Lowenstein P R, Castro M G
The Medical School, The University of Michigan, Ann Arbor, MI, United States.
The Medical School, The University of Michigan, Ann Arbor, MI, United States.
Adv Pharmacol. 2016;76:147-73. doi: 10.1016/bs.apha.2016.03.002. Epub 2016 Apr 23.
Malignant brain tumors are one of the most lethal cancers. They originate from glial cells which infiltrate throughout the brain. Current standard of care involves surgical resection, radiotherapy, and chemotherapy; median survival is currently ~14-20 months postdiagnosis. Given that the brain immune system is deficient in priming systemic immune responses to glioma antigens, we proposed to reconstitute the brain immune system to achieve immunological priming from within the brain. Two adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1-derived thymidine kinase which converts ganciclovir into a compound only cytotoxic to dividing glioma cells. The second adenovirus expresses the cytokine fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L differentiates precursors into dendritic cells and acts as a chemokine that attracts dendritic cells to the brain. HSV-1/ganciclovir killing of tumor cells releases tumor antigens that are taken up by dendritic cells within the brain tumor microenvironment. Tumor killing also releases HMGB1, an endogenous TLR2 agonist that activates dendritic cells. HMGB1-activated dendritic cells, loaded with glioma antigens, migrate to cervical lymph nodes to stimulate a systemic CD8+ T cells cytotoxic immune response against glioma. This immune response is specific to glioma tumors, induces immunological memory, and does neither cause brain toxicity nor autoimmune responses. An IND was granted by the FDA on 4/7/2011. A Phase I, first in person trial, to test whether reengineering the brain immune system is potentially therapeutic is ongoing.
恶性脑肿瘤是最致命的癌症之一。它们起源于浸润整个大脑的神经胶质细胞。目前的标准治疗方法包括手术切除、放疗和化疗；确诊后的中位生存期目前约为14 - 20个月。鉴于大脑免疫系统在启动针对胶质瘤抗原的全身免疫反应方面存在缺陷，我们提议重建大脑免疫系统，以在脑内实现免疫启动。将两种腺病毒载体注入切除腔或残留肿瘤中。一种腺病毒载体表达源自单纯疱疹病毒1型（HSV-1）的胸苷激酶，该酶将更昔洛韦转化为仅对分裂的胶质瘤细胞具有细胞毒性的化合物。第二种腺病毒表达细胞因子fms样酪氨酸激酶3配体（Flt3L）。Flt3L将前体细胞分化为树突状细胞，并作为趋化因子吸引树突状细胞进入大脑。HSV-1/更昔洛韦对肿瘤细胞的杀伤作用释放出肿瘤抗原，这些抗原被脑肿瘤微环境中的树突状细胞摄取。肿瘤杀伤还释放出高迁移率族蛋白B1（HMGB1），一种激活树突状细胞的内源性Toll样受体2（TLR2）激动剂。HMGB1激活的、负载胶质瘤抗原的树突状细胞迁移至颈淋巴结，以刺激针对胶质瘤的全身性细胞毒性CD8 + T细胞免疫反应。这种免疫反应对胶质瘤肿瘤具有特异性，可诱导免疫记忆，且既不会引起脑毒性也不会引发自身免疫反应。2011年4月7日，美国食品药品监督管理局（FDA）授予了该研究的研究性新药（IND）申请许可。一项旨在测试重建大脑免疫系统是否具有潜在治疗作用的I期人体首次试验正在进行中。
