What is the role of oncolytic virus in tumor diagnosis and treatment?
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What is the role of oncolytic virus in tumor diagnosis and treatment?
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What is the role of oncolytic virus in tumor diagnosis and treatment?
Cancer has always been a great threat to human health and survival.
Surgery, radiotherapy and chemotherapy can improve the survival rate of cancer patients, but the survival rate of most advanced cancer patients is usually very low or cannot afford the high chemotherapy costs.
The emergence of oncolytic viruses provides us with new strategies to alleviate and even treat malignant tumors.
The main purpose of this review is to introduce the latest developments in clinical applications or trials of various OVs, and look forward to the future based on the current advantages and disadvantages of OVs.
In 2013, more than 8 million people died of malignant tumors worldwide, rising from the third leading cause of death in 1990 to the second leading cause of death in 2013, second only to cardiovascular disease.
According to relevant data, since the mid-1970s, the mortality rate of malignant tumors among Chinese residents has increased by 83.1%.
Malignant tumors have become one of the main causes of cancer. Although there are many treatments, including surgical treatment, radiotherapy, chemotherapy and the latest immunotherapy, which can prolong the survival of cancer patients, they have some limitations.
Surgical treatment is mainly used for early-stage cancer patients, and severe side effects make it difficult for patients to tolerate radiotherapy and chemotherapy.
In addition, traditional immunotherapy still has many shortcomings; for example, the objective effectiveness of patients receiving immunotherapy is only 10% to 30%, so there is an urgent need to improve the efficiency of immunotherapy.
In summary, existing cancer treatments need to propose new treatment methods, which should have accurate tumor targeting, powerful tumor-killing properties, and low toxic and side effects.
Oncolytic virus therapy is a treatment method that uses the virus to replicate itself to kill cancer cells. There are many kinds of viruses, but not all viruses can be designed as oncolytic viruses (OV).
The typical characteristics of these OVs must include non-pathogenicity, the ability to target and kill cancer cells, and the ability to transform and express tumor killer factors through genetic engineering methods.
The history of using microorganisms to treat cancer can be traced back to 1890; a surgeon named William B. Colley at Memorial Hospital in New York was the first to observe tumor regression in patients infected with this pathogen, he called this This pathogen is an anti-tumor agent.
In 1935, Connell used Clostridium histolyticum to treat advanced cancer, and soon afterwards he observed tumor regression. Later, in the 1950s and 1970s, doctors consciously injected live viruses into cancer patients and showed positive activity.
However, some side effects are emerging. These early studies were carried out by using natural viruses because these viruses were not selectively designed for tumors, especially in immunosuppressed patients with leukemia or lymphoma (5 out of 8 patients suffered from West Nile virus treatment) Severe encephalitis).
OV has become a promising new era of cancer drugs. There is reason to believe that oncolytic virus therapy may become one of the main treatments for cancer.
The emergence of oncolytic virus therapy not only completely changed the standard of cancer treatment, but also revolutionized the concept of cancer treatment.
It is called the third revolution in cancer treatment after traditional chemotherapy and targeted therapy.
The origin and development of oncolytic virus therapy
The concept of using viruses to treat tumors has existed for more than 100 years. As early as 1904, it was reported that a 42-year-old woman with leukemia had a tumor regression due to influenza.
Then, in 1912, Italian doctors discovered that injecting rabies vaccine would cause cervical cancer to resolve, which led to the concept of OV therapy and a series of related studies.
In the 1950s and 1970s, researchers used wild-type viruses to conduct research. A large number of clinical trials are used to treat tumors, but due to the inability to effectively control the pathogenicity of the virus, OV ranks second in cancer treatment.
It was not until the 1980s that the emergence of genetic engineering technology made it possible to modify the genetic composition of viruses, and then genetic engineering attenuated and highly selective viruses appeared.
In 1991, preclinical animal experiments reported that HSV-1 modified by TK gene can inhibit the growth of mouse gliomas, prolong the survival period of mice, and has good safety. In 1996, a genetically modified adenovirus onyx-015 entered the first phase of clinical trials.
