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Review

The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment

& ORCID Icon
Pages 1-27 | Published online: 24 Feb 2021

References

  • Sostoa J, Dutoit V, Migliorini D. Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors. Int J Mol Sci. 2020;21(20):20. doi:10.3390/ijms21207449
  • Bommareddy PK, Peters C, Saha D, Rabkin SD, Kaufman HL. Oncolytic Herpes Simplex Viruses as a Paradigm for the Treatment of Cancer. Ann Rev Cancer Biol. 2018;2(1):155–173.
  • Liu P, Wang Y, Wang Y, et al. Effects of oncolytic viruses and viral vectors on immunity in glioblastoma. Gene Ther. 2020.
  • Totsch SK, Schlappi C, Kang KD, et al. Oncolytic herpes simplex virus immunotherapy for brain tumors: current pitfalls and emerging strategies to overcome therapeutic resistance. Oncogene. 2019;38(34):6159–6171.
  • Hua L, Wakimoto H. Oncolytic herpes simplex virus therapy for malignant glioma: current approaches to successful clinical application. Expert Opin Biol Ther. 2019;19(8):845–854.
  • Martikainen M, Essand M. Virus-Based Immunotherapy of Glioblastoma. Cancers. 2019;11:2.
  • Rius-Rocabert S, Garcia-Romero N, Garcia A, Ayuso-Sacido A, Nistal-Villan E. Oncolytic Virotherapy in Glioma Tumors. Int J Mol Sci. 2020;21:20.
  • Chiocca EA, Nassiri F, Wang J, Peruzzi P, Zadeh G. Viral and other therapies for recurrent glioblastoma: is a 24-month durable response unusual? Neuro Oncol. 2019;21(1):14–25.
  • Saha D, Martuza RL, Curry WT. Viral oncolysis of glioblastoma. In: Reiss CS, editor. Neurotropic Viral Infections. Vol. 2. New York: Springer; 2016:481–517.
  • Saha D, Ahmed SS, Rabkin SD. Exploring the Antitumor Effect of Virus in Malignant Glioma. Drugs Future. 2015;40(11):739–749.
  • Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013–2017. Neuro Oncol. 2020;22(12Suppl2):iv1–iv96.
  • Stylli SS. Novel Treatment Strategies for Glioblastoma. Cancers. 2020;12:10.
  • Alayo QA, Ito H, Passaro C, et al. Glioblastoma infiltration of both tumor- and virus-antigen specific cytotoxic T cells correlates with experimental virotherapy responses. Sci Rep. 2020;10(1):5095.
  • Saha D, Wakimoto H, Rabkin SD. Oncolytic herpes simplex virus interactions with the host immune system. Curr Opin Virol. 2016;21:26–34.
  • Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33(25):2780–2788.
  • Glorioso JC, Cohen JB, Goins WF, et al. Oncolytic HSV Vectors and Anti-Tumor Immunity. Curr Issues Mol Biol. 2020;41:381–468.
  • Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science. 1991;252(5007):854–856.
  • Zhang Q, Liu F. Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas. Cell Death Dis. 2020;11(6):485.
  • He B, Gross M, Roizman B. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A. 1997;94(3):843–848.
  • Cassady KA, Gross M, Roizman B. The second-site mutation in the herpes simplex virus recombinants lacking the gamma134.5 genes precludes shutoff of protein synthesis by blocking the phosphorylation of eIF-2alpha. J Virol. 1998;72(9):7005–7011.
  • MacLean AR, Fareed M, Robertson L, Harland J, Brown SM. Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in Glasgow strain 17+ between immediate early gene 1 and the ‘a’ sequence. J Gen Virol. 1991;72(Pt 3):631–639.
  • Chou J, Kern ER, Whitley RJ, Roizman B. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science. 1990;250(4985):1262–1266.
  • McKie EA, MacLean AR, Lewis AD, et al. Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours–evaluation of a potentially effective clinical therapy. Br J Cancer. 1996;74(5):745–752.
  • Kesari S, Randazzo BP, Valyi-Nagy T, et al. Therapy of experimental human brain tumors using a neuroattenuated herpes simplex virus mutant. Lab Invest. 1995;73(5):636–648.
  • Advani SJ, Sibley GS, Song PY, et al. Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors. Gene Ther. 1998;5(2):160–165.
  • Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med. 1995;1(9):938–943.
  • Kanai R, Zaupa C, Sgubin D, et al. Effect of gamma34.5 deletions on oncolytic herpes simplex virus activity in brain tumors. J Virol. 2012;86(8):4420–4431.
  • Domenis R, Cesselli D, Toffoletto B, et al. Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells. PLoS One. 2017;12(1):e0169932.
