The enhanced version of oncolytic virus is launched to "dissolve" cancer cells is its unique trick.

Oncolytic viruses can "dissolve" tumor cells and have become an important part of tumor immunotherapy. Recently, I scientists have successfully constructed an enhanced version of oncolytic virus, and related therapies have been approved for clinical trials.

Cancer is one of the major diseases that seriously affect human health and threaten human life. Chemotherapy and radiotherapy used in traditional cancer treatment have the pain point of "killing 100 enemies and damaging 3,000", which brings obvious toxic and side effects to cancer patients. Nowadays, targeted therapy and immunotherapy represented by PD-1/PD-L1 antibodies have certain curative effects, but they are far from meeting clinical needs.

Oncolytic viruses can "dissolve" tumor cells and have become an important part of tumor immunotherapy, but their efficacy is easily limited by the tumor immunosuppressive microenvironment. For this reason, Chinese scientists have developed a new generation of tumor immunotherapy drugs-recombinant human PD-1 antibody herpes simplex virus for injection. The new anti-tumor drug has passed the clinical trial approval of the State Food and Drug Administration and is currently conducting phase I clinical trials.

Xia Ningshao's research group at Xiamen University, who led the project, recently published a paper in the international journal Cancer Immunology Research, saying that they have constructed an enhanced version of oncolytic virus, which can "kill" tumor cells by directly "dissolving" tumor cells and activating the body's immune system, so as to improve the effect of cancer treatment.

The "befuddled" immune system no longer works

At present, cancer is one of the major diseases with high mortality in the world, and the incidence and mortality are still increasing, showing an upward trend. According to statistics, in 2018, there were about 18.08 million new cases of malignant tumors and about 9.56 million deaths in the world, and China accounted for about 23.7 and 30% respectively.

Cancer cells are derived from "blackened" normal cells, which can proliferate indefinitely and destroy normal tissues. The human immune system is like a sophisticated "police force", protecting the health of the human body 24 hours a day and night, and monitoring whether there are cancer cells like a radar. Therefore, using the body's immune system to fight cancer has become one of the most potential treatments.

However, at present, this "police force" can not completely and autonomously "remove the roots" of cancer cells: when the immune system detects the emergence of cancer cells, it will extract the characteristics of "suspect" cancer cells, that is, tumor-related antigens, and send "ace army" T cells to encircle and suppress. Once the T cells do it, the cancer cells will show the "good man card in disguise"-PD-L1 protein, and successfully escape through the "puzzle method.

It turns out that cunning cancer cells have long discovered the "soft underbelly" of T cells ". There is a protein on the surface of T cells called PD-1. When it encounters PD-L1 protein on the surface of cancer cells, T cells will not only think that cancer cells are "good people", but also enter a "standby" state, unable to identify and remove cancer cells normally.

Since the immune system's "own anti-virus software" does not work, scientists have turned their attention to "foreign aid". In this context, oncolytic virus therapy, which has the advantages of broad-spectrum, high efficiency and low side effects, has gradually entered people's field of vision, and has become a new hot spot in the field of cancer treatment research.

Uncover the "mask" of self-disguised cancer cells"

Oncolytic virus is a kind of virus with oncolytic activity, which is modified by natural or genetic engineering technology. Oncolytic virus therapy is an immunotherapy method that uses oncolytic virus to specifically kill tumor cells and release tumor-associated antigens to activate the body to produce anti-tumor immune response.

A "good" oncolytic virus can effectively "dissolve" cancer cells, and almost no harm to normal cells. Not only that, the oncolytic virus will also induce tumor cells to release more cytokines, "call" more T cells to participate in the fight against cancer, and improve the efficacy of tumor treatment.

In the 1990 s, the rapid development of molecular virology and genetic engineering technology made it possible to modify viral genes. So far, a total of 3 oncolytic virus products have been approved for tumor treatment in the world. More than 10 viruses, including herpes virus, enterovirus and vaccinia virus, have been developed into oncolytic virus drugs and entered clinical trials. Many domestic and foreign pharmaceutical companies are competing to carry out oncolytic virus tumor immunotherapy research, and actively explore the application potential of oncolytic virus tumor immune combination therapy.