In 2004, a non-pathogenic intestinal cell patient orphan-like virus, RIGVIR, was approved in Latvia for the treatment of melanoma and became the first OV approved by regulatory agencies for cancer treatment.
In October 2015, the U.S. Food and Drug Administration (FDA) approved the listing of T-VEC (talimogene laherparepvec, Imlygic).
In 2016, T-VEC was approved to be marketed in Europe and Canada, marking the maturity of OV technology in cancer treatment.
At present, three OV products have been approved for marketing, and another six OV products are undergoing Phase III clinical studies.
Compared with other tumor immunotherapy methods, OVs have the advantages of high killing efficiency, precise targeting, fewer side effects or drug resistance, and low cost.
All these make oncolytic virus therapy a promising anti-cancer therapy compared with surgical treatment, radiotherapy and chemotherapy and targeted therapy.
Application of oncolytic virus
Three viruses currently in clinical use, RIGVIR, Oncorine and T-VEC, have shown satisfactory therapeutic effects.
In addition, many OVs are in the pre-clinical testing stage; among them, herpes virus, adenovirus and vaccinia virus show good experimental results. Below, we will introduce the application of different OVs in tumor diagnosis and treatment.
At present, various advanced imaging technologies play an irreplaceable role in tumor diagnosis, especially CT and MRI, which play an irreplaceable role in tumor positioning and local invasion assessment.
However, the early detection of primary tumors and small metastases is still not available effectively, so it is necessary to discover imaging techniques with higher sensitivity and accuracy.
In recent years, the use of OV for accurate tumor imaging has attracted more and more attention. OV with specific genes can selectively infect tumor cells and replicate or express genes of interest in tumor cells.
We can detect gene expression products in cancer cells, such as fluorescence, to obtain noninvasive real-time in vivo molecular imaging. Fluorescence imaging is also one of the applications of OVs in accurate tumor imaging.
Green fluorescent protein (GFP) is derived from invertebrate marine animals and can be used to detect tumor behavior, including amplification, invasion and metastasis. In a study by Rojas JJ, compared with other imaging techniques, after injection of adenovirus with GFP gene, vesicular stomatitis virus (VSV), vaccinia virus and measles virus, the mouse model successfully expressed GFP.
The results show that OV has higher accuracy and flexibility for tumor imaging. In addition, OV also shows unique advantages in nuclear medicine imaging. Nuclear medicine equipment can detect the reporter gene expressed by OV in cancer cells to obtain the precise location of the tumor.
Currently commonly used reporter genes include hNIS, TK gene and hSSTR2. Imaging techniques commonly used to detect OVs tumors include optical molecular imaging (bioluminescence imaging and fluorescence imaging), single-photon emission CT (SPECT)/CT, PET and MRI.
All of these help to evaluate the safety and therapeutic effect of oncolytic virus therapy, as well as more specific diagnostic techniques to detect the source of the tumor.
Therefore, OVs have unique advantages in accurate imaging of tumor tissues, and the combination of OVs and imaging methods has great potential in the early diagnosis of tumors. See Table 1 for details.
The three oncolytic virus drugs currently approved for certain clinical cancer treatments are RIGVIR, Oncorine and T-VEC, and they have all achieved good therapeutic effects. See Table 2 for details.
The current clinical trials of OV are shown in Table 3 and Table 4.
Rigvir is a natural intestinal cytopathic human orphan type 7 (ECHO-7) picornavirus, which has been approved for the treatment of melanoma in Latvia, Georgia and Armenia.
At the same time, it became the world’s first OV approved by the regulatory authorities in 2004. Although it has been approved by the regulatory authorities, there are few articles describing its biological properties and efficacy in the treatment of malignant tumors.
Only three English-language articles related to Rigvir are public, including a review article, a case study of three patients, and a retrospective analysis of patients with early melanoma.
Among them, a retrospective study found that patients with early melanoma (IB, IIA, IIB, and IIC) who received surgical resection and Rigvir treatment (n=52) survived longer than those who received surgical resection alone (n=27).
