Abstract

Background

Diffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem.

Methods

Syngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models.

Results

Expression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity.

Conclusions

Virus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.

中文翻译：

---

Ad-CD40L 动员 CD4 T 细胞治疗脑干肿瘤。

摘要

背景

弥漫性中线胶质瘤，以前称为 DIPG（弥漫性内在桥脑胶质瘤），是最致命的儿童脑干肿瘤，中位生存期不到一年。在这里，我们研究了（i）将表达腺病毒的分化簇（CD）40配体（Ad-CD40L）直接递送至脑干肿瘤是否会诱导免疫介导的肿瘤清除，以及（ii）如果是这样，治疗是否与由于脑干中免疫介导的炎症而产生的可控制的毒性。

方法

用 Ad-CD40L 治疗免疫活性小鼠脑干中的同基因胶质瘤，并测定存活率、毒性和免疫特征。临床可翻译载体 rAd-Δ24-CD40L 的复制将严格限制在肿瘤细胞内，并在人类患者来源的弥漫性中线神经胶质瘤和免疫活性模型中进行了测试。

结果

Ad-CD40L 的表达仅限于脑干胶质瘤，感染前诱导完全排斥，与免疫细胞浸润相关，其中 CD4+ T 细胞对于治疗至关重要。将 Ad-CD40L 直接瘤内注射到已形成的脑干肿瘤中可以提高存活率并诱导一些完全治愈，但具有一些急性毒性。RNA 测序分析表明，Ad-CD40L 疗法可诱导与白细胞介素 (IL)-6、IL-1β 和肿瘤坏死因子 α 相关的神经炎症免疫反应。因此，为了生成复制和转基因表达严格限制在肿瘤细胞内的载体，我们构建了rAd-Δ24-CD40L，其骨架已进入弥漫性中线神经胶质瘤的临床试验。直接瘤内注射 rAd-Δ24-CD40L，并全身阻断 IL-6 和 IL-1β，产生了大量治愈病例，且毒性易于控制。

结论

病毒介导的 CD40L 递送有可能有效治疗弥漫性中线神经胶质瘤，且不会产生与神经炎症相关的毒性。