Evolutionary basis of a new gene- and immune-therapeutic approach for the treatment of malignant brain tumors: from mice to clinical trials for glioma patients.
Evolutionary basis of a new gene- and immune-therapeutic approach for the treatment of malignant brain tumors: from mice to clinical trials for glioma patients.
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DOI：
10.1016/j.clim.2017.07.006
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Castro MG
中科院分区：
文献类型：
--
作者：
Lowenstein PR;Castro MG
胶质瘤细胞是最具侵袭性的恶性肿瘤之一。在最初的手术和放化疗后，它们进展迅速，因此患者的中位生存期仍然不到两年。它们侵入整个大脑，这使得它们难以治疗，并且通常是致命的。虽然总是尝试全切除，但不能治愈。2016年的标准治疗包括手术切除、放疗和化疗（替莫唑胺）。目前中位生存期约为诊断后14-20个月，但在高复杂性的医学大学中心或临床试验中可能更高。为什么免疫系统不能识别日益增长的脑肿瘤还不完全清楚。我们认为，这种失败的一个原因是大脑缺乏树突状细胞在其他器官中发挥作用的细胞。大脑中功能性树突状细胞的缺乏导致大脑缺乏对胶质瘤抗原的系统性免疫反应。为了克服这个缺点，我们重建了大脑免疫系统，使其能够从大脑内部启动和启动抗胶质瘤免疫反应。为了实现脑免疫重建，将腺病毒载体注入切除腔或剩余肿瘤。一种腺病毒载体表达HSV-1衍生的胸苷激酶，将更昔洛韦转化为磷更昔洛韦，对分裂的细胞具有细胞毒性。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，然后被Flt3L招募到脑肿瘤微环境的树突状细胞吸收。同时释放HMGB1，一种激活树突状细胞的TLR2激动剂，刺激装载胶质瘤抗原的树突状细胞迁移到颈部淋巴结，启动系统性CD8+ T细胞毒性杀死脑肿瘤细胞。这种诱导的免疫反应引起胶质瘤特异性细胞毒性，诱导免疫记忆，而不引起脑毒性或自身免疫。2013年12月，一项I期临床试验在人类患者中验证了我们的假设（见：NCT01811992，细胞毒和免疫刺激联合治疗胶质瘤，ClinicalTrials.gov）。这项试验是第一次人体试验，旨在测试重新设计大脑免疫系统是否可以用于治疗恶性脑肿瘤。从实验室到临床试验的漫长而曲折的道路如下。
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 ~14–20 months 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 phosphoganciclovir 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 person trial to test the 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.
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影响因子：
4.8
作者：
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通讯作者：
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12.7
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影响因子：
4.8
作者：
Candolfi, Marianela;King, Gwendalyn D.;Castro, Maria G.
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影响因子：
3.3
作者：
BYRNES, AP;RUSBY, JE;CHARLTON, HM
通讯作者：
CHARLTON, HM
影响因子：
3.3
作者：
Bell, MD;Taub, DD;Perry, VH
通讯作者：
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