Despite the fact that the patient was declared disease-free after the operation, he only took Rigvir after the surgical wound had healed. Low-grade melanoma after surgical resection seems to be more sensitive to Rigvir treatment.
However, the potential of Rigvir to treat patients with high-grade melanoma is still unknown, because the English report only contains case studies and no more extensive trials).
However, we believe that with our further understanding of the anti-cancer mechanism of Rigvir, better treatments for malignant tumors will soon come out.
Oncorine is not only the first OV approved for clinical use in China, but also the first recombinant OV in the world.
After being approved by China’s State Food and Drug Administration (SFDA) in 2005, it was used to treat patients with head and neck cancer.
Oncorine is a recombinant human type 5 adenovirus injection. After various comprehensive randomized trials, researchers began clinical trials of Oncorine.
The surgical method is that the patient receives combined treatment with cisplatin and 5-FU, within a cycle of 2 to 43 weeks, at a rate of 5e11 to 1.5E12VP/day, for 5 consecutive days, with or without cancer acid.
The effective rates of combined chemotherapy and chemotherapy alone were 78.8% and 39.6%, respectively.
The high seroprevalence of several adenovirus serotypes (including the backbone of oncovirus, serotype 5) limits the ability of intravenous delivery of oncovirus to treat highly metastatic diseases, so the use of low seroprevalence or modified knob protein is A better way to deliver oncovirus.
These adenovirus vectors are currently undergoing clinical trials to test their safety and effectiveness after intravenous injection. Although the oncolytic adenovirus has been developed for more than 20 years, Oncorine is still the only adenovirus approved for cancer treatment and must be used in combination with chemotherapy.
Herpes is the first virus to fight cancer through genetic engineering. According to a 1991 study, HSV dlspTK (a TK deleted HSV-1) improved the overall survival rate of a mouse model of glioblastoma (50). Subsequently, with the development of related research, the production, preclinical and clinical trials of new HSV gamma34.5-deficient viruses appeared in this field.
These viruses lack both neurovirulence and the ability to inhibit the antiviral PKR response. In November 2017, it was announced in clinical trials that gamma34.5-deficient viruses include T-VEC (52), HSV1716 (Seprehvir), G207 and RP1. NV1020 retains a copy of gamma34.5 and also contains other attenuating mutations of TK, UL24, UL55 and UL56, which have also been tested in human patients.
In addition, a naturally occurring HSV mutant strain HF-10 retains a copy of gamma34.5, and has been clinically tested in patients with breast cancer and head and neck cancer.
Talimogenelaherparepvec was approved by the US FDA in 2015 for the treatment of unresectable metastatic melanoma, and then approved in Europe for locally advanced or metastatic skin melanoma.
T-VEC is approved for the treatment of advanced melanoma lesions of the skin through intratumoral injection, and has shown a single-agent efficacy.
Single-agent efficacy has also been used to evaluate the safety and effectiveness of patients with solid tumors of the liver, pancreas, and advanced nervous system, as well as T-VEC alone or in combination with checkpoint inhibitors, chemotherapy or radiotherapy in the treatment of melanoma.
According to an article published in 2017, the use of T-VEC and PD-1 inhibitor pembrolizumab to treat patients with advanced melanoma has achieved satisfactory results.
There are currently at least 70 serotypes of human adenovirus, serotype 5 is the most commonly used (6 of the 7 oncolytic adenoviruses used in clinical trials are serotype 5). So far, interesting clinical data have been published, including terminal lysine in solid tumors, CG0070 in bladder cancer, and DNX-2401 in malignant brain tumors.
So far, three oncolytic vaccinia viruses have been used clinically. They are from Wyeth (SillaJen, JX-594, pexastimogene devacirepvec/Pexa-Vec), Western Reserve (genetically modified, TG6002) and Lister (GeneLux, GLONC1/GLV). -1h68) Vaccinia strains.
As a representative of vaccinia virus, Pexa Vec is designed to express human GMCSF and has been tested in more than 300 patients. It has shown good effects in improving patient tolerance and extending patient life.
