Neoadjuvant checkpoint blockade for recurrent glioblastoma

项目概要/摘要 胶质母细胞瘤是人类最致命的癌症之一，很少有长期存活者， 治愈这种疾病。免疫治疗是一种有吸引力的策略，因为免疫细胞具有潜在的能力， 运输并摧毁浸润的肿瘤细胞。虽然免疫疗法，如检查点封锁， 革命性地治疗了几种癌症，其在GBM中的益处仅限于小型随机试验， 新辅助治疗，辅助治疗的III期试验获益有限。最近，我们发布了一份 新辅助PD-1抗体阻断的手术试验，以解决该药物在复发性 胶质母细胞瘤虽然这是一项小型的随机临床试验，但新辅助化疗的中位总生存期 治疗队列为自注册之日起417天（13.7个月），而辅助治疗队列为 228 d（7.5个月;风险比0.39）。新辅助PD-1阻断与T细胞的上调相关， 和干扰素-γ相关基因的表达，但下调细胞周期相关基因的表达， 肿瘤，这在单独接受辅助治疗的患者中没有观察到。这些发现表明 PD-1阻断剂的新辅助给药增强局部和全身抗肿瘤免疫应答 并且可能代表了一种更有效的方法来治疗这种均匀致命的脑肿瘤， 辅助治疗中的传统治疗。虽然具有挑衅性，但受益仅限于T细胞减少的患者。 浸润和IFN-γ信号升高。我们的假设是CTLA-4和PD-1的组合 在新辅助治疗环境中的阻断将显著增加肿瘤特异性T细胞浸润， PD-1阻断更有效。为了验证这一假设，我们将利用我们独特的样本访问权限， 患者数据来自一项正在进行的PD-1 +/- CTLA-4抗体阻断剂启动的临床试验， 复发性GBM患者的新辅助治疗。该项目的具体目标是： ·目的#1：评估新辅助免疫疗法与免疫抑制剂的组合的免疫原性、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阻断如何独立地修饰肿瘤 微环境和肿瘤特异性T细胞在新辅助检查点阻断后的扩增 复发性GBM患者。 ·目标#3：开发复发性GBM中的响应或适应性抗性的非侵入性成像生物标志物 用新辅助CTLA-4 +/- PD-1抗体阻断的组合治疗的患者。 这个项目可能是变革性的，因为更好地了解新辅助免疫疗法如何 改变肿瘤内的免疫反应可以给我们重要的教训， 胶质母细胞瘤中的有效抗肿瘤反应以及这种疾病中的适应性耐药性如何发生。

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.