Transcriptional retargeting of herpes simplex virus for cell-specific replication to control cancer
- 320 Downloads
Oncolytic virotherapy has emerged as a novel frontier in the treatment of cancer. Among the viruses that entered clinical trials are the oncolytic herpes simplex virus-1 (HSV-1). Current oncolytic HSV-1 approved for clinical practice, and those in clinical trials are attenuated viruses, often deleted in the neurovirulence gene γ134.5, and in additional genes, which may result in a much more attenuated virus with reduced replication efficiency. Therefore, the transcriptional retargeting strategy by modifying the regulator elements flanking essential viral genes to achieve tumor-specific replication while maintaining as much of the viral genome has been representing alternative promising oncolytic virotherapy modality.
Materials and methods
In this communication, we aimed to review extensive studies on transcriptional retargeting strategy with HSV-1 genome engineered on immediate–early ICP4 gene, late γ134.5 gene or early ICP6 gene as well as multiple-regulated oncolytic HSV1 through combining transcriptional retargeting and translational control. Design modality based on differential cellular background, advantage, and potential clinic limitation of the innovative oncolytic HSV-1 was described, and prospective and challenge of transcriptional retargeting strategy were collectively summarized.
Transcriptional retargeting strategy holds great promise in retaining tumor specificity as well as full replication capacity of oncolytic virus in the target cell as urgently required by clinical trials. Future efforts should be aimed toward the development of multiple-component targeted oncolytic virus such as combing the transcriptional retargeting strategy and genetically attenuated modulation or post-transcriptional control that will be the most effective at generating truly tumor selective vectors.
KeywordsOncolytic virotherapy Herpes simplex virus-1 (HSV-1) Conditionally replicative Transcriptional control Tumor selective promoter
We gratefully thank Dr. Robert S. Coffin (major researcher participating in construction of T-VEC and the management of T-VEC clinical trial) for his helpful review of the manuscript. This study was funded by the Natural Science Foundation of Science and Technology Commission of Shanghai Municipality (No. 16ZR1420000), China.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
This article does not contain any studies with human participations or animals performed by any of the authors.
- Miettinen MM, Sarlomo-Rikala M, Kovatich AJ, Lasota J (1999) Calponin and h-caldesmon in soft tissue tumors: consistent h-caldesmon immunoreactivity in gastrointestinal stromal tumors indicates traits of smooth muscle differentiation. Modern Pathol 12(8):756–762Google Scholar
- Nakamura H, Kasuya H, Mullen JT, Yoon SS, Pawlik TM, Chandrasekhar S, Donahue JM, Chiocca EA, Chung RY, Tanabe KK (2002) Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5. J Clin Investig 109(7):871–882CrossRefPubMedPubMedCentralGoogle Scholar
- Smith KD, Mezhir JJ, Bickenbach K, Veerapong J, Charron J, Posner MC, Roizman B, Weichselbaum RR (2006) Activated MEK suppresses activation of PKR and enables efficient replication and in vivo oncolysis by Deltagamma(1)34.5 mutants of herpes simplex virus 1. J Virol 80(3):1110–1120CrossRefPubMedPubMedCentralGoogle Scholar
- Yamamura H, Hashio M, Noguchi M, Sugenoya Y, Osakada M, Hirano N, Sasaki Y, Yoden T, Awata N, Araki N et al (2001) Identification of the transcriptional regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors. Cancer Res 61(10):3969–3977PubMedGoogle Scholar
- Zhang W, Ge K, Zhao Q, Zhuang X, Deng Z, Liu L, Li J, Zhang Y, Dong Y, Zhang S et al (2015) A novel oHSV-1 targeting telomerase reverse transcriptase-positive cancer cells via tumor-specific promoters regulating the expression of ICP4. Oncotarget 6(24):20345–20355CrossRefPubMedPubMedCentralGoogle Scholar