Advances and Potential Pitfalls of Oncolytic Viruses Expressing Immunomodulatory Transgene Therapy for Malignant Gliomas Qing Zhang1,2,3 and Fusheng Liu1,2,3

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Advances and Potential Pitfalls of Oncolytic Viruses Expressing Immunomodulatory Transgene Therapy for Malignant Gliomas Qing Zhang1,2,3 and Fusheng Liu1,2,3 Zhang and Liu Cell Death and Disease (2020) 11:485 https://doi.org/10.1038/s41419-020-2696-5 Cell Death & Disease REVIEW ARTICLE Open Access Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas Qing Zhang1,2,3 and Fusheng Liu1,2,3 Abstract Glioblastoma (GBM) is an immunosuppressive, lethal brain tumor. Despite advances in molecular understanding and therapies, the clinical benefits have remained limited, and the life expectancy of patients with GBM has only been extended to ~15 months. Currently, genetically modified oncolytic viruses (OV) that express immunomodulatory transgenes constitute a research hot spot in the field of glioma treatment. An oncolytic virus is designed to selectively target, infect, and replicate in tumor cells while sparing normal tissues. Moreover, many studies have shown therapeutic advantages, and recent clinical trials have demonstrated the safety and efficacy of their usage. However, the therapeutic efficacy of oncolytic viruses alone is limited, while oncolytic viruses expressing immunomodulatory transgenes are more potent inducers of immunity and enhance immune cell-mediated antitumor immune responses in GBM. An increasing number of basic studies on oncolytic viruses encoding immunomodulatory transgene therapy for malignant gliomas have yielded beneficial outcomes. Oncolytic viruses that are armed with immunomodulatory transgenes remain promising as a therapy against malignant gliomas and will undoubtedly provide new insights into possible clinical uses or strategies. In this review, we summarize the research advances related to oncolytic viruses that express immunomodulatory transgenes, as well as potential treatment pitfalls in patients with malignant gliomas. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Facts Open questions 1. Oncolytic virus-encoded immunomodulatory 1. Can the immune system attack and engulf transgene therapy for gliomas has yielded beneficial exogenous viruses? outcomes. 2. Are glioma stem cells resistant to viral therapy? 2. Oncolytic virus and tumor-targeting immune 3. Can the presence of nontumor cells such as tumor modulatory therapies have shown synergistic stroma cells impede the spread of oncolytic viruses? inhibition of malignant gliomas. 4. In personalized medicine, should potential 3. Oncolytic virus immunotherapy of malignant challenges be considered for the treatment of gliomas has been used in clinical trials. patients with malignant gliomas? 4. The combination of stem cell carriers with oncolytic virus therapy for gliomas enhances antitumor efficacy. Introduction Glioblastoma (GBM) is both the most aggressive and lethal malignant brain tumor in adults and accounts for Correspondence: Qing Zhang ([email protected])or more than 30% of intracranial tumors1,2. Current standard Fu-sheng Liu ([email protected]) 1Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical treatment options for malignant gliomas are multimodal University, Beijing 100070, China and include surgical resection, postoperative radio- 2 fi Department of Neurosurgery, Beijing Tiantan Hospital Af liated to Capital therapy, and concomitant chemotherapy with temozolo- Medical University, Beijing 100070, China 1,3,4 Full list of author information is available at the end of the article mide . Due to the invasive growth and recurrence Edited by T. Kaufmann © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Zhang and Liu Cell Death and Disease (2020) 11:485 Page 2 of 11 features of malignant gliomas, the prognosis for patients nontoxic prodrugs into toxic prodrugs22,23. Our research with malignant gliomas remains extremely poor, with a team independently developed a novel oHSV-1 containing median survival of nearly 15 months for newly diagnosed the CD therapeutic gene. Moreover, a clinical trial using patients5,6. Thus, more specific, safe, and efficient treat- an engineered oHSV-1 (ON-01) injected intratumorally ment strategies are required. A growing body of pre- into patients with recurrent or refractory intracranial clinical and clinical data suggest that genetically malignant gliomas is currently ongoing at Beijing Tiantan engineered oncolytic