  • Auffinger B, Spencer D, Pytel P, Ahmed AU, Lesniak MS. The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence. Expert Rev Neurother. 2015;15(7):741–752.
  • Deshors P, Toulas C, Arnauduc F, et al. Ionizing radiation induces endothelial transdifferentiation of glioblastoma stem-like cells through the Tie2 signaling pathway. Cell Death Dis. 2019;10(11):816.
  • Todo T, Martuza RL, Rabkin SD, Johnson PA. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc Natl Acad Sci U S A. 2001;98(11):6396–6401.
  • Wakimoto H, Kesari S, Farrell CJ, et al. Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res. 2009;69(8):3472–3481.
  • Cheema TA, Wakimoto H, Fecci PE, et al. Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci U S A. 2013;110(29):12006–12011.
  • Kambara H, Okano H, Chiocca EA, Saeki Y. An oncolytic HSV-1 mutant expressing ICP34.5 under control of a nestin promoter increases survival of animals even when symptomatic from a brain tumor. Cancer Res. 2005;65(7):2832–2839.
  • Chiocca EA, Nakashima H, Kasai K, Fernandez SA, Oglesbee M. Preclinical Toxicology of rQNestin34.5v.2: an Oncolytic Herpes Virus with Transcriptional Regulation of the ICP34.5 Neurovirulence Gene. Mol Ther Methods Clin Dev. 2020;17:871–893.
  • Cassady KA. Human cytomegalovirus TRS1 and IRS1 gene products block the double-stranded-RNA-activated host protein shutoff response induced by herpes simplex virus type 1 infection. J Virol. 2005;79(14):8707–8715.
  • Marshall EE, Bierle CJ, Brune W, Geballe AP. Essential role for either TRS1 or IRS1 in human cytomegalovirus replication. J Virol. 2009;83(9):4112–4120.
  • Friedman GK, Nan L, Haas MC, et al. gamma(1)34.5-deleted HSV-1-expressing human cytomegalovirus IRS1 gene kills human glioblastoma cells as efficiently as wild-type HSV-1 in normoxia or hypoxia. Gene Ther. 2015;22(4):348–355.
  • Shah AC, Parker JN, Gillespie GY, et al. Enhanced antiglioma activity of chimeric HCMV/HSV-1 oncolytic viruses. Gene Ther. 2007;14(13):1045–1054.
  • Ghonime MG, Jackson J, Shah A, et al. Chimeric HCMV/HSV-1 and Deltagamma134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory. Transl Oncol. 2018;11(1):86–93.
  • Cassady KA, Bauer DF, Roth J, et al. Pre-clinical Assessment of C134, a Chimeric Oncolytic Herpes Simplex Virus, in Mice and Non-human Primates. Mol Ther Oncolytics. 2017;5:1–10.
  • Uchida H, Marzulli M, Nakano K, et al. Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol Ther. 2013;21(3):561–569.
  • Xu H, Zong H, Ma C, et al. Epidermal growth factor receptor in glioblastoma. Oncol Lett. 2017;14(1):512–516.
  • Liu G, Ying H, Zeng G, Wheeler CJ, Black KL, Yu JS. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res. 2004;64(14):4980–4986.
  • Ahmed N, Salsman VS, Kew Y, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res. 2010;16(2):474–485.
  • Gambini E, Reisoli E, Appolloni I, et al. Replication-competent herpes simplex virus retargeted to HER2 as therapy for high-grade glioma. Mol Ther. 2012;20(5):994–1001.
  • Alessandrini F, Menotti L, Avitabile E, et al. Eradication of glioblastoma by immuno-virotherapy with a retargeted oncolytic HSV in a preclinical model. Oncogene. 2019;38(23):4467–4479.
  • Piwecka M, Rolle K, Belter A, et al. Comprehensive analysis of microRNA expression profile in malignant glioma tissues. Mol Oncol. 2015;9(7):1324–1340.
  • Mazzacurati L, Marzulli M, Reinhart B, et al. Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Mol Ther. 2015;23(1):99–107.
  • Grondin B, DeLuca N. Herpes simplex virus type 1 ICP4 promotes transcription preinitiation complex formation by enhancing the binding of TFIID to DNA. J Virol. 2000;74(24):11504–11510.
  • Sette P, Amankulor N, Li A, et al. GBM-Targeted oHSV Armed with Matrix Metalloproteinase 9 Enhances Anti-tumor Activity and Animal Survival. Mol Ther Oncolytics. 2019;15:214–222.
  • Lemos Matos A, Franco LS, McFadden G. Oncolytic Viruses and the Immune System: the Dynamic Duo. Mol Ther Methods Clin Dev. 2020;17:349–358.
