Tumor Selectivity Enhancement of Oncolytic Vaccinia Virus
Overview of Vaccinia Virus
Vaccinia virus, an orthopoxvirus of family Poxviridae, has a linear, double-stranded DNA genome, the size of which varies slightly among different strains, with an approximate length of 180-200 kb. Similar to other members of the family Poxviridae, the center of the vaccinia virus genome is a highly conserved region that encodes viral replication proteins. Non-conserved regions encoding proteins related to host-range determination and other proteins flank the conserved central region. Vaccinia virus is serologically and immunologically related to variola virus and cowpox virus and has been used as a live vaccine against smallpox. However, its origin and natural host remain unclear. Although smallpox was eradicated in 1980, studies on the vaccinia virus are still underway. As an expression vector of foreign genes, the vaccinia virus represents an excellent model for the study of virus-host interactions.
Mechanism of Action of Oncolytic Virus in Tumor Cells
Continuous viral replication in tumor cells harnesses the host cells' raw material, energy, and reaction sites, causing tumor cell lysis. Additionally, the released progeny virus can infect peripheral tumor cells, leading to a continuous amplification of antitumor effects. Vaccinia virus can lyse cells effectively, and the lysed cells release cell death signals and virus death signals. Simultaneously, tumor-associated antigens and virus-associated antigens at the site of infection are also exposed to the immune system, thereby stimulating the corresponding inflammatory responses. Thus, local immunosuppression is overcome, and the body can produce a specific immune response. The immune response can also be cross-presented to the host through tumor-associated antigens to induce in situ immune effects. In addition, the vaccinia virus can infect intra-tumoral vascular endothelial cells, causing them to undergo apoptosis and disintegrating tumor vasculature. This indirectly mediates tumor cell apoptosis.
Fig.1 Mechanisms of action of oncolytic virus therapy.
(Fukuhara, 2016)
Vaccinia Viruses Mediated Therapeutic Genes as Immunotherapeutic Cancer Vectors
- Immunoregulatory factors
JX 594 is the most comprehensive oncolytic vaccinia virus, which has been used in clinical studies to date and has successfully entered phase III clinical trials.
- Chemokines
Tumor-specific T cells are restricted from entering tumors. Chemokines expressed by oncolytic viruses, such as CXCR3, CXCL9, CXCL10, and CXCL11, can specifically attract T cells to tumors, thereby inducing a strong systemic antitumor immune response that significantly enhances the efficacy of oncolytic virus therapy.
- Tumor-specific antibodies
The emergence of antibody therapies indicates that targeted antibodies are gradually becoming a very promising therapeutic strategy. The vaccinia virus EphA2 TEA VV has displayed strong antitumor activity in a lung cancer xenograft model.
- Apoptosis-inducing genes
TRAIL, SMAC, and caspase-3 can disrupt apoptosis and may be one of the factors that contribute to tumorigenesis in malignant tumors. SMAC is a mitochondrial key regulator of apoptosis, expressed in most tissues and organs.
- Tumor-suppressor genes
The most frequently studied tumor-suppressor genes include p53, APC, p16, DCC, Rb, LFIRE, Cyld, PTEN, and MnSOD, of which the p53 gene is the most commonly studied because it is the most common tumor-suppressor target in cancer gene therapy. Mutations or deletions in the p53 gene are critical for tumorigenesis. Mutation of the p53 gene destroys the gene's ability to inhibit tumors.
- Suicide genes
These are also referred to as drug-sensitivity genes. Prodrug-converting enzymes can be introduced into tumor cells using the vaccinia virus as a vector. The enzyme encoded by this gene can metabolize prodrugs that are nontoxic to normal cells and convert them into toxic products in tumor cells, thereby causing tumor cell death.
- Angiogenesis inhibitors
Angiostatic factors such as BAI1, HGFK1, and VEGF are present in normal tissues and organs. Researchers have reported the presence of BAI1 in the tissue of renal cell carcinoma; however, BAI1 expression in normal kidney tissue was significantly increased rather than in tumor tissue, and BAI1 levels decreased with increased malignancy.
- Silencing of gene expression
RNA interference (RNAi) refers to the silencing of a target gene via the generation of short double-stranded RNA molecules to regulate the introduction of short interfering double-stranded RNA (siRNA) or short hairpin RNAs (shRNA), capable of processing siRNA inside cells. Selecting a specific target for RNA interference can induce apoptosis in tumor cells displaying aberrant gene expression patterns.
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