Oncolytic herpes simplex virus immunotherapy for brain tumors: current pitfalls and emerging strategies to overcome therapeutic resistance

Article metrics


Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancer-related mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, replication, and spread, and in so doing focus on host anti-viral immune responses and the immune microenvironment. Strategies to overcome such challenges including viral re-engineering, modulation of the immunoregulatory microenvironment and combinatorial therapies with virotherapy, such as checkpoint inhibitors, radiation, and vaccination, are also examined in detail.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1


  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

  2. 2.

    Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol. 2017;19(suppl_5):v1–88.

  3. 3.

    Krull KR, Hardy KK, Kahalley LS, Schuitema I, Kesler SR. Neurocognitive outcomes and interventions in long-term survivors of childhood cancer. J Clin Oncol. 2018;36:2181–9.

  4. 4.

    Shah AC, Benos D, Gillespie GY, Markert JM. Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. J Neurooncol. 2003;65:203–26.

  5. 5.

    Friedman GK, Pressey JG, Reddy AT, Markert JM, Gillespie GY. Herpes simplex virus oncolytic therapy for pediatric malignancies. Mol Ther. 2009;17:1125–35.

  6. 6.

    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;1:938–43.

  7. 7.

    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;252:854–6.

  8. 8.

    Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7:867–74.

  9. 9.

    Streby KA, Geller JI, Currier MA, Warren PS, Racadio JM, Towbin AJ, et al. Intratumoral injection of HSV1716, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients. Clin Cancer Res. 2017;23:3566–74.

  10. 10.

    Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther. 2000;10:859–66.

  11. 11.

    Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley D, Nicoll J, 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 Ther. 2002;9:398–406.

  12. 12.

    Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, Fraser M, et al. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Ther. 2004;11:1648–58.

  13. 13.

    Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.

  14. 14.

    Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci. 2016;107:1373–9.

  15. 15.

    Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics. 2017;14:333–44.

  16. 16.

    Bernstock JD, Wright Z, Bag AK, Gessler F, Gillespie GY, Markert JM, 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:e1592–8.

  17. 17.

    Markert JM, Liechty PG, Wang W, Gaston S, Braz E, Karrasch M, et al. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther. 2009;17:199–207.

  18. 18.

    Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984;9:1–25.

  19. 19.

    Sarkaria JN, Hu LS, Parney IF, Pafundi DH, Brinkmann DH, Laack NN, et al. Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. 2018;20:184–91.

  20. 20.

    Liu R, Martuza RL, Rabkin SD. Intracarotid delivery of oncolytic HSV vector G47Delta to metastatic breast cancer in the brain. Gene Ther. 2005;12:647–54.

  21. 21.

    Zhu H, Su Y, Zhou S, Xiao W, Ling W, Hu B, et al. Immune analysis on mtHSV mediated tumor therapy in HSV-1 seropositive mice. Cancer Biol Ther. 2007;6:724–31.

  22. 22.

    Maroun J, Munoz-Alia M, Ammayappan A, Schulze A, Peng KW, Russell S. Designing and building oncolytic viruses. Future Virol. 2017;12:193–213.

  23. 23.

    Kesari S, Lasner TM, Balsara KR, Randazzo BP, Lee VM, Trojanowski JQ, et al. A neuroattenuated ICP34.5-deficient herpes simplex virus type 1 replicates in ependymal cells of the murine central nervous system. J Gen Virol. 1998;79(Pt 3):525–36.

  24. 24.

    Sundaresan P, Hunter WD, Martuza RL, Rabkin SD. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J Virol 2000;74:3832–41.

  25. 25.

    Zhou G, Avitabile E, Campadelli-Fiume G, Roizman B. The domains of glycoprotein D required to block apoptosis induced by herpes simplex virus 1 are largely distinct from those involved in cell-cell fusion and binding to nectin1. J Virol. 2003;77:3759–67.

  26. 26.

    Spear PG. Herpes simplex virus: receptors and ligands for cell entry. Cell Microbiol. 2004;6:401–10.

  27. 27.

    Brencicova E, Diebold SS. Nucleic acids and endosomal pattern recognition: how to tell friend from foe? Front Cell Infect Microbiol. 2013;3:37.

  28. 28.

    Laquerre S, Anderson DB, Stolz DB, Glorioso JC. Recombinant herpes simplex virus type 1 engineered for targeted binding to erythropoietin receptor-bearing cells. J Virol. 1998;72:9683–97.

  29. 29.

    Trybala E, Liljeqvist JA, Svennerholm B, Bergstrom T. Herpes simplex virus types 1 and 2 differ in their interaction with heparan sulfate. J Virol. 2000;74:9106–14.

  30. 30.