  • Berraondo P, Etxeberria I, Ponz-Sarvise M, Melero I. Revisiting Interleukin-12 as a Cancer Immunotherapy Agent. Clin Cancer Res. 2018;24(12):2716–2718.
  • Nguyen HM, Guz-Montgomery K, Saha D. Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy. Cells. 2020;9:2.
  • Roth JC, Cassady KA, Cody JJ, et al. Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to aotus nonhuman primates. Hum Gene Ther Clin Dev. 2014;25(1):16–27.
  • Nguyen KG, Vrabel MR, Mantooth SM, et al. Localized Interleukin-12 for Cancer Immunotherapy. Front Immunol. 2020;11:575597.
  • Zhang W, Fulci G, Wakimoto H, et al. Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models. Neoplasia. 2013;15(6):591–599.
  • Friedman GK, Bernstock JD, Chen D, et al. Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression. Sci Rep. 2018;8(1):13930.
  • Markert JM, Cody JJ, Parker JN, et al. Preclinical evaluation of a genetically engineered herpes simplex virus expressing interleukin-12. J Virol. 2012;86(9):5304–5313.
  • Barnard Z, Wakimoto H, Zaupa C, et al. Expression of FMS-like tyrosine kinase 3 ligand by oncolytic herpes simplex virus type I prolongs survival in mice bearing established syngeneic intracranial malignant glioma. Neurosurgery. 2012;71(3):741–748.
  • Tamura K, Wakimoto H, Agarwal AS, et al. Multimechanistic tumor targeted oncolytic virus overcomes resistance in brain tumors. Mol Ther. 2013;21(1):68–77.
  • Jahan N, Lee JM, Shah K, Wakimoto H. Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus. Int J Cancer. 2017;141(8):1671–1681.
  • Rozanov DV, Savinov AY, Golubkov VS, et al. Engineering a leucine zipper-TRAIL homotrimer with improved cytotoxicity in tumor cells. Mol Cancer Ther. 2009;8(6):1515–1525.
  • Kretz AL, Trauzold A, Hillenbrand A, et al. TRAILblazing Strategies for Cancer Treatment. Cancers. 2019;11:4.
  • Zhang G, Jin G, Nie X, et al. Enhanced antitumor efficacy of an oncolytic herpes simplex virus expressing an endostatin-angiostatin fusion gene in human glioblastoma stem cell xenografts. PLoS One. 2014;9(4):e95872.
  • Tomita Y, Kurozumi K, Yoo JY, et al. Oncolytic Herpes Virus Armed with Vasculostatin in Combination with Bevacizumab Abrogates Glioma Invasion via the CCN1 and AKT Signaling Pathways. Mol Cancer Ther. 2019;18(8):1418–1429.
  • Zhang W, Fulci G, Buhrman JS, et al. Bevacizumab with angiostatin-armed oHSV increases antiangiogenesis and decreases bevacizumab-induced invasion in U87 glioma. Mol Ther. 2012;20(1):37–45.
  • Bolyard C, Meisen WH, Banasavadi-Siddegowda Y, et al. BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy. Clin Cancer Res. 2017;23(7):1809–1819.
  • Brush MH, Weiser DC, Shenolikar S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol. 2003;23(4):1292–1303.
  • Rojas M, Vasconcelos G, Dever TE. An eIF2alpha-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2alpha. Proc Natl Acad Sci U S A. 2015;112(27):E3466–3475.
  • Peters C, Paget M, Tshilenge KT, et al. Restriction of Replication of Oncolytic Herpes Simplex Virus with a Deletion of gamma34.5 in Glioblastoma Stem-Like Cells. J Virol. 2018;92:15.
  • Nakashima H, Nguyen T, Kasai K, et al. Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma. Clin Cancer Res. 2018;24(11):2574–2584.
  • Wieder T, Eigentler T, Brenner E, Rocken M. Immune checkpoint blockade therapy. J Allergy Clin Immunol. 2018;142(5):1403–1414.
  • Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39.
  • Filley AC, Henriquez M, Dey M. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget. 2017;8(53):91779–91794.
  • Reardon DA, Freeman G, Wu C, et al. Immunotherapy advances for glioblastoma. Neuro Oncol. 2014;16(11):1441–1458.
  • Khasraw M, Reardon DA, Weller M, Sampson JH. PD-1 Inhibitors: do they have a Future in the Treatment of Glioblastoma? Clin Cancer Res. 2020;26(20):5287–5296.
  • Lin C, Ren W, Luo Y, et al. Intratumoral Delivery of a PD-1-Blocking scFv Encoded in Oncolytic HSV-1 Promotes Antitumor Immunity and Synergizes with TIGIT Blockade. Cancer Immunol Res. 2020;8(5):632–647.
