Banerjee Kaushik, Núñez Felipe J, Haase Santiago, McClellan Brandon L, Faisal Syed M, Carney Stephen V, Yu Jin, Alghamri Mahmoud S, Asad Antonela S, Candia Alejandro J Nicola, Varela Maria Luisa, Candolfi Marianela, Lowenstein Pedro R, Castro Maria G
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States.
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States.
Front Mol Neurosci. 2021 Mar 11;14:621831. doi: 10.3389/fnmol.2021.621831. eCollection 2021.
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
胶质母细胞瘤（GBM）是成人中最常见且侵袭性最强的原发性脑肿瘤，预后极差。血脑屏障（BBB）药物递送效率低下、免疫抑制性肿瘤微环境（TME）以及耐药性的产生是胶质瘤治疗成功的关键障碍。由于胶质瘤是通过一系列基因改变逐步发生的，能够修饰靶细胞基因组成的基因治疗似乎是克服当前治疗策略所面临障碍的一种有前景的方法。基因治疗是一个快速发展的领域，其最终目标是使用病毒或非病毒递送载体实现治疗分子的特异性递送。基因治疗还可用于增强对肿瘤抗原的免疫反应，对TME进行重新编程以阻断胶质瘤介导的免疫抑制并使血管生成正常化。目前正在研发纳米颗粒介导的基因治疗以克服BBB用于胶质瘤治疗。增强抗胶质瘤疗效的另一种方法是使用溶瘤病毒进行病毒免疫治疗，溶瘤病毒具有免疫原性。溶瘤病毒由于癌细胞特异性的病毒复制而杀死肿瘤细胞，并且还可引发抗肿瘤免疫。然而，脱靶效应以及治疗和转导效率方面仍存在担忧。在本综述中，我们描述了临床和临床前研究中针对胶质瘤的当前基因治疗方法的原理、策略以及优缺点。这包括由病毒和非病毒递送平台组成的不同递送系统，以及自杀/前药、溶瘤、细胞因子和肿瘤抑制因子介导的基因治疗方法。此外，还讨论了通过破坏BBB的基因治疗和抗表皮生长因子受体变体III/血管内皮生长因子受体基因治疗在胶质瘤治疗方面的进展。最后，我们讨论了基因治疗介导的胶质瘤人体临床试验结果。总之，我们强调了基因治疗的进展、前景和 remaining challenges，旨在拓宽我们的理解并突出GBM的治疗手段。 （注：原文中“remaining challenges”未翻译完整，推测可能是“剩余挑战”之类的意思，但按要求需完全按照原文翻译）
