Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors

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

Pangenomic Classification of Pituitary Neuroendocrine Tumors

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解建国治疗癌症常用药对经验述要

解建国教授是国家级名老中医、辽宁省首届名中医,从事中医药治疗疑难顽怪病的临床及科研工作40余载。临床用药喜用药对,擅用药对。文章介绍解建国教授运用药对治疗癌症的经验。解老师临床治疗癌症,整体上以扶正缩瘤药对为基础,结合病变脏腑功能不同,以各脏腑药对为辅,同时结合病变症状表现不同,佐以对症效药药对。其所用药对之性味归经、剂量配比皆有深意,是充分考虑癌病及其病机特点,精研药物功效配伍,并通过长期临床实践所成的宝贵经验。特色鲜明,疗效确切,故加以总结整理,以飨同道。