viruses may be effective therapeutic Hospital (China Clinical Trials registration number: agents used in the treatment of malignant gliomas. ChiCTR1900022570). Oncolytic virus (OV) therapy is a novel and promising A preclinical study demonstrated that intratumoral therapeutic approach for tumors that involves selectively administration of OVs could drive the development of infecting and killing tumor cells. Prior research studies systemic antitumor immunity and result in elimination of demonstrated that αvβ3 integrin and nectin-1 are contralateral tumors24. Moreover, oncolytic virus- required for efficient infection of cells by herpesvirus and mediated destruction of the tumor tissues was closely adenovirus, respectively7,8, and the underlying mechanism related to robust stimulation of innate antiviral immune may involve OV-induced cell destruction by cancer- responses and adaptive antitumor T-cell responses25.To specific genetic alteration, as well as sequential virus further augment the antitumor effects, certain research release and viral infection. It was first reported that studies have transduced immunomodulatory therapeutic – – tumors could be inhibited or shrunk in patients with transgenes, such as IL-1526 28, IL-1229 32, IL-433,34, and cervical cancer and rabies virus positivity9. Researchers TRAIL35,36, via oncolytic virus, which can effectively found that a conditionally and genetically modified inhibit or kill tumor cells through the antitumor immune replication-competent oncolytic virus was selectively toxic response. Therefore, oncolytic viruses that encode – to tumor cells and nontoxic to normal cells10 12. Cassel immunomodulatory transgenes are gradually becoming a et al. reported that a genetically engineered oncolytic virus research hot spot in the field of glioma treatment. The was evaluated as an adjunctive therapeutic agent for gene required for oncolytic virus growth is typically patients with malignant melanoma13. Subsequently, placed under the control of a tumor-specific promoter or oncolytic viruses, including G207 and HSV1716, were enhancer. In 2019, Yan et al. constructed a novel used for clinical research in patients with malignant recombinant oncolytic adenovirus that expresses IL-15 gliomas in the USA and the UK14. In 2015, the FDA and under the control of the E2F-1 promoter; it was found approved the use of an oncolytic virus in the USA to treat that this novel adenovirus could selectively kill tumor cells patients with melanoma15. In addition, recent advances in and exhibit increased antitumor effects both in vitro and viral therapy, of which the most promising are perhaps in vivo26. Moreover, oncolytic viruses that were armed viruses such as DNX-2401, PVS-RIPO, and Toca 511, with immunomodulatory transgenes have been evaluated have shown complete durable responses in ~20% of GBM in several preclinical and clinical trials for the treatment of – patients who received virus intratumorally16 18. However, malignant gliomas. Genetically engineered virotherapy for the clinical trial did not meet its primary endpoints. These malignant gliomas has so far been proven safe and encouraging results obtained with PVS-RIPO, Toca 511, effective. Nevertheless, many innovative strategies are and DNX-2401 have been granted a fast track designation currently under development to improve intratumoral by the FDA for expedited drug review processes. viral expansion and antitumor efficacy without compro- Our research team previously found that the mising security. Overall, previous studies on genetically Endo–Angio fusion gene that is expressed in glioma stem engineered virotherapy with immunomodulatory trans- cells (GSCs) could be administered via infection by genes have resulted in breakthroughs regarding several oncolytic HSV-1, which carries an exogenous difficulties, which may contribute toward new insights Endo–Angio fusion gene19. Furthermore, Friedman et al. into future therapeutics for patients with malignant summarized the milestones of oncolytic viruses carrying gliomas. exogenous genes for cancer treatment20. In 2014, we also demonstrated that in animal models of human GSCs, an Research advancements oncolytic HSV-1 that encodes an endostatin–angiostatin Oncolytic viruses are a distinct class of antitumor agents fusion gene could greatly enhance antitumor efficacy with a unique mechanism of action that selectively compared to HSV-1 without the fusion gene by generat- replicate
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