Neoadjuvant checkpoint blockade for recurrent glioblastoma

项目摘要/摘要 胶质母细胞瘤是人类最致命的癌症之一，长期存活者很少，目前尚无明确的 治疗这种疾病的药物。免疫治疗是一种吸引人的策略，因为它具有潜在的免疫细胞能力。 运输到并摧毁浸润性肿瘤细胞。尽管免疫疗法，如检查站封锁，已经 革命性地治疗了几种癌症，它在GBM中的益处仅限于 新的佐剂设置，以及佐剂设置的第三阶段试验中的有限益处。最近，我们发表了一篇 新佐剂PD-1抗体阻断的外科试验，以解决该药对复发患者的免疫学影响 胶质母细胞瘤。虽然这是一项小规模的随机临床试验，但新辅助剂的中位总存活率 治疗队列自登记之日起417天(13.7个月)，而辅助治疗队列为417天(13.7个月) 228d(7.5个月；危险比0.39)。新佐剂PD-1阻断与T细胞上调有关- 和干扰素-γ相关基因表达，但下调细胞周期相关基因表达 肿瘤，这在单独接受辅助治疗的患者中看不到。这些发现表明， 新辅助应用PD-1阻滞剂可增强局部和全身抗肿瘤免疫反应 可能代表着一种比治疗这种一致致命的脑瘤更有效的方法 在辅助环境下的传统治疗。虽然具有挑衅性，但这种益处仅限于T细胞 炎性细胞浸润和干扰素-γ标志物升高。我们的假设是CTLA-4和PD-1的结合 在新辅助治疗环境中阻断将显著增加肿瘤特异性T细胞的渗透，从而允许 PD-1的阻断效果更好。为了验证这一假设，我们将利用我们对样本和 患者数据来自一项由研究人员发起的正在进行的临床试验，该试验使用PD-1+/-CTLA-4抗体阻断在 复发性基底膜患者的新辅助治疗。该项目的具体目标是： ·目标1：评估新佐剂组合的免疫原性、毒性和临床益处 复发性GBM患者CTLA-4+PD-1抗体阻断治疗 目的2：评价PD-1和CTLA-4单抗阻断对肿瘤的独立修饰作用 新辅助检查点阻断后微环境与肿瘤特异性T细胞的扩增 复发的基底膜患者。 ·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记物 接受新辅助CTLA-4+/-PD-1抗体阻断联合治疗的患者。 这个项目可能具有潜在的变革性，因为它可以更好地理解新辅助免疫疗法是如何 改变肿瘤内的免疫反应可能会给我们上重要的一课 胶质母细胞瘤中产生的抗肿瘤反应以及适应性抵抗是如何在这种疾病中发生的。

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.