Late nineteenth century
A 42-year-old woman with leukemia suddenly recovered after a suspected infection with influenza virus.
Italian doctors reported a case in which a patient with advanced cervical cancer had a significant remission after injection of rabies vaccine.
The above seemingly bizarre cases have opened up new ideas for tumor immunity, that is, the oncolytic virus that “strikes poison with poison.” To solve the fourth part of the “Poison” series, we walked into the vibrant oncolytic virus therapy together. The introduction of oncolytic viruses will be divided into two parts. This article mainly introduces the related concepts and treatment mechanisms of oncolytic viruses.
Oncolytic viruses are natural or artificially modified viruses that can selectively replicate in tumor tissues, thereby killing tumor cells, but have no killing effect on normal tissues. In addition to directly killing tumor cells, oncolytic viruses can participate in multiple stages of anti-tumor immunity and exert their anti-tumor activity. The virus can induce a strong immune response and enhance the body’s anti-tumor response.
Recombinant viral genome transformation technology has gradually matured, which has greatly improved the efficacy, specificity and safety of oncolytic viruses in tumor treatment. Only a small number of patients have benefited from the anti-cancer therapy “Oncolytic” Therapy).
1. Virus-mediated tumor killing mechanism
(1) Cytotoxic killing effect directly mediated by virus: the virus uses the energy and raw materials of tumor cells and uses it as a place to achieve its own proliferation, on the one hand, it causes the growth of tumor cells to be blocked, and on the other hand, a large number of progeny are amplified The virus lyses the cells. In addition, certain viruses such as adenovirus can produce substances with cytotoxicity and oncolytic activity, and the death protein encoded by the adenovirus E3 region can directly mediate tumor cell lysis.
(2) Oncolytic viruses can also indirectly kill tumors by destroying tumor vasculature. Because the growth of tumors depends on the tumor vasculature to provide nutrients, destroying the tumor vasculature can effectively inhibit tumor growth. Studies have shown that the oncolytic vesicular stomatitis virus (Vesicular Stomatitis Virus, VSV) can directly infect and destroy tumor blood vessels in the body through intravenous administration without affecting normal blood vessels.
VSV oncolytic virus specifically destroys tumor blood vessels, which is conducive to virus spread and replication in tumor tissues, and then recruits neutrophils and other immune cells to the tumor site infected by the virus, starting the neutrophils in the body. Cell-mediated inflammation, which leads to the formation of microthrombi in tumor blood vessels. The microthrombus in the tumor blood vessels affects the blood vessels to provide nutrients to the tumor tissues, which ultimately leads to the slowdown of tumor cell proliferation and induction of apoptosis, thus greatly enhancing the anti-tumor activity of the VSV oncolytic virus.
2. Antitumor immune response mechanism
The immune response caused by oncolytic virus infection can be summarized as follows:
(1) The virus has a strong stimulating effect on the immune cells already present in the tumor tissue, which can greatly change the microenvironment of the tumor and change it from an immunosuppressed environment to an immune activation state, which is the first killing;
(2) Virus-infected tumor cells can express some so-called “danger signals” (such as cytokines, etc.). These “danger signals” can induce immune cells outside the tumor to infiltrate into the tumor, and the activated non-specific immune cells will Kill and engulf those infected but not killed tumor cells, this is the second killing;
(3) Tumor cells lysed by oncolytic viruses release large amounts of tumor proteins, which can be engulfed by non-specific immune cells, and certain tumor-specific antigens can be expressed by these antigen presenting cells and induce T cells to attack uninfected tumor cells This process is similar to the “tumor vaccine”, but it occurs inside the tumor tissue, so it is an “in situ immunization” process, which eventually induces specific CD8+ T cells to cause the third tumor killing.
In order to construct viruses with natural infectivity and increased immunogenicity, these characteristics can be met by methods of deleting, inserting or transferring foreign genes. Many offspring oncolytic viruses have been constructed to express foreign genes as well as viruses with the ability to produce special cytokines (such as human tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, Interleukin 7, interleukin 12, interferon beta, etc.) can even enhance the host’s response to viral infection. This method of allowing the virus to express foreign genes is like “arming” an oncolytic virus, which can enhance the cell lysis ability of the virus.
