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Microbes & Immunity Genetic therapy with HSV-1 vectors

ICP47 gene promoter to become an IE gene, improving the amplicon-expressed fusion protein 4B1-EGFP to combine
self-replication ability of the G47∆ virus and making the the advantages of cytochrome protein p450 4B1 (a
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G47∆ virus a safer and more effective oncolytic virus. In potentially biologically activated suicide gene) expression.
a mouse tumor model, this virus strain was significantly In addition, a strong bystander effect of cell-to-cell contact
more effective at inhibiting tumors than G207 was. 64 was clearly observed. Amplicons have also been used to
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In addition, while engineering the HSV-1 virus deliver TK and cytosine deaminase to murine 9L gliomas
itself, the investigators constructed a series of oncolytic and human Gli36 glioma cells, which were subsequently
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HSV-1 strains that carry immune activation, tumor treated with GCV and 5-fluorocytosine (5-FC).
therapy, and tumor-targeting genes, thereby enhancing In addition, oncolytic viruses combined with
tumor-inhibiting activity and tumor targeting. Several chemotherapy or radiotherapy have been used in preclinical
tumor suppressor genes have become the main targets models. However, the molecular mechanisms underlying
of HSV-1 viral vectors. Todo et al. integrated the IL-12 this coordinated effect are currently unknown. A widely
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or soluble B7-1 gene into the genome of G207, applied it accepted hypothesis suggests that radiation therapy or
in clinical trials and achieved good therapeutic results. chemotherapy enhances the expression level of GADD34
Ino et al. integrated IL-12, IL-18, and B7-1 into the (blocking the cell cycle to G1/G2) and thus improves
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UMGH-1 virus with a genome structure similar to the replication capacity of the virus, thereby enhancing
that of the G207 genome, forming four novel MGH-l antitumor effects (Figure 5) The upregulation of GADD34
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mutant viruses carrying exogenous genes. Based on the expression has been reported in HSV-1-infected head and
results of the in vitro cytotoxicity test and the growth neck cancer, cholangiocarcinoma, and lung cancer cells
inhibition effect on transplanted tumors, the four viruses after radiation. 75-77 Therefore, multiple mechanisms are
were superior to MGH-1 in terms of killing effect. To likely involved in the combined treatment of oncolytic
improve the targeting of virus strains, genes essential viruses and traditional therapies, and this synergistic
for virus replication were placed under the control of treatment approach helps to maximize oncolytic efficiency
tumor-specific promoters or enhancers to proliferate while reducing treatment-related virulence effects.
in tumor cells specifically. The ICP4 and γ34.5 genes
are controlled by a pancreatic cancer-specific promoter In recent years, scientists at the British Cancer Institute
and brain tumor-specific promoter, respectively, and the have made important progress in using transgenic herpes
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obtained recombinant viruses target pancreatic cancer viruses to successfully treat head and neck cancer. At
and malignant glioma, respectively, and can effectively the Royal Marsden Hospital, 17 lymphoma patients
inhibit tumor growth. 67,68 received modified HSVGM-CSF (deletion of ICP34.5
and ICP47, insertion of GM-CSF) while receiving
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Other oncolytic HSV-1 strains arise from spontaneous conventional radiotherapy or chemotherapy for cancer.
mutations in the virus. For example, HF10, an oncolytic The results revealed that 93% of the subjects experienced
virus with high safety obtained by clinical screening, has no recurrence after resection of the tumor, and 82% of the
a 3.8 kb deletion (11,6515 – 12,0347 bp) at the junction patients experienced no recurrence after 2 years. Only 2
between UL and UL/IRL in its genome; a 6,025 – 8,319 bp of the 13 patients who received high-dose transgenic virus
deletion in TRL; and a 110 488 – 116 514 bp DNA fragment therapy relapsed. Knowing that the above-mentioned
in HSV-1 inserted in the reverse direction, preventing the study is only a small-scale trial, further investigations are
expression of UL43, UL49.5, UL55, and LAT. Two clinical still necessary for safety testing and validation of transgenic
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trials have been conducted using the HF10 strain: One herpesvirus therapy for clinical use. However, the existing
in 6 patients with recurrent breast cancer who received experimental results show that the use of oncolytic HSV-1
HF10 with significant tumor regression and no significant therapy to treat tumors has broad potential.
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adverse effects and the other in three patients with head
and neck squamous cell carcinoma who received HF10 5.2. Vaccine development applications
with no significant tumor regression, but a large number HSV-1 vectors carrying exogenous antigens as antiviral
of tumor cells died or became fibrotic according to infection prevention vectors have the following advantages:
pathological tests. HF10 has also been tested as a helper (1) different inoculation methods can trigger a strong and
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virus in animal models for tumor suppression. continuous immune response; (2) viral DNA is free outside
Trials utilizing HSV-1 amplicons for oncolytic therapy the host cell genome in the form of episomes, avoiding the
are also ongoing. In rodent and human glial cell lines, potential safety hazards caused by random integration; and
cyclophosphamide (CPA) was successfully transformed (3) the ability to carry TK genes can combine with specific
into a toxic metabolite in tumor cells through the use of the antiviral drugs and kill virus-infected cells.

Volume 2 Issue 2 (2025) 26 doi: 10.36922/mi.7947