Abstract

Introduction

Glioblastoma multiforme (GBM) is a deadly brain tumor with a short expected median survival, despite current standard-of-care treatment. We explored the combination of intermediate stereotactic dose radiation therapy and immune checkpoint inhibitor therapy as a novel treatment strategy for GBM.

Methods

Glioma xenograft-bearing mice were exposed to high dose brain-directed radiation (10 Gy single exposure) as well as mouse anti-PD-1 antibody. The tumor-bearing animals were randomized to four groups: no treatment, radiation alone, anti-PD-1 alone, and radiation + anti-PD-1. Survival was followed, and tumor growth was monitored using MRI. Immunohistochemistry, gene expression arrays, and flow cytometry were used to characterize the treatment-induced effects. Pharmacologic inhibitors of T-lymphocytes, bone marrow derived macrophages, and microglia were used to assess the respective roles of different immune populations in observed treatment effects.

Results

We found the combined treatment with high dose radiation and immunotherapy to be highly effective with a 75% complete pathologic response and dramatically improved survival outcomes. We found both CD8+ T-cells and macrophages to be necessary for the full effect of combined therapy, with T lymphocytes appearing to play a role early on and macrophages mediating a later phase of the combined treatment effect. Radiation treatment appeared to trigger macrophage repolarization, increasing M1/M2 ratio.

Conclusions

These findings point to a novel immunologic mechanism underlying the interaction between radiotherapy and immunotherapy. They also provide the basis for clinical investigation of immunogenic dose radiation in combination with immune checkpoint blockade as a potential treatment approach for newly diagnosed high grade gliomas.

中文翻译：

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中等立体定向剂量放疗和免疫检查点阻滞诱导的复极化巨噬细胞有助于神经胶质瘤小鼠的长期存活。

摘要

介绍

尽管目前采用标准护理方法，但多形胶质母细胞瘤（GBM）是一种致命的脑肿瘤，预期中位生存期较短。我们探索了中级立体定向放射治疗和免疫检查点抑制剂治疗相结合的GBM新型治疗策略。

方法

带有胶质瘤异种移植物的小鼠暴露于高剂量的脑定向辐射（单次暴露10 Gy）以及小鼠抗PD-1抗体。荷瘤动物被随机分为四组：不治疗，单独放疗，单独抗PD-1和放疗+抗PD-1。追踪生存情况，并使用MRI监测肿瘤的生长。免疫组织化学，基因表达阵列和流式细胞仪用于表征治疗诱导的作用。T淋巴细胞，骨髓来源的巨噬细胞和小胶质细胞的药理抑制剂用于评估观察到的治疗效果中不同免疫群体的各自作用。

结果

我们发现高剂量放疗和免疫疗法相结合的治疗具有75％的完整病理反应，并显着改善了生存结果，是非常有效的方法。我们发现CD8 + T细胞和巨噬细胞对于联合治疗的全部效果都是必需的，T淋巴细胞似乎在早期发挥作用，而巨噬细胞则在联合治疗的后期发挥作用。放射治疗似乎会触发巨噬细胞复极化，从而增加M1 / M2比。

结论

这些发现指向放射疗法和免疫疗法之间相互作用的基础的新型免疫学机制。它们还为结合新的高级别神经胶质瘤的潜在治疗方法，结合免疫检查点阻滞的免疫原性剂量放射临床研究提供了基础。