"Although oncolytic virus therapy has shown certain tumor treatment effects in clinical treatment and experimental studies, its efficacy is largely limited by the tumor immunosuppressive microenvironment." The researchers said. It turns out that oncolytic viruses, in the process of infecting and killing tumor cells, trigger an antiviral response of the immune system, resulting in elevated levels of interferon in the tumor microenvironment. This change will cause cancer cells to become "alert" and produce more PD-L1 proteins on their surface-which can specifically bind to PD-1 proteins on the surface of T cells, thereby inhibiting the activation and proliferation of T cells. T cells that enter the "standby" state cannot perform their normal function of identifying and removing cancer cells, and the efficacy of oncolytic viruses is naturally greatly reduced.

"If you do not break up the PD-1 and PD-L1,T cells will be difficult to completely 'clean' cancer cells." The researchers told reporters. Finding the key to the problem, they creatively engineered the oncolytic virus-allowing it to integrate PD-1 antibody genes. Thus, when the enhanced version of the oncolytic virus replicates in cancer cells, PD-1 antibodies are also produced at the same time.

The so-called PD-1 antibody is a protein that can specifically bind to PD-1 protein. The researchers said that PD-1 the antibody binds to the PD-1 on the T cell, the cancer cell PD-L1 cannot bind to the PD-1 on the T cell, thus unveiling the "mask" of cancer cell camouflage, and the T cell will not "stand by" and can identify and remove cancer cells side by side with the enhanced version of the oncolytic virus.

And "seemingly smart" cancer cells may not understand until they die: it is to provide a place to replicate oncolytic viruses to attack more cancer cells; it is also to produce PD-1 antibodies that make the disguised "good person card" ineffective. In the end, he was trapped in a cocoon and "killed" himself!

Join hands with the immune system to "encircle and suppress" cancer cells

Is the enhanced version of oncolytic virus really as safe and effective as the theory predicts? In this regard, the research team based on cell models and animal models, carried out a large number of research experiments, and achieved a more comprehensive understanding.

The research team found in mouse experiments that the enhanced version of oncolytic virus has a better tumor treatment effect than the ordinary version of oncolytic virus. It has the advantages of PD-1 antibody therapy and the advantages of oncolytic virus therapy. It can also make up for the lack of single use of these two therapies. Truly achieve "1 1>2", two-pronged approach, complement each other.

It turns out that in the process of "killing" cancer cells, the enhanced oncolytic virus will also lead to the release of "alarm factor" DAMPs, thus attracting more T cells to participate in the battle. The energy of PD-1 antibodies is continuously produced and gathered around cancer cells, so that T cells are not confused, thereby maintaining the "fighting capacity" of T cells ".

Not only that, the enhanced version of the oncolytic virus also has the advantages of "pulling a hair and moving the whole body" and "avoiding recurrence. The reason is that once the immune system is activated, not only the T cells "go to the battlefield", but the anti-tumor antibodies produced by the B cells in the immune system can also participate in the battle, so that the tumor in the non-drug-administered area is cleared by the immune system together. And after the siege, the immune cells did not retire. In a bilateral tumor-bearing mouse model that mimics advanced liver cancer, the team found that the cured mice have long-lasting anti-tumor immune memory and can resist re-attack by the same cancer cells.

"This is due to the fact that a portion of the T and B cells will evolve into 'good memory' memory cells that will remember the characteristics of the cancer cells and be 'blacklisted'. When the same cancer cells reappear, they will be able to identify them in the first place and directly encircle them, thus avoiding recurrence." The researchers explained.

The researchers told reporters that the drug is aimed at a variety of malignant tumors, such as head and neck cancer, lung cancer, colorectal cancer, melanoma, cervical cancer, bladder cancer, pancreatic cancer, liver cancer, etc., and can be injected intratumoral, intravenous drip or chest/abdominal cavity. Local administration. At present, the drug is still in the clinical trial stage and needs more clinical verification.

At present, among the innovative tumor drugs in the domestic market, imported drugs occupy a dominant position, which poses a huge potential threat to the safety of tumor drugs in China. This time, my country's self-developed new anti-cancer drug "Recombinant Human PD-1 Antibody Herpes Simplex Virus for Injection" successfully entered the clinic, which undoubtedly injected new strength into the research and development of innovative tumor drugs in my country, and also brought more to more cancer patients. hope.