Antitumor immune response mechanism of oncolytic virus
Oncolytic viruses can be roughly divided into 4 types according to their development process:
(1) Wild-type virus strains or naturally attenuated strains, such as Newcastle disease virus, Coxsackie virus and Reovirus;
(2) Genetically engineered selective attenuated strains, mainly to delete certain key genes of the virus to achieve the tumor selectivity of virus replication, such as ONYX-015, G207, etc.
(3) Gene-loaded virus strains mainly load foreign therapeutic genes on the basis of the aforementioned two oncolytic viruses, such as JX- loaded with granulocyte macrophage colony stimulating factor (GM-CSF) 594 and T-VEC, etc.;
(4) Transcription-targeted virus strains, that is, inserting tissue or tumor-specific promoters in front of the necessary genes of the virus to control oncolytic virus replication in tumor cells, such as G92A.
Oncolytic viruses can be roughly divided into 4 types according to development process
Route of dose
(1) Oral dose
Oral virus vaccines can be used in poliovirus, rotavirus, rabies virus, typhoid virus, etc. However, the immunity generated by the oral route is weaker than the parenteral route, and many viruses are not affected by the pH of the gastrointestinal tract and various enzymes. Active; Some other pathogens that naturally spread through the gastrointestinal tract may inadvertently spread through the faecal-oral route or aerosol, creating additional safety issues.
(2) Intravenous dose
The intravenous route is another convenient route of administration and one of the main directions of current research. However, there are still some difficulties to be overcome in intravenous administration. For example, like other drugs, intravascular medicine is not specific; the antibodies produced by the pre-existing immunity will neutralize the virus particles that have not reached the target site, reducing their effect. Therefore, it is necessary to increase the concentration of the virus that reaches the target site by increasing the dose, but this may increase the body’s inflammatory response.
(3) Radioactive dose
The two better ways to administer radioactive intervention are arterial medication and tumor site medication. Other possible approaches include portal vein medication, intra-gallbladder medication, and pleural and peritoneal medication. The intra-arterial route has many advantages like chemical embolization and radioactive embolization. The virus can be selectively delivered to the target cells. The time that the drug stays is related to the embolization material and the expansion balloon. And due to the limited volume of blood and target organs, this method It can effectively avoid the neutralization and non-targeting effect of circulating antibodies. Drugs at the tumor site inject the virus directly into the tumor tissue, cascading within the tissue. This method is not easy to control and monitor in terms of distribution. Even the application of ultrasound, CT, and magnetic resonance localization injection is not completely risk-free, and it is expensive. Especially for patients who need multiple treatments, it will eventually affect the commercial development and development of this method. Clinical application.
(4) rute of somatic cells as a carrier
Another method of transferring the virus into the human body has not been used in clinical trials, but it has been concerned for a long time, that is, using the cells in the patient as a viral vector. This transfer strategy is to use an autologous cell that is inherently tumor-prone to act as a viral vector, especially immune cells, and expect that cells infected by this indirect in vivo treatment method will carry oncolytic viruses to reach distant malignant tumor sites. This method is also known as the “Trojan Horse” strategy, and this method has proven effective in many animal models. Many cells have become candidates for viral vectors, but further experiments are needed to confirm. In the early stage of clinical trials, it was found that autologous fat-derived mesenchymal tissue stem cells can serve as viral vectors and passed FDA certification. The earliest clinical trials for ovarian cancer were conducted in 2014.
—— To be continued ——
Medicilon (stock code: 688202) is a drug development outsourcing service company (CRO). Founded on February 2, 2004, the company has gone through 16 years and has established a compound synthesis, compound activity screening, structural biology, pharmacodynamic evaluation, pharmacokinetic evaluation, toxicology evaluation, preparation research in Shanghai It is a comprehensive technical service platform that conforms to international standards and is registered with new drugs, and has been recognized by the international drug management department. Medicipuya’s animal laboratory facilities have obtained AAALAC (International Animal Assessment and Certification Association) certification and the National Drug Administration NMPA GLP certificate, and have reached the US Food and Drug Administration GLP standards.
Medicilon has extensive experience in global cooperation. Since 2015, Medicilon has served more than 500 active customers worldwide. It has served many global pharmaceutical companies such as Takeda Pharmaceuticals, Johnson & Johnson Pharmaceuticals, GlaxoSmithKline, Roche Pharmaceuticals, etc. R&D outsourcing services are provided by well-known domestic and foreign clients such as Swiss Medicine, Yangzijiang Pharmaceutical, CSPC, Huahai Pharmaceutical, and Zhongsheng Pharmaceutical.