 抗体阻断临床试验的患者数据复发性 GBM 患者的新辅助治疗该项目的具体目标是： • 目标#1：评估新辅助疗法组合的免疫原性、毒性和临床益处 CTLA-4 + PD-1 抗体阻断复发性 GBM 患者。 • 目标#2：评估 PD-1 和 CTLA-4 mAb 阻断如何独立改变肿瘤新辅助检查点阻断后微环境和肿瘤特异性 T 细胞的扩增复发性 GBM 患者。 • 目标#3：开发复发性 GBM 反应或适应性抵抗的非侵入性成像生物标志物接受新辅助 CTLA-4 +/- PD-1 抗体阻断联合治疗的患者。该项目可能具有变革性，可以更好地理解新辅助免疫疗法改变肿瘤内的免疫反应可以给我们重要的教训，让我们了解免疫的关键要求胶质母细胞瘤中有效的抗肿瘤反应以及这种疾病中如何发生适应性抵抗。