Osteosarcoma is a type of bone cancer that usually develops in the osteoblast, cells accounting for ~20% of all primary bone tumors. Oncolytic virus (OV) therapy is the use of a replication-competent virus for the treatment of cancer. OVs are non-pathogenic live viruses, which have intrinsic cancer-selective killing activity, or can be engineered to express attenuating genes or arming genes. OV therapy has shown success in preclinical and clinical testing as a novel cancer treatment modality with high safety profiles and low off-target toxicities.
Osteosarcoma (OS), also called osteogenic sarcoma (OGS), is the most common malignant bone tumor. Osteosarcoma is thought to arise from primitive mesenchymal bone-forming cells, and its histologic hallmark is the exhibition of osteoblastic differentiation and the production of malignant osteoid. OS is most prevalent in teenagers and young adults within the fastest growing areas of the long bones. Symptoms of OS mainly include swelling or pain near a bone or joint, bone injury or bone break for no clear reason. Traditional treatment, involving chemotherapy, surgery and, sometimes, radiation therapy, usually shows a limited curative effect. It is urgent to develop novel therapeutic strategies.
Fig.1 Osteosarcoma (OS).
Because of the complex genetic make-up, OS is a challenging malignancy to identify novel targets for therapy. OV therapy may be a potential therapeutic option, not dependent on the consistent expression of a single target.
Ad is a non-enveloped, dsDNA virus with a linear genome of 36 kb, belonging to Adenoviridae family. Ad has many appealing characteristics of a therapeutic viral vector, including the ability to infect both dividing and non-dividing cells, rapid increase in viral titers, and non-integration of the viral genome into the host genome to reduce risk of mutagenic effects. Ad-OC-E1A is a chimeric, engineered adenovirus using the osteocalcin promoter expressing the E1A gene. It has been applied to a clinical trial for the treatment of metastasized osteosarcoma and showed activity in preclinical models of osteosarcoma and its pulmonary metastasis.
HSV is a double-stranded DNA virus belonging to the Herpesviridae family. The genome of HSV is 152 kb encoding more than 80 genes, approximately half of which are involved in the replication. Oncolytic virotherapy with HSV is effective in many different types of tumors including colorectal cancer, melanoma and osteosarcoma. Commonly, NV1020 and G207 viral strains genetically engineered from HSV-1 are used to evaluate the efficacy of oncolytic HSV in osteosarcoma. HSV1716 (SEPREHVIR (R)), with a single viral gene deletion (ICP34.5), has been applied in Phase I clinical study evaluating HSV in patients with osteosarcoma.
Vaccinia virus (VACV) is a double-stranded DNA virus of the Poxviridae family. It has a wide host range and natural tumor tropism. VACV has shown antitumor activity in clinical trials for chronic lymphocytic leukemia, metastatic malignant melanoma, prostate cancer, and osteosarcoma. JX-594 is an oncolytic VACV expressing human GM-CSF and with TK gene deletion. It has been applied to the Phase 1 trial in pediatric patients with unresectable refractory solid tumors, including osteosarcoma.
Fig.2 Targets for oncolytic virotherapy in osteosarcoma. (Hingorani, 2014)
In addition to the viruses mentioned above, several other viruses are being analyzed as oncolytic agents for the treatment of osteosarcoma, including reovirus, Semliki forest virus (SFV), vesicular stomatitis virus (VSV), measles virus, and Newcastle disease virus (NDV). They present either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells.
With recent improvements in modern genetic engineering techniques, oncolytic viruses can be manipulated to alter the capsid to reduce pathogenicity and immunogenicity, to the secret antibody to boost the anti-tumor immune response, to express cytokine/chemokine to attract immune cells migration to the tumor site, and even to be loaded with immune checkpoint inhibitors. For example, we can choose tumor-specific promoters (TSPs) for conditionally replicating to improve the specificity of OVs. We can engineer a virus that relies on a pathway that is upregulated in tumor cells for successful tumor infection thereby rendering the virus incapable of infecting healthy tissue.
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