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Compatibility of Immunocancer Virus and Immune Barrier Inhibitor

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[메디게이트뉴스] A friend of a doctor from Australia heard about a clinical trial of a cancer drug developed from the measles virus, a chickenpox vaccine. Post articles that contribute to dementia and take this opportunity to link the virus to cancer, the performance of anti-cancer immunotherapy virus T-WPS, the opportunity to develop other immunotherapeutic viruses and other antiviral agents (eg PD-1 / PDL). -1, CTLA-4 inhibitors (CAR-T).

Various viruses cause human illness. People have developed vaccines using viruses or viral derivatives to prevent the spread of the virus. Getting the flu vaccine to prevent the flu, which is common in winter, increases your immunity to the flu. Researchers have developed the virus as a vaccine to prevent malignancy as well as to selectively remove cancer cells. Where do scientists come from this idea? They wonder what the role of the virus is and how effective it is.

The possibility of the virus killing cancer cells began in the 1900s when people witnessed the disappearance of cancerous tissues from people who had been vaccinated against rabies. Since then, attempts have been made to alternately develop the virus as a cancer treatment. Most experiments failed because the viruses that allowed the cancer cells to kill were also toxic to humans. They had to develop a virus that could only attack cancer cells without damaging normal cells. In some cases, viruses have been created that are less toxic to humans, but they have been limited to killing only cancer cells in certain tissues, such as the skin or liver.

Amid continued failures, the first cancer virus approved by the US Food and Drug Administration (FDA) in 2015 was developed and remains the only example of 2019. This therapeutic agent is immunotherapeutically known as talimogene laherparepvec (T-VEC). T-WPS is a virus that selectively kills only cancer cells, divides only into cancer cells, except normal cells, to increase the population and then break the cell membrane (see Box below).

This treatment removes two genes from the herpes simplex genome 1 (HVS-1) genome, which causes blisters when people are tired around the mouth. stimulating factor) gene. Because the virus multiplies in cells, proteins are produced by this gene that stimulate the production of immune cells.

The virus that kills cancerous tissues enters a similar frequency in normal or cancerous cells, which stop working in normal cells but actively proliferate in cancer cells (see Box below). Viruses propagated in cancer cells slide off the cell membrane and spread outside the cell and spread around. The cells of the sliding membranes are killed and when the cell membrane bursts, new viruses, GM-CSF proteins and cancer cell antigens are released. They cause an immune response to remove cancer cells from all areas of the body, as well as from surrounding cancer cells.

In Phase 3 trials, 436 patients with stationary melanoma were divided into two groups to compare the effects of GM-CSF and T-WPS. According to conventional treatment, GM-CSF is injected into the subcutaneous tissue every 28 days for 28 days, and T-WPS is injected into the cancer tissue every two weeks. Median survival for the first phase of chemotherapy increased by 4.3 months to 23.2 months, versus 18.9 months for existing therapies and 2.1% to 16.3% for patients lasting more than 6 months. Obtained

Researchers in this area showed great interest in 10.8% of patients. Patients had all of the cancerous tissues injected with T-WPS and cancerous tissue elsewhere in the body. T-WPS appeared to elicit an immune response throughout the body to eliminate the cancer. Only one in ten patients was cured, and with all patients considered, prolonging life by only 4.3 months may seem like a very unsuccessful success. Of course, some patients had no therapeutic effect. However, given the treatment of terminal patients with melanoma, which is almost impossible to treat, the results were very good as anticancer drugs.

Oncolytic virus and systemic antitumor permeability. Injecting a therapeutic virus T-WPS selectively multiplies only in cancer cells, killing and releasing cancer cells to further infect nearby cancer cells. In addition, human immune cells infiltrate into cancer tissues and control the functions of immune cells to dodge cancer cells, so that immune cells recognize and attack cancer cells. The therapeutic effect spreads throughout the body, killing cancer tissue that has fallen out of the treatment area.

The treatment is as simple as getting a cold shot. Treating cancer with the virus has minimal side effects and has little effect on the health and daily life of patients and has little effect on quality of life. In addition, there is no economic burden as there is no need to be hospitalized. The greatest side effects, fever and headache, can be resolved by eating aspirin or tilenol. Therefore, you can return to work immediately after the procedure. The treatment was highly anticipated by frontline physicians and patients. Thanks to virus-based treatment, the survival rate in patients with melanoma cancer has improved significantly over a decade ago.