A clinical trial of the Coxsackie virus called Cavatak is underway, and many trials are based on the Phase 2 data of the 2015 stage II and IV melanoma.
According to a report, the initial DRR is 21%, which is the regression of distant non-injectable lesions.
Retroviral replication vectors (Tocagen, Toca-511, vocimagene AMIRETROPEVEC) are different from the OV discussed above.
These vectors are insoluble, but on the contrary, they replicate selectively in dividing cells and have defective innate immunity and interferon response. sex. Regarding the clinical trials of retroviruses, it is striking that Toca 511 is currently in phase 2/3 clinical trials of malignant glioma and has shown positive interim results.
In addition, retroviruses may become a powerful “weapon” for the treatment of certain malignant tumors, especially gliomas.
Vesicular stomatitis virus
At present, VSV research is mainly aimed at the treatment of liver cancer. For example, an engineered VSV variant that overexpresses interferon b is undergoing clinical trials for liver cancer.
Anti-cancer mechanism of oncolytic virus
As a promising cancer gene therapy agent, OVs have the unique ability to selectively replicate in cancer cells and cause inflammation and even death of cancer cells.
Exposure to cancer-related antigens further leads to the host immune response. As shown in Figure 1, the anti-cancer mechanisms of OV include direct oncolysis or cytotoxicity to cancer cells, or indirect induction of bystander effects (including destruction of tumor blood vessels) and tumor immunotherapy.
At present, the two most challenging problems of oncolytic virus therapy are as follows:
(i) To ensure that the virus can invade and replicate in tumor cells to the greatest extent without infecting healthy tissues and cells, so as to minimize damage Damage to the body;
(ii) Prevent the virus from being eliminated by the body’s powerful immune system, resulting in a significant reduction in efficacy.
For these two problems, on the one hand, we can further modify the genome to enhance the specificity of OV; on the other hand, we can try to construct an appropriate unit vector for OV.
You can choose healthy cells in the body to help OV achieve immune escape. On this basis, targeted drug therapy can be combined with oncolytic virus therapy to enable OV to carry targeted drugs in a certain way, thereby enhancing the anti-cancer effect.
It is believed that the future development direction of oncolytic virus therapy will be an organic combination of genetic modification, viral vector construction and targeted drug therapy.
Combination of cancer treatment strategy and oncolytic virus therapy
Tumor-targeted cell-delivered therapeutic oncolytic virus
The blood system is a very defensive environment. In this environment, innate immunity and adaptive immunity can neutralize virus particles and significantly reduce efficacy.
Therefore, finding a suitable vector to deliver OV to tumor tissues for effective treatment has become a top priority. Carrier cell research is moving in the direction of using cells.
These cells can not only provide the shielding of antibodies and complement, but also make non-target organs and tumor sites lose their targeting, and exert their anti-tumor effects.
Currently, the most commonly used cell carriers are cell carriers, including antigen-specific T cells (AST), cytokine-induced killer cells (CIK), mesenchymal stem cells, and blood-growing endothelial cells (BOECs).
An ideal cell vector must have the following characteristics: first, it must be susceptible to virus infection; second, it can help the virus locate tumor tissues when the immune system cannot recognize it; finally, it can release offspring viruses to attack distant cancer cell.
In addition, the emergence of nanocarriers has attracted great attention. Nanocarriers with higher delivery efficiency include lipid nanocarriers, polymer nanocarriers, organic nanocarriers and metal nanocarriers.
They can enhance the ability of OVs to increase the concentration of therapeutic drugs at the tumor site, tumor selectivity and targeting, and evade immune response.
Genetically engineered oncolytic virus
In order to improve the therapeutic effect, modification of OVs through genetic engineering, including genome insertion and deletion, can provide additional therapeutic molecules to cancer cells and effectively avoid the widespread resistance of single-target anticancer drugs.
Currently, there are nearly a hundred therapeutic exogenous genes in research, such as cell death-related molecules, anti-angiogenesis molecules, and small RNA molecules that inhibit tumor-related genes (including miRNA, siRNA, shRNA and lncRNA). Suicide gene therapy is also one of the methods of tumor gene therapy, also known as virus-mediated enzymatic prodrug therapy (VDEPT).