  • Passaro C, Alayo Q, De Laura I, et al. Arming an Oncolytic Herpes Simplex Virus Type 1 with a Single-chain Fragment Variable Antibody against PD-1 for Experimental Glioblastoma Therapy. Clin Cancer Res. 2019;25(1):290–299.
  • Kim Y, Yoo JY, Lee TJ, et al. Complex role of NK cells in regulation of oncolytic virus-bortezomib therapy. Proc Natl Acad Sci U S A. 2018;115(19):4927–4932.
  • Bhargava AK, Rothlauf PW, Krummenacher C. Herpes simplex virus glycoprotein D relocates nectin-1 from intercellular contacts. Virology. 2016;499:267–277.
  • Muller-Durovic B, Lanna A, Covre LP, Mills RS, Henson SM, Akbar AN. Killer Cell Lectin-like Receptor G1 Inhibits NK Cell Function through Activation of Adenosine 5ʹ-Monophosphate-Activated Protein Kinase. J Immunol. 2016;197(7):2891–2899.
  • Katsunuma S, Honda H, Shinoda T, et al. Synergistic action of nectins and cadherins generates the mosaic cellular pattern of the olfactory epithelium. J Cell Biol. 2016;212(5):561–575.
  • Xu B, Ma R, Russell L, et al. An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma. Nat Biotechnol. 2018.
  • Dmitrieva N, Yu L, Viapiano M, et al. Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy. Clin Cancer Res. 2011;17(6):1362–1372.
  • Tsidulko AY, Kazanskaya GM, Volkov AM, et al. Chondroitin sulfate content and decorin expression in glioblastoma are associated with proliferative activity of glioma cells and disease prognosis. Cell Tissue Res. 2020;379(1):147–155.
  • Kim Y, Lee HG, Dmitrieva N, Kim J, Kaur B, Friedman A. Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and anti tumor efficacy: a mathematical model. PLoS One. 2014;9(7):e102499.
  • Jaime-Ramirez AC, Dmitrieva N, Yoo JY, et al. Humanized chondroitinase ABC sensitizes glioblastoma cells to temozolomide. J Gene Med. 2017;19:3.
  • Alvarez-Garcia V, Tawil Y, Wise HM, Leslie NR. Mechanisms of PTEN loss in cancer: it’s all about diversity. Semin Cancer Biol. 2019;59:66–79.
  • Han F, Hu R, Yang H, et al. PTEN gene mutations correlate to poor prognosis in glioma patients: a meta-analysis. Onco Targets Ther. 2016;9:3485–3492.
  • Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep. 2020;47(6):4587–4629.
  • Russell L, Swanner J, Jaime-Ramirez AC, et al. PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance. Nat Commun. 2018;9(1):5006.
  • Mou X, Zhou Y, Jiang P, et al. The regulatory effect of UL-16 binding protein-3 expression on the cytotoxicity of NK cells in cancer patients. Sci Rep. 2014;4:6138.
  • Haberthur K, Brennan K, Hoglund V, et al. NKG2D ligand expression in pediatric brain tumors. Cancer Biol Ther. 2016;17(12):1253–1265.
  • Wirsching HG, Zhang H, Szulzewsky F, et al. Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma. JCI Insight. 2019;4:13.
  • Wirsching HG, Arora S, Zhang H, et al. Cooperation of oncolytic virotherapy with VEGF-neutralizing antibody treatment in IDH wildtype glioblastoma depends on MMP9. Neuro Oncol. 2019;21(12):1607–1609.
  • Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol. 2005;169(4):681–691.
  • Hicks A, Grandi P, Paglia M, et al. Abstract 4698: ONCR-1, a novel herpes simplex virus expressing MMP9 and ULBP3 transgenes, evokes potent oncolysis and development of antitumor immune responses. Cancer Res. 2018;78(13Supplement):4698.
  • Tyminski E, Leroy S, Terada K, et al. Brain tumor oncolysis with replication-conditional herpes simplex virus type 1 expressing the prodrug-activating genes, CYP2B1 and secreted human intestinal carboxylesterase, in combination with cyclophosphamide and irinotecan. Cancer Res. 2005;65(15):6850–6857.
  • Kasai K, Nakashima H, Liu F, et al. Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs. Mol Ther Nucleic Acids. 2013;2:e113. doi:10.1038/mtna.2013.38
  • Markert JM, Razdan SN, Kuo H-C, et al. A Phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Therapy. 2014;22(5):1048–1055. doi:10.1038/mt.2014.22
  • Kicielinski KP, Chiocca EA, Yu JS, Gill GM, Coffey M, Markert JM. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol Ther. 2014;22(5):1056–1062.
  • Forsyth P, Roldan G, George D, et al. A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas. Mol Ther. 2008;16(3):627–632.
