Department of Neurosurgery, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States; Department of Cell and Developmental Biology, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States.
Department of Neurosurgery, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States; Department of Cell and Developmental Biology, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States.
Clin Immunol. 2018 Apr;189:43-51. doi: 10.1016/j.clim.2017.07.006. Epub 2017 Jul 15.
Glioma cells are one of the most aggressive and malignant tumors. Following initial surgery, and radio-chemotherapy they progress rapidly, so that patients' median survival remains under two years. They invade throughout the brain, which makes them difficult to treat, and are universally lethal. Though total resection is always attempted it is not curative. Standard of care in 2016 comprises surgical resection, radiotherapy and chemotherapy (temozolomide). Median survival is currently ~14-20months post-diagnosis though it can be higher in high complexity medical university centers, or during clinical trials. Why the immune system fails to recognize the growing brain tumor is not completely understood. We believe that one reason for this failure is that the brain lacks cells that perform the role that dendritic cells serve in other organs. The lack of functional dendritic cells from the brain causes the brain to be deficient in priming systemic immune responses to glioma antigens. To overcome this drawback we reconstituted the brain immune system for it to initiate and prime anti-glioma immune responses from within the brain. To achieve brain immune reconstitution 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 phospho-ganciclovir which becomes cytotoxic to dividing 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 for dendritic cells. This results in HSV-1/ganciclovir killing of tumor cells, and the release of tumor antigens, which are then taken up by dendritic cells recruited to the brain tumor microenvironment by Flt3L. Concomitant release of HMGB1, a TLR2 agonist that activates dendritic cells, stimulates dendritic cells loaded with glioma antigens to migrate to the cervical lymph nodes to prime a systemic CD8+ T cytotoxic killing of brain tumor cells. This induced immune response causes glioma-specific cytotoxicity, induces immunological memory, and does not cause brain toxicity or autoimmunity. A Phase I Clinical Trial, to test our hypothesis in human patients, was opened in December 2013 (see: NCT01811992, Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma, at ClinicalTrials.gov). This trial is a first in human trial to test whether the re-engineering of the brain immune system can serve to treat malignant brain tumors. The long and winding road from the laboratory to the clinical trial follows below.
神经胶质瘤细胞是最具侵袭性和恶性的肿瘤之一。在初始手术后和放化疗后，它们迅速进展，导致患者的中位生存期仍不到两年。它们在大脑中广泛浸润，这使得它们难以治疗，并且普遍致命。尽管总是尝试进行完全切除，但这并不能治愈疾病。2016 年的标准治疗包括手术切除、放疗和化疗（替莫唑胺）。目前，诊断后中位生存期约为 14-20 个月，但在高复杂度的医学中心或临床试验中可能更高。为什么免疫系统无法识别不断生长的脑肿瘤，目前还不完全清楚。我们认为，免疫失败的一个原因是大脑缺乏在其他器官中发挥树突状细胞作用的细胞。大脑缺乏功能性树突状细胞，导致大脑无法对脑肿瘤抗原产生系统免疫反应的初始和激活。为了克服这一缺陷，我们重建了大脑免疫系统，以便从大脑内部启动和激活针对脑肿瘤的免疫反应。为了实现大脑免疫重建，腺病毒载体被注入切除腔或残留肿瘤中。一种腺病毒载体表达 HSV-1 衍生的胸苷激酶，该激酶将更昔洛韦转化为磷酸更昔洛韦，从而对分裂细胞产生细胞毒性。第二种腺病毒表达细胞因子 fms 样酪氨酸激酶 3 配体（Flt3L）。Flt3L 将前体分化为树突状细胞，并作为树突状细胞的趋化因子。这导致 HSV-1/更昔洛韦杀死肿瘤细胞，并释放肿瘤抗原，然后由 Flt3L 募集到脑肿瘤微环境中的树突状细胞摄取。同时释放 TLR2 激动剂高迁移率族蛋白 B1（HMGB1），激活树突状细胞，刺激负载脑肿瘤抗原的树突状细胞迁移到颈淋巴结，以激活针对脑肿瘤细胞的全身性 CD8+T 细胞细胞毒性杀伤。这种诱导的免疫反应引起脑肿瘤特异性细胞毒性，诱导免疫记忆，并且不会引起脑毒性或自身免疫。一项 1 期临床试验于 2013 年 12 月（请参阅：NCT01811992，用于脑肿瘤的细胞毒性和免疫刺激联合治疗，在 ClinicalTrials.gov 上），旨在人类患者中测试我们的假设，现已开放。这是一项首例在人体中测试脑免疫系统重构是否可用于治疗恶性脑肿瘤的临床试验。从实验室到临床试验的漫长曲折道路如下。