Different from other combination therapies, OV can achieve specific local expression effects by carrying therapeutic transgenes, which to a certain extent means more precise tumor killing.
In addition, the long-term expression effect of related genes can be obtained by directly modifying foreign genes on replicable egg cells. Due to the heterogeneity of tumor cells, monotherapy is unlikely to achieve satisfactory results. Therefore, the combination of OV therapy and other therapies may be a better way to improve the efficacy and maximize the survival rate of patients.
Combination of radiotherapy and oncolytic virus therapy
The combination of radiotherapy and oncolytic virus therapy has a synergistic effect on tumor treatment in multiple models. In addition, radiation therapy can also be used in combination with oncolytic vaccinia virus to improve efficacy. A study showed that the synergistic effect depends on radiation-induced suppression of JNK signal.
In addition, VACV-scAb-VEGF can increase the sensitivity of the tumor site to radiotherapy. In a study using a mouse xenograft as a model, VACV-scAb-VEGF enhanced the anti-tumor effect.
The combination of radiotherapy and oncolytic virus therapy can produce enhanced anti-tumor effects.
Chemotherapy combined with oncolytic virus therapy
There are precedents for the combination of standard chemotherapy and viral therapy. For example, adenovirus has been successfully used in combination with cisplatin, 5-FU, doxorubicin, temozolomide, irinotecan and paclitaxel, and the combined drug has shown enhanced anti-tumor effects.
At the same time, this combination therapy also shows higher safety and further prolongs the patient’s survival period. In addition, the combined application of vaccinia virus and paclitaxel also showed a synergistic effect.
In xenograft models, sorafenib combined with oncolytic vaccinia virus showed good anti-tumor effects, while trials on patients showed good safety and clinical response, and it has been approved for systemic liver, kidney and thyroid cancer. treatment.
Combined application of immune checkpoint inhibitors and oncolytic virus therapy
Although there are few reports on the combination of immune checkpoint inhibitors and oncolytic virus therapy, the combination of immune checkpoint inhibitors against PD-1 or/and CTLA-4 and oncolytic virus therapy provides new cancer treatments.
Checkpoint inhibitors and OV therapy have a synergistic effect in initiating or enhancing the immune response.
Several related studies have been conducted, and the results show that OVs have stronger anti-tumor effects when used in combination with immune checkpoint inhibitors.
In addition, unpublished studies have shown that the combination of immune checkpoint inhibitors and oncolytic virus therapy does not increase side effects. It is expected that more immune checkpoint inhibitors will be found in combination with OVs to obtain better therapeutic effects.
Although many clinical trials of oncolytic virus therapy have confirmed the good therapeutic effect of oncolytic virus therapy, the therapy still has certain limitations.
First of all, oncolytic virus therapy does not have a stable effect on different individuals, because everyone’s physical environment is different, and OVs are too easily cleared by the human immune system.
Secondly, the biological safety of oncolytic virus therapy is worthy of further study, especially for people with weakened immunity.
Third, the types of OV currently available for clinical treatment or trials are limited. In order to solve these problems and further improve the efficacy of oncolytic virus therapy, we can organically combine the use of OVs, the construction of cell vectors, and the tumor-killing drugs or molecules carried by OVs through genetic engineering to achieve the best therapeutic effect.
Extend the survival period of patients. In addition, more clinical trials are needed to ensure the biological safety of oncolytic virus therapy, and more OVs should be constructed as soon as possible for clinical treatment.
In addition, it is believed that with the breakthrough of related research, oncolytic virus therapy will soon be extended to the treatment of cancer.
Cao GD, He XB, Sun Q, Chen SH, Wan K, Xu X, Feng XD, Li PP, Chen B and Xiong MM (2020) .The Oncolytic Virus in Cancer Diagnosisand Treatment.Front Oncol 10. :1786. doi:10.3389/fonc.2020.01786
What is the role of oncolytic virus in tumor diagnosis and treatment?
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