  • Parker Kerrigan BC, Shimizu Y, Andreeff M, Lang FF. Mesenchymal stromal cells for the delivery of oncolytic viruses in gliomas. Cytotherapy. 2017;19(4):445–457.
  • Chaichana KL, Pinheiro L, Brem H. Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas. Ther Deliv. 2015;6(3):353–369.
  • Sonabend AM, Ulasov IV, Tyler MA, Rivera AA, Mathis JM, Lesniak MS. Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells. 2008;26(3):831–841.
  • Duebgen M, Martinez-Quintanilla J, Tamura K, et al. Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy. J Natl Cancer Inst. 2014;106(6):dju090.
  • Martinez-Quintanilla J, Shah K. Response. J Natl Cancer Inst. 2015;107(1):370.
  • Krause MN, Sancho-Martinez I, Izpisua Belmonte JC. RE: stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy. J Natl Cancer Inst. 2015;107(1):368.
  • Duhrsen L, Hartfuss S, Hirsch D, et al. Preclinical analysis of human mesenchymal stem cells: tumor tropism and therapeutic efficiency of local HSV-TK suicide gene therapy in glioblastoma. Oncotarget. 2019;10(58):6049–6061.
  • Pastorakova A, Jakubechova J, Altanerova U, Altaner C. Suicide Gene Therapy Mediated with Exosomes Produced by Mesenchymal Stem/Stromal Cells Stably Transduced with HSV Thymidine Kinase. Cancers. 2020;12:5.
  • Wei D, Hou J, Zheng K, et al. Suicide Gene Therapy Against Malignant Gliomas by the Local Delivery of Genetically Engineered Umbilical Cord Mesenchymal Stem Cells as Cellular Vehicles. Curr Gene Ther. 2019;19(5):330–341.
  • Karachi A, Dastmalchi F, Mitchell D, Rahman M. Temozolomide for Immunomodulation in the Treatment of Glioblastoma. Neuro Oncol. 2018.
  • Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016;3(3):198–210.
  • Yip S, Miao J, Cahill DP, et al. MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res. 2009;15(14):4622–4629.
  • Kanai R, Rabkin SD, Yip S, et al. Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells. J Natl Cancer Inst. 2012;104(1):42–55.
  • Saha D, Rabkin SD, Martuza RL. Temozolomide antagonizes oncolytic immunovirotherapy in glioblastoma. J Immunother Cancer. 2020;8:1.
  • Kleijn A, van den Bossche W, Haefner ES, et al. The Sequence of Delta24-RGD and TMZ Administration in Malignant Glioma Affects the Role of CD8(+)T Cell Anti-tumor Activity. Mol Ther Oncolytics. 2017;5:11–19.
  • Das S, Marsden PA. Angiogenesis in glioblastoma. N Engl J Med. 2013;369(16):1561–1563.
  • Vollmann-Zwerenz A, Leidgens V, Feliciello G, Klein CA, Hau P. Tumor Cell Invasion in Glioblastoma. Int J Mol Sci. 2020;21:6.
  • Lu L, Saha D, Martuza RL, Rabkin SD, Wakimoto H. Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma. J Neurooncol. 2015;121(1):91–100.
  • Vredenburgh JJ, Desjardins A, Herndon JE, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253–1259.
  • Gilbert MR, Dignam JJ, Armstrong TS, et al. A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma. N Eng J Med. 2014;370(8):699–708.
  • Saha D, Wakimoto H, Peters CW, Antoszczyk SJ, Rabkin SD, Martuza RL. Combinatorial Effects of VEGFR Kinase Inhibitor Axitinib and Oncolytic Virotherapy in Mouse and Human Glioblastoma Stem-Like Cell Models. Clin Cancer Res. 2018;24(14):3409–3422.
  • Piao Y, Liang J, Holmes L, et al. Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro Oncol. 2012;14(11):1379–1392.
  • Ishida J, Onishi M, Kurozumi K, et al. Integrin inhibitor suppresses bevacizumab-induced glioma invasion. Transl Oncol. 2014;7(2):292–302.
  • Hardcastle J, Kurozumi K, Dmitrieva N, et al. Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1. Mol Ther. 2010;18(2):285–294.
  • Ning J, Wakimoto H, Peters C, Martuza RL, Rabkin SD. Rad51 Degradation: role in Oncolytic Virus-Poly(ADP-Ribose) Polymerase Inhibitor Combination Therapy in Glioblastoma. J Natl Cancer Inst. 2017;109(3):1–13.
  • Otsuki A, Patel A, Kasai K, et al. Histone Deacetylase Inhibitors Augment Antitumor Efficacy of Herpes-based Oncolytic Viruses. Mol Ther. 2008;16(9):1546–1555.
