采用 Ad-TK 和 Ad-Flt3L 的联合细胞毒性和免疫刺激基因治疗：从啮齿动物到神经胶质瘤患者的转化发展。
Combined cytotoxic and immune-stimulatory gene therapy using Ad-TK and Ad-Flt3L: Translational developments from rodents to glioma patients.
机构信息
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48108, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48108, USA; Rogel Cancer Centre, University of Michigan Medical School, Ann Arbor, MI 48108, USA.
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48108, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48108, USA; Rogel Cancer Centre, University of Michigan Medical School, Ann Arbor, MI 48108, USA; Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI 48108, USA.
出版信息
Mol Ther. 2023 Oct 4;31(10):2839-2860. doi: 10.1016/j.ymthe.2023.08.009. Epub 2023 Aug 12.
Gliomas are the most prevalent and devastating primary malignant brain tumors in adults. Despite substantial advances in understanding glioma biology, there have been no regulatory drug approvals in the US since bevacizumab in 2009 and tumor treating fields in 2011. Recent phase III clinical trials have failed to meet their prespecified therapeutic primary endpoints, highlighting the need for novel therapies. The poor prognosis of glioma patients, resistance to chemo-radiotherapy, and the immunosuppressive tumor microenvironment underscore the need for the development of novel therapies. Gene therapy-based immunotherapeutic strategies that couple the ability of the host immune system to specifically kill glioma cells and develop immunological memory have shown remarkable progress. Two adenoviral vectors expressing Ad-HSV1-TK/GCV and Ad-Flt3L have shown promising preclinical data, leading to FDA approval of a non-randomized, phase I open-label, first in human trial to test safety, cytotoxicity, and immune-stimulatory efficiency in high-grade glioma patients (NCT01811992). This review provides a thorough overview of immune-stimulatory gene therapy highlighting recent advancements, potential drawbacks, future directions, and recommendations for future implementation of clinical trials.
神经胶质瘤是成年人中最常见和最具破坏性的原发性恶性脑肿瘤。尽管对神经胶质瘤生物学的理解有了很大的进展，但自 2009 年贝伐单抗和 2011 年肿瘤治疗电场以来，美国还没有监管药物批准。最近的三期临床试验未能达到其预设的治疗主要终点，这凸显了需要新的治疗方法。神经胶质瘤患者预后不良、对化疗和放疗的耐药性以及免疫抑制性肿瘤微环境都强调了需要开发新的治疗方法。基于基因治疗的免疫治疗策略，结合了宿主免疫系统特异性杀伤神经胶质瘤细胞的能力，并能产生免疫记忆，已经取得了显著的进展。两种表达 Ad-HSV1-TK/GCV 和 Ad-Flt3L 的腺病毒载体已经显示出有前途的临床前数据，这导致了 FDA 批准了一项非随机、一期、开放标签、首次人体试验，以测试高危神经胶质瘤患者的安全性、细胞毒性和免疫刺激效率（NCT01811992）。这篇综述全面概述了免疫刺激基因治疗，强调了最近的进展、潜在的缺点、未来的方向以及对临床试验未来实施的建议。
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