    Friedman GK, Bernstock JD, Chen D, Nan L, Moore BP, Kelly VM, 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;8:13930.

  31. 31.

    Wang PY, Swain HM, Kunkler AL, Chen CY, Hutzen BJ, Arnold MA, et al. Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility. Gene Ther. 2016;23:135–43.

  32. 32.

    Jackson JD, McMorris AM, Roth JC, Coleman JM, Whitley RJ, Gillespie GY, et al. Assessment of oncolytic HSV efficacy following increased entry-receptor expression in malignant peripheral nerve sheath tumor cell lines. Gene Ther. 2014;21:984–90.

  33. 33.

    Miest TS, Cattaneo R. New viruses for cancer therapy: meeting clinical needs. Nat Rev Microbiol. 2014;12:23–34.

  34. 34.

    Menotti L, Cerretani A, Hengel H, Campadelli-Fiume G. Construction of a fully retargeted herpes simplex virus 1 recombinant capable of entering cells solely via human epidermal growth factor receptor 2. J Virol. 2008;82:10153–61.

  35. 35.

    Uchida H, Marzulli M, Nakano K, Goins WF, Chan J, Hong CS, et al. Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol Ther. 2013;21:561–9.

  36. 36.

    Leoni V, Vannini A, Gatta V, Rambaldi J, Sanapo M, Barboni C, et al. A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors. PLoS Pathog. 2018;14:e1007209.

  37. 37.

    Kanai R, Tomita H, Shinoda A, Takahashi M, Goldman S, Okano H, et al. Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of gamma 34.5-mediated virulence. Gene Ther. 2006;13:106–16.

  38. 38.

    Zhou G, Roizman B. Construction and properties of a herpes simplex virus 1 designed to enter cells solely via the IL-13alpha2 receptor. Proc Natl Acad Sci USA 2006;103:5508–13.

  39. 39.

    Kamiyama H, Zhou G, Roizman B. Herpes simplex virus 1 recombinant virions exhibiting the amino terminal fragment of urokinase-type plasminogen activator can enter cells via the cognate receptor. Gene Ther. 2006;13:621–9.

  40. 40.

    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;65:2832–9.

  41. 41.

    Nakashima H, Nguyen T, Kasai K, Passaro C, Ito H, Goins WF, et al. Toxicity and efficacy of a novel GADD34-expressing oncolytic HSV-1 for the treatment of experimental glioblastoma. Clin Cancer Res. 2018;24:2574–84.

  42. 42.

    Wakimoto H, Kesari S, Farrell CJ, Curry WT Jr., Zaupa C, Aghi M, et al. Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res. 2009;69:3472–81.

  43. 43.

    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;79:8707–15.

  44. 44.

    Friedman GK, Nan L, Haas MC, Kelly VM, Moore BP, Langford CP, 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;22:348–55.

  45. 45.

    Nakashima H, Kaufmann JK, Wang PY, Nguyen T, Speranza MC, Kasai K, et al. Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma. J Clin Invest. 2015;125:4269–80.

  46. 46.

    Okemoto K, Wagner B, Meisen H, Haseley A, Kaur B, Chiocca EA. STAT3 activation promotes oncolytic HSV1 replication in glioma cells. PLoS ONE. 2013;8:e71932.

  47. 47.

    Kaur B, Cripe TP, Chiocca EA. "Buy one get one free": armed viruses for the treatment of cancer cells and their microenvironment. Curr Gene Ther. 2009;9:341–55.

  48. 48.

    Dmitrieva N, Yu L, Viapiano M, Cripe TP, Chiocca EA, Glorioso JC, et al. Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy. Clin Cancer Res 2011;17:1362–72.

  49. 49.

    Evans SM, Judy KD, Dunphy I, Jenkins WT, Hwang WT, Nelson PT, et al. Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res. 2004;10:8177–84.

  50. 50.

    Friedman GK, Haas MC, Kelly VM, Markert JM, Gillespie GY, Cassady KA. Hypoxia moderates gamma(1)34.5-deleted herpes simplex virus oncolytic activity in human glioma xenoline primary cultures. Transl Oncol. 2012;5:200–7.

  51. 51.

    Aghi MK, Liu TC, Rabkin S, Martuza RL. Hypoxia enhances the replication of oncolytic herpes simplex virus. Mol Ther. 2009;17:51–6.

  52. 52.

    Longo SL, Griffith C, Glass A, Shillitoe EJ, Post DE. Development of an oncolytic herpes simplex virus using a tumor-specific HIF-responsive promoter. Cancer Gene Ther. 2011;18:123–34.

  53. 53.