  • Gallinari P, Marco SD, Jones P, Pallaoro M, Steinkühler C. HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res. 2007;17(3):195–211.
  • Alvarez-Breckenridge CA, Yu J, Price R, et al. The histone deacetylase inhibitor valproic acid lessens NK cell action against oncolytic virus-infected glioblastoma cells by inhibition of STAT5/T-BET signaling and generation of gamma interferon. J Virol. 2012;86(8):4566–4577.
  • Nakashima H, Kaufmann JK, Wang PY, et al. Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma. J Clin Invest. 2015;125(11):4269–4280.
  • Areeb Z, Stylli SS, Ware TM, et al. Inhibition of glioblastoma cell proliferation, migration and invasion by the proteasome antagonist carfilzomib. Med Oncol. 2016;33(5):53.
  • Vlachostergios PJ, Voutsadakis IA, Papandreou CN. The shaping of invasive glioma phenotype by the ubiquitin-proteasome system. Cell Commun Adhes. 2013;20(5):87–92.
  • Yoo JY, Hurwitz BS, Bolyard C, et al. Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic antitumor effects. Clin Cancer Res. 2014;20(14):3787–3798.
  • Yoo JY, Jaime-Ramirez AC, Bolyard C, et al. Bortezomib Treatment Sensitizes Oncolytic HSV-1–Treated Tumors to NK Cell Immunotherapy. Clin Cancer Res. 2016;22(21):5265–5276.
  • Marhaba R, Nazarenko I, Knofler D, et al. Opposing effects of fibrosarcoma cell-derived IL-1 alpha and IL-1 beta on immune response induction. Int J Cancer. 2008;123(1):134–145.
  • Mishra R, Polic B, Welsh RM, Szomolanyi-Tsuda E. Inflammatory cytokine-mediated evasion of virus-induced tumors from NK cell control. J Immunol. 2013;191(2):961–970.
  • Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Autocrine MK. TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell. 2009;5(5):504–514.
  • Esaki S, Nigim F, Moon E, et al. Blockade of transforming growth factor-beta signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models. Int J Cancer. 2017;141(11):2348–2358.
  • Wick A, Desjardins A, Suarez C, et al. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma. Invest New Drugs. 2020.
  • Bazzoni R, Bentivegna A. Role of Notch Signaling Pathway in Glioblastoma Pathogenesis. Cancers. 2019;11:3.
  • Otani Y, Yoo JY, Chao S, et al. Oncolytic HSV-Infected Glioma Cells Activate NOTCH in Adjacent Tumor Cells Sensitizing Tumors to Gamma Secretase Inhibition. Clin Cancer Res. 2020;26(10):2381–2392.
  • Huck L, Pontier SM, Zuo DM, Muller WJ. beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression. Proc Natl Acad Sci U S A. 2010;107(35):15559–15564.
  • Carbonell WS, DeLay M, Jahangiri A, Park CC, Aghi MK. beta1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Cancer Res. 2013;73(10):3145–3154.
  • Lee TJ, Nair M, Banasavadi-Siddegowda Y, et al. Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin beta1 Blocking Antibody OS2966. Mol Cancer Ther. 2019;18(6):1127–1136.
  • Fujii K, Kurozumi K, Ichikawa T, et al. The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus. Cancer Gene Ther. 2013;20(8):437–444.
  • Weller M, Nabors LB, Gorlia T, et al. Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome. Oncotarget. 2016;7(12):15018–15032.
  • Alvarez-Breckenridge CA, Yu J, Price R, et al. NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors. Nat Med. 2012;18(12):1827–1834.
  • Han J, Chen X, Chu J, et al. TGFbeta Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response. Cancer Res. 2015;75(24):5273–5282.
  • Meisen WH, Wohleb ES, Jaime-Ramirez AC, et al. The Impact of Macrophage- and Microglia-Secreted TNFalpha on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment. Clin Cancer Res. 2015;21(14):3274–3285.
  • Saha D, Martuza RL, Rabkin SD. Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade. Cancer Cell. 2017;32(2):253–267.
  • Prionisti I, Buhler LH, Walker PR, Jolivet RB. Harnessing Microglia and Macrophages for the Treatment of Glioblastoma. Front Pharmacol. 2019;10:506.
  • Sergerie Y, Rivest S, Boivin G. Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis. J Infect Dis. 2007;196(6):853–860.
  • Pointer KB, Zhang RR, Kuo JS. Oncolytic Herpes Simplex Virus Glioblastoma Therapy is Potentiated by Tumor Necrosis Factor-alpha Inhibition. Neurosurgery. 2015;77(2):N18–20.
  • Yoo JY, Swanner J, Otani Y, et al. Oncolytic HSV therapy increases trametinib access to brain tumors and sensitizes them in vivo. Neuro Oncol. 2019;21(9):1131–1140.
