herpes_simplex_virus_type_1

Herpes simplex virus type 1

Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH. NOTCH induced immunosuppressive myeloid cell recruitment limited anti-tumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy 1)


Conditionally replicating herpes simplex viruses Type 1 (HSV-1) are promising therapeutic agents for glioma. They can replicate in situ, spread and exhibit oncolytic activity via a direct cytocidal effect. In addition, specific antitumor immunity is effectively induced in the course of oncolytic activities. G47Δ is a genetically engineered HSV-1 with triple mutations that realized augmented viral replication in tumor cells, strong induction of antitumor immunity and enhanced safety in normal tissues. A clinical trial of G47Δ in patients with recurrent glioblastoma has started in 2009. One of the advantages of HSV-1 is its capacity to incorporate large and/or multiple transgenes within the viral genome. In preclinical studies, “arming” of an oncolytic HSV-1 with transgenes encoding immunomodulatory molecules, such as interleukin 12, has been shown to greatly augment the efficacy of oncolytic HSV-1 therapy. Oncolytic virus therapy using HSV-1 may be a useful treatment for glioma that can also function as an efficient in situ tumor vaccination 2).


Herpes simplex virus type 1 encephalitis after meningioma resection 3).


Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.

Friedman et al. conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre-and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis.

Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes.

Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically “cold” tumors to “hot.” (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.) 4).


1)
Otani Y, Yoo JY, Lewis CT, Chao S, Swanner J, Shimizu T, Kang JM, Murphy SA, Rivera-Caraballo K, Hong B, Glorioso JC, Nakashima H, Lawler SE, Banasavadi-Siddegowda Y, Heiss JD, Yan Y, Pei G, Caliguri MA, Zhao Z, Chiocca EA, Yu J, Kaur B. NOTCH induced MDSC recruitment after oHSV virotherapy in CNS cancer models modulates anti-tumor immunotherapy. Clin Cancer Res. 2022 Jan 12:clincanres.2347.2021. doi: 10.1158/1078-0432.CCR-21-2347. Epub ahead of print. PMID: 35022322.
2)
Todo T. Active immunotherapy: oncolytic virus therapy using HSV-1. Adv Exp Med Biol. 2012;746:178-86. doi: 10.1007/978-1-4614-3146-6_14. Review. PubMed PMID: 22639168.
3)
Álvarez de Eulate-Beramendi S, Santirso-Rodríguez D, Piña-Batista KM, Gutiérrez-Morales JC. Herpes simplex virus type 1 encephalitis after meningioma resection. Neurologia. 2015 Sep;30(7):455-7. doi: 10.1016/j.nrl.2013.08.007. Epub 2014 Apr 30. English, Spanish. PubMed PMID: 24792498.
4)
Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, Kachurak K, Nan L, Kang KD, Totsch S, Schlappi C, Martin AM, Pastakia D, McNall-Knapp R, Farouk Sait S, Khakoo Y, Karajannis MA, Woodling K, Palmer JD, Osorio DS, Leonard J, Abdelbaki MS, Madan-Swain A, Atkinson TP, Whitley RJ, Fiveash JB, Markert JM, Gillespie GY. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas. N Engl J Med. 2021 Apr 10. doi: 10.1056/NEJMoa2024947. Epub ahead of print. PMID: 33838625.
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  • Last modified: 2022/01/13 18:33
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