Purpose: Radiation therapy may enhance anti-tumor immune responses by several mechanisms including induction of immunogenic cell death. We performed a phase 2 study of pembrolizumab with re-irradiation in patients with recurrent glioblastoma. Methods: Sixty recurrent glioblastoma patients received pembrolizumab with re-irradiation alone (cohort A, bevacizumab-naïve; n=30) or with bevacizumab continuation (cohort B, n=30). Dual primary endpoints including overall response rate (ORR) and overall survival at either 12 (OS-12; cohort A) or six months (OS-6; cohort B) were assessed per cohort relative to historical benchmarks. Paired paraffin-embedded formalin-fixed tumor samples were assessed for immunologic biomarkers by immunohistochemistry using digital quantification and Co-Detection-by-InDEXing (CODEX). Results: Study therapy was well tolerated with most toxicities being grade ≤ 3. For cohort B, the primary endpoint of OS-6 was achieved (57%), however survival was not improved for cohort A patients. The ORR was 3.3% and 6.7% for cohorts A and B, respectively. CODEX analysis of paired tumor samples from 5 patients revealed an increase of activated T cells in the tumor microenvironment after study therapy. Conclusions: Compared to historical controls, re-irradiation plus pembrolizumab appeared to improve survival among bevacizumab-refractory patients but not among bevacizumab-naïve patients. CODEX revealed evidence of intratumoral infiltration of activated immune effector cells. A randomized, properly controlled trial of PD-1 blockade plus re-irradiation is warranted to further evaluate this regimen for bevacizumab refractory patients, but alternative approaches are needed for bevacizumab-naïve patients.

中文翻译：

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再照射加 pembrolizumab：复发性胶质母细胞瘤患者的 II 期研究


目的：放射治疗可能通过多种机制增强抗肿瘤免疫反应，包括诱导免疫原性细胞死亡。我们在复发性胶质母细胞瘤患者中进行了 pembrolizumab 再照射的 2 期研究。方法：60 例复发性胶质母细胞瘤患者接受帕博利珠单抗联合单独再照射 （队列 A，贝伐珠单抗初治;n=30） 或继续贝伐珠单抗治疗 （队列 B，n=30）。相对于历史基准，每个队列评估了双主要终点，包括总缓解率 （ORR） 和 12 个月 （OS-12;队列 A） 或 6 个月 （OS-6;队列 B） 的总生存期。通过使用数字定量和 InDEXing 共检测 （CODEX） 的免疫组织化学评估配对石蜡包埋的福尔马林固定肿瘤样本的免疫生物标志物。结果： 研究治疗耐受性良好，大多数毒性为 ≤ 级 3 级。对于队列 B，达到 OS-6 的主要终点 （57%），但队列 A 患者的生存率没有提高。队列 A 和队列 B 的 ORR 分别为 3.3% 和 6.7%。对 5 名患者的配对肿瘤样本的 CODEX 分析显示，研究治疗后肿瘤微环境中活化的 T 细胞增加。结论：与历史对照相比，再照射加 pembrolizumab 似乎提高了贝伐珠单抗难治性患者的生存率，但没有提高贝伐珠单抗初治患者的生存率。CODEX 揭示了活化免疫效应细胞瘤内浸润的证据。有必要进行 PD-1 阻断加再照射的随机、适当对照试验，以进一步评估贝伐珠单抗难治性患者的方案，但对于未接受过贝伐珠单抗治疗的患者，需要替代方法。