  • Gerriets V, Bansal P, Khaddour K. Tumor Necrosis Factor (TNF) Inhibitors. In: StatPearls [Internet]. StatPearls Publishing; 2019.
  • Kurozumi K, Hardcastle J, Thakur R, et al. Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61. Mol Ther. 2008;16(8):1382–1391.
  • Haseley A, Boone S, Wojton J, et al. Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma. Cancer Res. 2012;72(6):1353–1362.
  • Thorne AH, Meisen WH, Russell L, et al. Role of cysteine-rich 61 protein (CCN1) in macrophage-mediated oncolytic herpes simplex virus clearance. Mol Ther. 2014;22(9):1678–1687.
  • Delwar ZM, Kuo Y, Wen YH, Rennie PS, Jia W. Oncolytic Virotherapy Blockade by Microglia and Macrophages Requires STAT1/3. Cancer Res. 2018;78(3):718–730.
  • Omuro A, Vlahovic G, Lim M, et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol. 2018;20(5):674–686.
  • Saha D, Martuza RL, Rabkin SD. Oncolytic herpes simplex virus immunovirotherapy in combination with immune checkpoint blockade to treat glioblastoma. Immunotherapy. 2018;10(9):779–786.
  • Pombo Antunes AR, Scheyltjens I, Duerinck J, Neyns B, Movahedi K, Van Ginderachter JA. Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. Elife. 2020;9.
  • Pearson JRD, Cuzzubbo S, McArthur S, et al. Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment. Front Immunol. 2020;11:2703.
  • Quail DF, Joyce JA. The Microenvironmental Landscape of Brain Tumors. Cancer Cell. 2017;31(3):326–341.
  • Razavi SM, Lee KE, Jin BE, Aujla PS, Gholamin S, Li G. Immune Evasion Strategies of Glioblastoma. Front Surg. 2016;3:11.
  • Hodges TR, Ott M, Xiu J, et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol. 2017;19(8):1047–1057.
  • Storey KM, Lawler SE, Jackson TL. Modeling Oncolytic Viral Therapy, Immune Checkpoint Inhibition, and the Complex Dynamics of Innate and Adaptive Immunity in Glioblastoma Treatment. Front Physiol. 2020;11:151.
  • Ribas A, Dummer R, Puzanov I, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170(6):1109–1119.
  • Binello E, Qadeer ZA, Kothari HP, Emdad L, Germano IM. Stemness of the CT-2A Immunocompetent Mouse Brain Tumor Model: characterization In Vitro. J Cancer. 2012;3:166–174.
  • Oh T, Fakurnejad S, Sayegh ET, et al. Immunocompetent murine models for the study of glioblastoma immunotherapy. J Transl Med. 2014;12:107.
  • Seyfried TN. el-Abbadi M, Ecsedy JA, Bai HW, Yohe HC. Influence of host cell infiltration on the glycolipid content of mouse brain tumors. J Neurochem. 1996;66(5):2026–2033.
  • Khalsa JK, Cheng N, Keegan J, et al. Immune phenotyping of diverse syngeneic murine brain tumors identifies immunologically distinct types. Nat Commun. 2020;11(1):3912.
  • Mecca C, Giambanco I, Donato R, Arcuri C. Targeting mTOR in Glioblastoma: rationale and Preclinical/Clinical Evidence. Dis Markers. 2018;2018:9230479.
  • Krakstad C, Chekenya M. Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics. Mol Cancer. 2010;9:135.
  • Fu X, Tao L, Rivera A, Zhang X. Rapamycin enhances the activity of oncolytic herpes simplex virus against tumor cells that are resistant to virus replication. Int J Cancer. 2011;129(6):1503–1510.
  • Zakaria C, Sean P, Hoang HD, et al. Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis. PLoS Pathog. 2018;14(8):e1007264.
  • Kanai R, Rabkin SD. Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors. CNS Oncol. 2013;2(2):129–142.
  • Advani SJ, Markert JM, Sood RF, et al. Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1. Gene Ther. 2011;18(11):1098–1102.
  • Kanai R, Wakimoto H, Martuza RL, Rabkin SD. A novel oncolytic herpes simplex virus that synergizes with phosphoinositide 3-kinase/Akt pathway inhibitors to target glioblastoma stem cells. Clin Cancer Res. 2011;17(11):3686–3696.
  • Cheema TA, Kanai R, Kim GW, et al. Enhanced antitumor efficacy of low-dose Etoposide with oncolytic herpes simplex virus in human glioblastoma stem cell xenografts. Clin Cancer Res. 2011;17(23):7383–7393.