    Mittnacht S, Straub P, Kirchner H, Jacobsen H. Interferon treatment inhibits onset of herpes simplex virus immediate-early transcription. Virology. 1988;164:201–10.

  54. 54.

    Rasmussen SB, Sorensen LN, Malmgaard L, Ank N, Baines JD, Chen ZJ, et al. Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems. J Virol. 2007;81:13315–24.

  55. 55.

    Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–35.

  56. 56.

    Fulci G, Dmitrieva N, Gianni D, Fontana EJ, Pan X, Lu Y, et al. Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses. Cancer Res. 2007;67:9398–406.

  57. 57.

    Thorne AH, Meisen WH, Russell L, Yoo JY, Bolyard CM, Lathia JD, et al. Role of cysteine-rich 61 protein (CCN1) in macrophage-mediated oncolytic herpes simplex virus clearance. Mol Ther. 2014;22:1678–87.

  58. 58.

    Filley AC, Dey M. Immune system, friend or foe of oncolytic virotherapy? Front Oncol. 2017;7:106.

  59. 59.

    Mitchell BM, Stevens JG. Neuroinvasive properties of herpes simplex virus type 1 glycoprotein variants are controlled by the immune response. J Immunol. 1996;156:246–55.

  60. 60.

    Ghonime MG, Jackson J, Shah A, Roth J, Li M, Saunders U, et al. Chimeric HCMV/HSV-1 and Deltagamma134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory. Transl Oncol. 2018;11:86–93.

  61. 61.

    Fulci G, Breymann L, Gianni D, Kurozomi K, Rhee SS, Yu J, et al. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses. Proc Natl Acad Sci USA. 2006;103:12873–8.

  62. 62.

    Han J, Chen X, Chu J, Xu B, Meisen WH, Chen L, et al. TGFbeta treatment enhances glioblastoma virotherapy by inhibiting the innate immune response. Cancer Res. 2015;75:5273–82.

  63. 63.

    Currier MA, Eshun FK, Sholl A, Chernoguz A, Crawford K, Divanovic S, et al. VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells. Mol Ther. 2013;21:1014–23.

  64. 64.

    Alvarez-Breckenridge CA, Yu J, Price R, Wojton J, Pradarelli J, Mao H, et al. NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors. Nat Med. 2012;18:1827–34.

  65. 65.

    Alvarez-Breckenridge CA, Yu J, Price R, Wei M, Wang Y, Nowicki MO, 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;86:4566–77.

  66. 66.

    Leddon JL, Chen CY, Currier MA, Wang PY, Jung FA, Denton NL, et al. Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity. Mol Ther Oncolytics. 2015;1:14010.

  67. 67.

    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 USA. 2000;97:2208–13.

  68. 68.

    Ring EK, Li R, Moore BP, Nan L, Kelly VM, Han X, et al. Newly characterized murine undifferentiated sarcoma models sensitive to virotherapy with oncolytic HSV-1 M002. Mol Ther Oncolytics. 2017;7:27–36.

  69. 69.

    Roizman B. The function of herpes simplex virus genes: a primer for genetic engineering of novel vectors. Proc Natl Acad Sci USA. 1996;93:11307–12.

  70. 70.

    Markert JM, Cody JJ, Parker JN, Coleman JM, Price KH, Kern ER, et al. Preclinical evaluation of a genetically engineered herpes simplex virus expressing interleukin-12. J Virol. 2012;86:5304–13.

  71. 71.

    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;27:69–78.

  72. 72.

    Cheema TA, Wakimoto H, Fecci PE, Ning J, Kuroda T, Jeyaretna DS, et al. Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci USA. 2013;110:12006–11.

  73. 73.

    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;24:3409–22.

  74. 74.

    Hardcastle J, Kurozumi K, Dmitrieva N, Sayers MP, Ahmad S, Waterman P, et al. Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1. Mol Ther. 2010;18:285–94.

  75. 75.

    Tanaka T, Manome Y, Wen P, Kufe DW, Fine HA. Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth. Nat Med. 1997;3:437–42.

  76. 76.

    Passaro C, Alayo Q, DeLaura I, McNulty JJ, Grauwet K, Ito H, 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;25:290–9.

  77. 77.

    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

  78. 78.

    Liu Z, Ravindranathan R, Kalinski P, Guo ZS, Bartlett DL. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun. 2017;8:14754.

  79. 79.

    Facciabene A, Motz GT, Coukos G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 2012;72:2162–71.

  80. 80.

    Ricklefs FL, Alayo Q, Krenzlin H, Mahmoud AB, Speranza MC, Nakashima H, et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv. 2018;4:eaar2766.

  81. 81.

    Zhai L, Ladomersky E, Lenzen A, Nguyen B, Patel R, Lauing KL, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol. 2018;15:447–57.

