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Review
. 2024 Aug;30(8):781-794.
doi: 10.1016/j.molmed.2024.05.014. Epub 2024 Jun 17.

Safety of non-replicative and oncolytic replication-selective HSV vectors

Alberto L Epstein  1 , Samuel D Rabkin  2
Affiliations
Review

Safety of non-replicative and oncolytic replication-selective HSV vectors

Alberto L Epstein et al. Trends Mol Med. 2024 Aug.

Abstract

Herpes simplex virus type 1 (HSV-1) is a DNA virus and human pathogen used to construct promising therapeutic vectors. HSV-1 vectors fall into two classes: replication-selective oncolytic vectors for cancer therapy and defective non-replicative vectors for gene therapy. Vectors from each class can accommodate ≥30 kb of inserts, have been approved clinically, and demonstrate a relatively benign safety profile. Despite oncolytic HSV (oHSV) replication in tumors and elicited immune responses, the virus is well tolerated in cancer patients. Current non-replicative vectors elicit only limited immune responses. Seropositivity and immune responses against HSV-1 do not eliminate either the vector or infected cells, and the vectors can therefore be re-administered. In this review we highlight vectors that have been translated to the clinic and host-virus immune interactions that impact on the safety and efficacy of HSVs.

Keywords: cancer therapy; clinical trials; gene therapy; herpes simplex virus; oncolytic virus.

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Conflict of interest statement

Declaration of interests A.L.E. is cofounder, chief scientific officer, and shareholder of EG 427 SAS. He is a coinventor on patents related to the use of replication-incompetent HSV-based vectors owned by the University of Versailles Saint Quentin (France) and EG 427. S.D.R. is a coinventor on patents relating to oncolytic HSVs that are owned and managed by Georgetown University and Massachusetts General Hospital, and which have received royalties from Amgen and ActiVec Inc. He is on the Scientific Advisory Board of EG 427 SAS, has received honoraria and equity, and has acted as a consultant and received honoraria from Replimune and Cellinta.

Figures

Figure 1.
Figure 1.. HSV-1 vector types.
(Left). Replication-selective oncolytic HSV for cancer therapy. The virus can replicate in and kill target cancer cells, generating more oHSV that can spread in the tumor, repeating the cycle. (Right). Non-replicative HSV vectors for gene therapy. Vector transduction/infection of target normal cells is minimally intrusive except for the consequences of transgene expression. Transgene products, but not the virus, can spread to other cells, acting on receptors or taken up by cells, or function in the cells where they are expressed, depending on the product. Both vector types are structurally identical and packaged in the same virus particles unless genetically altered, and only differ in their genome.
Figure 2.
Figure 2.. Genetic structure of (A) oHSVs in clinical trials, completed or current, and (B) non-replicative HSV-1 vectors NP2 and KB103 (B-VEC).
A. The HSV genome consists of unique long (UL) and unique short (Us) regions bracketed by terminal repeat long (TRL) and internal repeat long (IRL), and internal repeat short (IRs) and terminal repeat short (TRs). Transgene inserts are in blue font, and below the arrow, deletions are indicated with below the genome. OHSV names are indicated on right and genomic alterations are indicated: 1716 [60]; G207 [41]; G47Δ [44]; T-Vec [46]; M032 [57]; CAN-3110 [65]; C134 [103]; NV1020 [70]; and HF10 [72]. B. IE genes are indicated in red, deletion by Δ, and location indicated on the genome. COL7A1 and PENK driven by the HCMV IE promoter are inserted into the deleted ICP4 region. IE ICP22 is downregulated by expression from an E promoter.
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Resources

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