Oncolytic Virus Combination Therapies-with Conventional Radiotherapy
Conventional Radiotherapy
Tumor radiotherapy is a local treatment method that uses radiation to treat tumors. Radiation includes α, β, and γ rays generated by radioisotopes and x-rays, electron beams, proton beams, and other particle beams generated by various x-ray therapy machines or accelerators. The history of radiotherapy is only a few decades, but with the help of the development of CT imaging technology and computer technology, it has developed from two-dimensional radiotherapy to three-dimensional or even four-dimensional radiotherapy technology. The principle that radiotherapy can treat cancer is that the energy carried by a large amount of radiation can destroy the chromosomes of the cells and stagnate the growth of the cells, so it can be used to fight the rapidly growing and dividing cancer cells. The current mainstream of radiotherapy technology is stereotactic radiotherapy (SRT) and stereotactic radiosurgery (SRS).
Table.1 Mainstream Radiotherapy Technology
| Mainstream Radiotherapy Technology | ||
|---|---|---|
| Stereotactic radiotherapy（SRT） | Three-dimensional conformal radiotherapy（3DCRT） | The irradiation range is large, and the dose distribution in the irradiation area is uniform, which can not only irradiate head tumors but also accurately treat body tumors. |
| Three-dimensional conformal intensity modulated radiotherapy（IMRT） | IMRT requires uniform dose distribution in the target area and surface of the conformal treatment. Therefore, the dose rate in each irradiation field must be adjusted as required, and the dose in the target area is high and the dose in the surrounding tissues is low. | |
| Stereotactic radiosurgery（SRS） | X-knife | A large dose of tumor tissue is irradiated in a short time, producing an effect similar to surgical resection. |
| Y-knife | 3D, Ono, cluster, fractionated, high-dose irradiation, which requires higher positioning accuracy and faster dose attenuation outside the target area. | |
| Cyber Knife | ||
About 70% of cancer patients need to use radiation therapy in the process of cancer treatment, and about 40% of cancers can be cured by radiotherapy. Radiation therapy has become increasingly prominent in the role and status of cancer therapy, and has become one of the main means of treating malignant tumors.
Combination Therapy of Oncolytic Virus with Conventional Radiotherapy
Nowadays, overcoming malignant tumors is still a major research topic in the medical community. The current methods of treating tumors are mainly surgery, chemotherapy and radiotherapy. Radiosensitivity is the key to determine the success or failure of tumor radiotherapy. Finding ways to improve tumor radiosensitivity has become a research hotspot in the field of tumor therapy. Oncolytic virus therapy is a new tumor gene therapy approach that has emerged in recent years. This therapy uses genetic engineering methods to transform the virus so that the virus can selectively replicate in the tumor and produce oncolytic effects. There is no cross-tolerance between oncolytic virus therapy and traditional radiotherapy. The combined application of the two methods can achieve superposition or synergy.
Example
Herpes simplex virus type I is a commonly used oncolytic virus, which can kill tumor cells with a low multiplicity of infection (MOI), and anti-virus antibodies in the blood do not affect the anti-tumor effect. The larger DNA of the virus can accommodate large-size foreign genes and will not be integrated into the host chromosome. In addition, antiviral drugs such as acyclovir can ensure the safety of the treatment. The recombinant HSV-1 currently in clinical trials has R-7020, G207, OncoVEXGM-CSF, all of which are knocked out the γ34.5 gene, the protein encoded by which can resist the phosphorylation of protein kinase R that inhibits viral infection in normal cells. So the HSV-1 knocked out of the γ34.5 gene cannot replicate in normal cells, thereby reducing the neurotoxicity of the virus, and the protein kinase R content in tumor cells is low, so the virus can replicate in them. Radiation can upregulate the expression of GADD3 gene in cells, and GADD3 is partially homologous to the γ34.5 gene, so the combination with radiotherapy can increase the replication and cytotoxicity of HSV-1 in HSV-1-based oncolytic virus therapy.
In clinical research, several different oncolytic viruses combined with radiotherapy have entered clinical trials. Among them, R-7020 was originally developed as HSV-1 and HSV-2 vaccines, and it was found to have a wide range of anti-tumor effects in later research. In a phase I clinical trial of colon cancer liver metastasis, the virus was injected through the hepatic artery, and no serious adverse reactions were found at the 108 dose level, and 7 of 12 patients had a CEA level drop of more than 50% after treatment. And the imaging evaluation is partial remission (PR). In-depth study of the oncolytic virus and the biological mechanism of its combined application with radiation, especially the human immune response and the impact of the tumor microenvironment on the distribution and proliferation of viruses are essential for the development of safer and more efficient oncolytic viruses and will also provide better guidance for application of combined therapy of virus and radiotherapy.
With its mature OncoVirapy™ Platform as the core, Creative Biolabs has established a one-stop oncolytic virus therapy development service, including oncolytic virus genetic engineering, oncolytic virus construction, and in vitro validation of oncolytic virus therapy.