Clinical trials of combination therapy with immunodeficiency inhibitors are ongoing. According to a study published in 2017, the virus helps T cells, immune cells, penetrate cancerous tissues and improve the efficiency of the immune barrier (PD-1 / PDL-1 inhibitors).(Ribas et al. 2017; Cell 170: 1109-1119). A paper published in 2018 also found increased efficacy when combined with CTLA-4 in Phase II trials.Honest and more. Ј Clink Oncol. 36: 1658-1667)

Combined therapy with chimeric antigen receptor-T is expected to be developed in the future. According to papers published in 2019, 16 of the 26 patients with terminal melanoma (61.5%) were completely cured.Franke et al. 2019. In Cancer. doi10.1002 / ijc.32172; Louis et al. 2019 FAX 228: 644-649Since only 26 patients were treated, it is difficult to fully understand the full potential of the drug. However, the selection of patients who are eligible for treatment is expected to increase the effect of treatment further. T-WPS is the only existing oncolytic virus that is approved for the first time to lyse cancer cells and provides a good precedent.

Some of the viruses at the time of clinical trials will be FDA-approved in the near future. The kupox virus, which began clinical trials in Australia, is relatively early but is one of those viruses. The virus in sheep causes cows to have red spots called vaccines, but people have used them to make vaccines that help in the immunization of measles. Now, one step away, American scientist Humano Yong has developed a new weapon that manipulates the virus genome, attacking various solid cancer cells without attacking normal cells.

All patients with triple-negative breast cancer, melanoma, lung cancer, bladder cancer, gastric cancer and colorectal cancer, which are currently very difficult to treat, are enrolled to find the most effective cancer. Preclinical animal studies have excellent anticancer effects, but when used in patients, they will first determine which carcinoma is most effective, and then select one carcinoma to continue phase 2/3 of the study. Once approved by the FDA for a cancer, additional clinical trials will be conducted to expand the indications thereafter.

The "Immune Gate Inhibitor", which was selected in the scientific "Amazing Development of the Year" in 2013, proved to be effective. However, this therapy was only effective for some patients, so new methods of immunotherapy were needed. Viral immunotherapy will in itself open up new immunotherapy. In addition, the development of combination therapy with immune gateway inhibitors is expected to significantly expand the therapeutic class of patients. Contemporary researchers are learning endlessly from nature and exploring new worlds, and some studies have no precedent. It is difficult in any country to get an unprecedented creative research grant, but I am looking forward to having an unprecedented research environment in Korea.

Box. Safe therapeutic virus T-WPS developed to attack only cancer cells

T-WPS was produced by removing the ICP34.5 and ICP47 genes from the genome of the herpes simplex virus 1 (HSV-1) and inserting a single cytokine gene (GM-CSF). Viruses with ICP 34.5 removed inhibit protein synthesis in normal human cells, making it impossible to replicate and explode. In contrast, explosive propagation is still possible in melanoma cells for the following reasons:

Human healthy cells synthesize only the proteins needed to maintain their survival and function. To prevent energy consumption, a brake called PKR is used to prevent excessive protein synthesis. If the virus penetrates the human cells, it ignores this break. ICP 34.5 ignores the break and activates the function of eIF-2, part of the cell's protein production plant, allowing protein synthesis to continue uninterrupted. Human cells use all their energy to synthesize the proteins needed to reproduce viruses, and they continually explode using constantly synthesized proteins. Therefore, infection with natural viruses is harmful to humans and eliminates this trait for viruses developed for therapeutic use.

However, about 70% of melanoma cells have cancer-induced mutations in BRAF or NRAS, which inhibit PKR activity, resulting in continuous protein production. Cancer cells are self-mutilated to inhibit PKR activity and multiply without thinking healthy cells around them. In other words, because PKR function was suppressed in cancer cells, the protein was constantly synthesized, and as a result, the virus that removed ICP34.5 was able to proliferate.

ICP47 Prevents Antigen Binding to MHC Class 1. Once the antigen binds to MHC on the surface of an antigen presenting cell, it is determined whether an immune response against this protein will occur. ICP47 provides secretion to prevent immune cells from spotting even if they produce viral proteins in healthy cells. Therefore, the elimination of ICP47 promotes binding of viral proteins as well as antigens to MHC cancer cells, leading to an immune response. As a result, tumor cells activate an immune response in how to remove cancer cells, and vice versa, HSV-1 eliminates impairs immunity in normal cells and is safe for patients.

※ The columns are the opinion of the columnist and may not correspond to the editorial direction of this magazine.

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