  • Hong B, Muili K, Bolyard C, et al. Suppression of HMGB1 Released in the Glioblastoma Tumor Microenvironment Reduces Tumoral Edema. Mol Ther Oncolytics. 2019;12:93–102.
  • Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic Virotherapy for the Treatment of Malignant Glioma. Neurotherapeutics. 2017;14(2):333–344.
  • Eissa IR, Bustos-Villalobos I, Ichinose T, et al. The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Cancers (Basel. 2018;10:10.
  • Harrow S, Papanastassiou V, Harland J, et al. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Therapy. 2004;11(22):1648–1658.
  • Rampling R, Cruickshank G, Papanastassiou V, et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Therapy. 2000;7(10):859–866.
  • Papanastassiou V, Rampling R, Fraser M, et al. The potential for efficacy of the modified (ICP 34.5(-)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Therapy. 2002;9(6):398–406.
  • Bernstock JD, Vicario N, Li R, et al. Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice. Cancer Gene Ther. 2020;27(3–4):246–255.
  • Markert JM, Medlock MD, Rabkin SD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7(10):867–874.
  • Markert JM, Liechty PG, Wang W, et al. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Therapy. 2009;17(1):199–207.
  • Whisenhunt TR, Rajneesh KF, Hackney JR, Markert JM. Extended disease-free interval of 6 years in a recurrent glioblastoma multiforme patient treated with G207 oncolytic viral therapy. Oncolytic Virother. 2015;4:33–38.
  • Friedman GK, Pressey JG, Reddy AT, Markert JM, Gillespie GY. Herpes simplex virus oncolytic therapy for pediatric malignancies. Mol Ther. 2009;17(7):1125–1135.
  • Waters AM, Johnston JM, Reddy AT, et al. Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors. Hum Gene Ther Clin Dev. 2017;28(1):7–16.
  • Bernstock JD, Wright Z, Bag AK, et al. Stereotactic Placement of Intratumoral Catheters for Continuous Infusion Delivery of Herpes Simplex Virus −1 G207 in Pediatric Malignant Supratentorial Brain Tumors. World Neurosurg. 2019;122:e1592–e1598.
  • Bernstock JD, Bag AK, Fiveash J, et al. Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors. Hum Gene Ther. 2020;31(19–20):1132–1139.
  • Taguchi S, Fukuhara H, Todo T. Oncolytic virus therapy in Japan: progress in clinical trials and future perspectives. Jpn J Clin Oncol. 2019;49(3):201–209.
  • Parker JN, Gillespie GY, Love CE, Randall S, Whitley RJ, Markert JM. Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc Natl Acad Sci U S A. 2000;97(5):2208–2213.
  • Hellums EK, Markert JM, Parker JN, et al. Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model. Neuro Oncol. 2005;7(3):213–224.
  • Parker JN, Meleth S, Hughes KB, Gillespie GY, Whitley RJ, Markert JM. Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12. Cancer Gene Ther. 2005;12(4):359–368.
  • Patel DM, Foreman PM, Nabors LB, Riley KO, Gillespie GY, Markert JM. Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma. Hum Gene Ther Clin Dev. 2016;27(2):69–78.
  • Hunter WD, Martuza RL, Feigenbaum F, et al. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection in nonhuman primates. J Virol. 1999;73(8):6319–6326.
  • Malara N, Donato G Blood-Brain Barrier Breakdown by Combined Detection of Circulating Tumor and Endothelial Cells in Liquid Biopsy. In: Liquid Biopsy.2019.
  • Spear PG. Herpes simplex virus: receptors and ligands for cell entry. Cell Microbiol. 2004;6(5):401–410.
  • Braut T, Krstulja M, Kujundzic M, et al. Epidermal growth factor receptor protein expression and gene amplification in normal, hyperplastic, and cancerous glottic tissue: immunohistochemical and fluorescent in situ hybridization study on tissue microarrays. Croat Med J. 2009;50(4):370–379.
  • Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med. 2011;135(1):55–62.
  • Adhikaree J, Moreno-Vicente J, Kaur AP, Jackson AM, Patel PM, Mechanisms R. Barriers to Successful Immunotherapy for Treating Glioblastoma. Cells. 2020;9:2.
  • Grabowski MM, Sankey EW, Ryan KJ, et al. Immune suppression in gliomas. J Neurooncol. 2020.
  • Stronen E, Toebes M, Kelderman S, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016;352(6291):1337–1341.
  • Mineta T, Rabkin SD, Martuza RL. Treatment of malignant gliomas using ganciclovir-hypersensitive, ribonucleotide reductase-deficient herpes simplex viral mutant. Cancer Res. 1994;54(15):3963–3966.
  • Reisoli E, Gambini E, Appolloni I, et al. Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice. Cancer Gene Ther. 2012;19(11):788–795.