On October 22, 2019, Xie Zhen's research group at the Beijing National Research Center for Information Science and Technology at Tsinghua University published a study in Nature Communications, which constructed a modular synthetic gene line to regulate the selective replication of oncolytic adenovirus in tumor cells, thereby specifically killing tumor cells and stimulating anti-tumor immunity. This study provides a novel solution for the precise engineering of oncolytic adenovirus, and improves the effect and safety of tumor immunotherapy targeted by oncolytic virus.
(Source: Nature Communications)
Oncolytic virus, as the name suggests, is a "modified" virus used to attack tumor cells. As an emerging tumor immunotherapy method, oncolytic viruses have received widespread attention in recent years.
Scientists have genetically modified some common viruses that are less damaging to the human body (such as herpes virus, pox virus, adenovirus) so that these viruses can specifically attack and destroy cancer cells, while causing less damage to normal cells.
Theoretically, oncolytic viruses can selectively replicate tumor cells to lyse tumor cells, synthesize and release immune effectors or other therapeutic drugs, activate the anti-tumor immune response, and achieve tumor killing control through a variety of ways.
However, due to the difficulty of increasing specificity and immune response, improving the effectiveness of oncolytic virus therapy remains challenging. The existing oncolytic virus regulation methods mainly regulate the specificity of oncolytic viruses through the absence of complementary or tumor-specific promoters, and the regulatory mechanism is relatively single, which cannot effectively cope with the problems of toxic side effects and safety risks caused by marker loss, tumor microenvironment immunosuppression and off-target effects. Although there have been many exciting clinical results of oncolytic viruses, how to improve the targeting and controllability of oncolytic viruses is still a huge challenge.
In the latest study, the researchers first optimized the hepatocellular carcinoma specific promoter and microRNA sensor, and used these artificial gene elements to build a gene switch circuit, which was loaded into the adenovirus vector.
After the introduction of human cells, the hepatocellular carcinoma specific promoter and microRNA signals in the integrated cells are sensed, and the hepatocellular carcinoma cells are judged by logical operations, thereby controlling the selective replication of adenovirus in hepatocellular carcinoma cells and lysing tumor cells.
Figure | Modified oncolytic virus specifically attacks tumor cells (Source: MIT Technology)
In addition, the researchers cloned different immune effector genes into adenovirus vectors. The experimental results of mouse models showed that oncolytic adenovirus that can express and release immune factors can improve the regulation ability of tumor immune microenvironment, help enrich killer T cells at tumor sites, and further enhance anti-tumor immune response.
Finally, the researchers analyzed the key factors affecting the combined use of oncolytic virus and immune effector factors through simulation and computational models, which provided ideas and references for improving the effectiveness of combined oncolytic virus therapy.
The research was supported by the National Natural Science Foundation of China Innovation Group Project, the Beijing National Research Center for Information Science and Technology of Tsinghua University, and the Beijing Hopson Gene Technology Co., Ltd. Xie Zhen of the Beijing National Research Center for Information Science and Technology of Tsinghua University is the corresponding author of the paper, and Huang Huiya and Liao Weixi of the Department of Automation of Tsinghua University and Liu Yiqi of Beijing Hopson Gene Technology Co., Ltd. are the co-first authors of the paper. Chinese Lu Yinying, director of the Liver Tumor Diagnosis and Treatment and Research Center of the Fifth Medical Center of the General Hospital of the Chinese People's Liberation Army, and Cao Yubing, Liu Qiang and Guo Yakun of Beijing Hopson Gene Technology Co., Ltd., participated in the project research.
< h1 class="ql-align-justify" > interview with Huang Huiya, co-first author of the research paper and department of automation at Tsinghua University</h1>
DeepTech: What are the unique advantages of oncolytic viruses in tumor treatment?
Huang Huiya: Compared with other small molecule drugs, oncolytic viruses are a class of platform drugs that target tumor cell therapy through multiple pathways. First of all, oncolytic virus can specifically target infected tumor cells without affecting the normal cell growth state, and kill tumor cells by directly lysis of tumor cells; second, oncolytic viruses as heterologous substances can activate the immune response state of the tumor microenvironment, improve the level of immune response, and make "cold" tumors become "hot" tumors; third, tumor cells directly lysed by oncolytic viruses can release a large number of tumor-specific antigens, thereby activating the body's specific anti-tumor immune response; fourth, Oncolytic virus itself can be used as an expression carrier for other therapeutic drugs, specifically expressing anti-tumor drugs in the tumor microenvironment to improve the killing effect on tumors; fifth, oncolytic viruses can benefit patients in the clinic by directly combining with other anti-tumor drugs. Therefore, oncolytic virus drugs are more regulatable and have better therapeutic effects.
DeepTech: Oncolytic virus treatment has been developed for decades, what level is it at now? What are the main challenges at hand?
Huang Huiya: At present, the anti-tumor ability of oncolytic viruses has been verified in multiple clinical trials. In 2015, the FDA approved Amgen's oncolytic herpes simplex virus for melanoma treatment. In addition, the therapeutic effect of oncolytic virus was further demonstrated through multiple clinical trials of trifocal breast cancer and brain tumors combined with T-Vec and immune checkpoint inhibitor anti-PD-1 antibodies. At present, in addition to herpes simplex virus, there are a large number of virus types used for the modification of oncolytic viruses, such as adenovirus, pox virus, Newcastle disease virus and M1 virus, which are at different stages of clinical verification. However, the current oncolytic virus regulation mechanism is mainly through tumor-specific promoters, or through tumor cell mutations complementary viral gene deletion. The regulatory mechanism is relatively simple, and there are still some problems with the accuracy and stability of targeting tumor cells. With the in-depth study of oncolytic viruses and the rapid development of gene synthesis, editing, and assembly technology, the development of engineered oncolytic viruses through synthetic biology can effectively solve this problem.
DeepTech: Why are oncolytic viruses often used in combination with other immunotherapies?
Huang Huiya: Oncolytic virus therapy kills tumors through viral proliferation, and activates the immunosuppressive tumor microenvironment, which is conducive to the combined application with other immunotherapies. A variety of therapies combined with different treatment mechanisms are beneficial in overcoming recurrence caused by tumor heterogeneity.
DeepTech: Can the idea of programming synthetic gene lines be used to modify other cellular functions, such as immune cells?
Huang Huiya: It can be applied to the modification of other cells, and a variety of gene line switches are currently applied to the improvement of CAR-T therapy to improve the targeting of CAR-T cells and reduce the cytotoxicity of the cell therapy process.
DeepTech: Are there any plans for clinical trials going forward?
Huang Huiya: At present, our research results are promoting preclinical research and clinical trial approval applications.