  82. 82.

    Ring EK, Markert JM, Gillespie GY, Friedman GK. Checkpoint proteins in pediatric brain and extracranial solid tumors: opportunities for immunotherapy. Clin Cancer Res. 2017;23:342–50.

  83. 83.

    Pulluri B, Kumar A, Shaheen M, Jeter J, Sundararajan S. Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance. Pharm Res. 2017;123:95–102.

  84. 84.

    Aldape K, Brindle KM, Chesler L, Chopra R, Gajjar A, Gilbert MR, et al. Challenges to curing primary brain tumours. Nat Rev Clin Oncol. 2019. [Epub ahead of print]

  85. 85.

    Saha D, Martuza RL, Rabkin SD. Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell. 2017;32:253–67 e5.

  86. 86.

    Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol. 2018;36:1658–67.

  87. 87.

    Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin. 2017;67:65–85.

  88. 88.

    Bradley JD, Kataoka Y, Advani S, Chung SM, Arani RB, Gillespie GY, et al. Ionizing radiation improves survival in mice bearing intracranial high-grade gliomas injected with genetically modified herpes simplex virus. Clin Cancer Res. 1999;5:1517–22.

  89. 89.

    Markert JM, Razdan SN, Kuo HC, Cantor A, Knoll A, Karrasch M, 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 Ther. 2014;22:1048–55.

  90. 90.

    Waters AM, Johnston JM, Reddy AT, Fiveash J, Madan-Swain A, Kachurak K, 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;28:7–16.

  91. 91.

    Banchereau J, Palucka K. Immunotherapy: cancer vaccines on the move. Nat Rev Clin Oncol. 2018;15:9–10.

  92. 92.

    Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res. 2013;119:421–75.

  93. 93.

    Stronen E, Toebes M, Kelderman S, van Buuren MM, Yang W, van Rooij N, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016;352:1337–41.

  94. 94.

    Draper SJ, Heeney JL. Viruses as vaccine vectors for infectious diseases and cancer. Nat Rev Microbiol. 2010;8:62–73.

  95. 95.

    Suschak JJ, Williams JA, Schmaljohn CS. Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity. Hum Vaccin Immunother. 2017;13:2837–48.

  96. 96.

    Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534:396–401.

  97. 97.

    Flingai S, Czerwonko M, Goodman J, Kudchodkar SB, Muthumani K, Weiner DB. Synthetic DNA vaccines: improved vaccine potency by electroporation and co-delivered genetic adjuvants. Front Immunol. 2013;4:354.

  98. 98.

    Bookstaver ML, Tsai SJ, Bromberg JS, Jewell CM. Improving vaccine and immunotherapy design using biomaterials. Trends Immunol. 2018;39:135–50.

  99. 99.

    Lynn GM, Laga R, Darrah PA, Ishizuka AS, Balaci AJ, Dulcey AE, et al. In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity. Nat Biotechnol. 2015;33:1201–10.

  100. 100.

    Yarchoan M, Johnson BA 3rd, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17:209–22.

Download references


This research was supported in part by grants from the Food and Drug Administration Office of Orphan Products Development (R01FD005379), the Department of Defense (W81XWH-15–1–0108) Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, and the Kaul Pediatric Research Institute to GKF and R01CA217179 to JMM and GYG. JDB was supported by the UAB Medical Scientist Training Program (MSTP) and an American Brain Tumor Association summer fellowship. SKT was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA183926. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. FDA or the Department of Defense. The authors apologize to colleagues we couldn’t cite given limitations on the number of references.

Author information

Correspondence to Joshua D. Bernstock or Gregory K. Friedman.

Ethics declarations

Conflict of interest

JMM, RJW, and GYG are founders of and own stock and stock options (<8% interest) in Aettis, Inc., a biotech company that holds intellectual property surrounding oHSV. GYG currently serves as one of five unpaid members of the Board of Directors for Aettis, Inc. JMM, RJW, and GYG were also founders of and owned stock and stock options (<8%) in Catherex Inc., a biotechnology company that had licensed additional intellectual property related to oHSV. Catherex, Inc., was sold to Amgen, Inc., on 18 December 2015, and they no longer participate in any decision making or have any control of any aspect of Catherex or Amgen, although they did receive proceeds from the sale of the company. GYG has served as a paid advisor to a Program Project at the Ohio State University that seeks to find improved methods for application of distinct oHSV to treat localized and metastatic cancers. This is generally, but not specifically, related to the subject matter of this investigation. JDB has positions/equity in CITC Ltd. JDB, ASI, and GML have positions/equity Avidea Technologies. RJW is a member of the Board of Directors of Gilead Sciences. The remaining authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark