Start the "fighting" mode. This CAR-T wants to "eat" tetracycline.
Just like Popeye’s love to eat spinach, this CAR-T has to “eat†tetracycline to work – CAR-T is a new type of cell therapy that has been around for many years but has been clinically applied in recent years. A few days ago, "Molecular Science" published the research work of Chinese scientists on the safety of CAR-T: Shanghai Ocean University International Marine Biological Science Research Center, Bion Bio and other units cooperated, using China's own patented lentiviral vector technology, Integrating the "tetracycline-regulated" gene switch into CAR-T, the most widely used leukemia treatment, now achieves control of CAR-T cells, only when CAR-T senses the presence of a specific compound of tetracycline. Will start the "fighting" mode, diligently killing the enemy, and once there are indicators that T cells have "red eye" signs, just stop the supply of tetracycline, CAR-T gladiators will lack energy downtime to prevent the body's " Suicidal" damage. T cells "full fire", accompanied by terrible "storm" The emergence of immunotherapy has made the body's immune system "strive", by adding extracorporeal genetic components to T cells or restarting the immune killing function to form a "living force" against tumors. At present, the most effective method for treating leukemia is CAR-T therapy, which is to export T cells and put a CAR (chimeric antigen receptor) with "navigation" and "detection" in vitro, and then return to the body to deal with it. Cancer cells, but the offensive "firepower" of T cells can be controlled by artificial intervention, but not by the regulation mechanism within the receptor. In the case of "out of control", it is likely to cause severe cytokine release syndrome (CRS). “CRS is vividly referred to as the 'cytokine storm' by the industry.†Yang Guanghua, a co-author of the paper and author of Shanghai Ocean University, explained that cytokine storms are caused by the interaction between T cells, macrophages and tumor cells. Because the "Reload Warrior" T cell has a navigation and detection system, it can acutely feel the presence of tumor cells, and the intracellular pathway is stimulated to release a large number of cytokines, which are the immune cells killing tumor cells. "Important firepower" that can make it apoptotic. "The cytokine-induced storm is unavoidable in CAR-T treatment." Yang Guanghua said that it is not only a side effect in treatment, but also a clinical manifestation of treatment of tumors. American girl Emily is the first child with leukemia cured by CAR-T. She has a terrible "storm" experience. According to records, after the cells were injected into the body, Emily quickly developed a fever, sudden drop in blood pressure, and severe coma. In the intensive care unit, she was snorted for two weeks by a ventilator. At the time, the doctors thought she could not survive. The test report showed that her body's IL-6 protein surged, indicating that her immune system is constantly attacking herself. Subsequently, the doctor decided to use her an immunosuppressive drug to stop this self-attack. Within a few hours after the medication, Emily's condition immediately became better, and further tests showed that the cancer cells in her body had disappeared. It can be seen that the “storm†induced by CAR-T is inevitable. However, because CAR-T has a high cure rate of 80%-90%, although this therapy is quite dangerous, it was approved by the US Food and Drug Administration (FDA) for clinical use last year and was approved for entry into the US in April this year. Medical insurance. How to make CAR-T with high cure rate bid farewell to high risk? The academic community has conducted a lot of research and proposed a variety of technical routes, such as administration of immunosuppressive drugs, implant-inducible suicide gene system, and hormonal treatment in severe cases, but the current "storm" complications are still becoming standard medical care. Obstacles. It is generally believed in the industry that the difficulty of CAR-T application is not concentrated in the early stage of cell therapy, but in the later side treatment and quality control. "Inhibitor's 'remediation' is difficult to grasp the initiative." Yang Guanghua said that through the "energy" control of genetic components will be more active, but also more operability. Change the virus to be a friendly, add a "remote control" to the T cell. “The CAR-T technology patent is almost covered by the United States,†said Yang Guanghua. In fact, the US medical field is still constantly exploring new mechanisms, such as the April report of Nature, commemorating the new cell theory and new inhibitors of the Sloan-Kettering Cancer Center (MSK) to prevent "storms" and patents. . "We can't follow the thoughts of others to control the 'storm', and then we will encounter the 'patent threshold' when applied." Yang Guanghua said that he led the team from another angle in 2009, trying to give T cells. Add a "remote control" to increase the control of T cells in CAR-T technology. "Lentiviral vectors are an effective tool for people to perform genetic engineering operations." Yang Guanghua said that lentiviral vectors can "invade" cells like viruses, but they are not toxic and can insert target fragments into target cells to achieve gene expression. Transformation. It is not easy to "domesticize" the virus into a friendly army, the clinical requirements are strict, and mass production and purification are very difficult. The Yang Guanghua team tried to improve the CAR-T through the lentiviral vector and enabled it to achieve industrial production. At the same time, Shanghai Bion Biomedical Technology Co., Ltd. was established based on this technology. "Different from common chemical synthetic drugs, the large-scale production and purification of gene drugs is very difficult. At present, in the large-scale production of gene vectors, the purification rate of Bion Bio has been 10 times higher than that of international counterparts." Yang Guanghua said that lentivirus The production of the vector includes a series of complicated steps such as plasmid acquisition, cell transfection, virus collection and purification, each step affects the activity of the finally obtained vector, and therefore needs to be continuously optimized in the process to obtain a high quality carrier. During the transduction process, the team explored and optimized the key conditions of carrier dosage, transduction conditions, T cell culture, and enhancer use, and finally achieved success. “All technologies have been patented. The core invention patent has been authorized by the international patent system PCT.†Yang Guanghua said, “We also have patented technology for large-scale production of viral carriers, which can meet the needs of domestic and foreign pharmaceutical companies, hospitals, etc. -T induces the need for lentiviruses for clinical trials in Phase I and Phase II." In vitro experiments prove that the "tetracycline regulation system" is highly efficient "Switching system through molecular synthesis techniques such as gene synthesis, restriction enzyme digestion, etc., we integrate the 'tetracycline regulatory system' with the CD19-CAR structure into the lentiviral vector." Yang Guanghua said that while the T cell is undergoing CAR transformation The "tetracycline remote control" is also assembled synchronously. After taking tetracycline, the CAR-T that enters the human body begins to function; after stopping taking the drug, CAR-T will no longer be expressed, and the drug dose can be used to control the strength of CAR-T. The advantage of this is that when the patient has an unbearable adverse reaction, stopping the administration of tetracycline can stop the CAR-T functioning in the patient's body. When the patient's tolerance is gradually improved, the patient can continue to start treatment by taking the drug. . During the interval, B cells can be restored to enhance the anticancer effect. "Pre-clinical basic research has achieved very good results." Yang Guanghua said that in this study, they developed a new inducible cell, iCAR19, by incorporating a "tetracycline regulatory system" into the CD19-CAR construct. T. The experimental data showed that the new iCAR19 T cell proliferation, cytokine production, CAR expression, and CD19-specific cytotoxicity were strong. After 48 hours of induction with the tetracycline derivative, the relative CAR expression of the induced cells was 5 times that of the uninduced cells, indicating that the administration of tetracycline can stimulate the fighting power of the "tetracycline warrior". In addition, cells treated with tetracycline derivatives have a very significant high specific cleavage of target cells. These results indicate that the implant system successfully controls the activity of iCAR19 T cells. "The stronger our control of T cells, the stronger the clinical safety will be." Yang Guanghua said that the new cells also maintain a strong anti-tumor effect. “This technology needs to be verified by animal experiments, clinical trials and other steps before it is actually applied to human body. We are further optimizing this technology for problems that may be encountered during actual use. Adjustments to carry out in-vivo experimental verification as soon as possible.†Yang Guanghua said that the team’s goal is clinical application, so GMP production standards are followed during the experimental phase, and all manufacturing processes and subsequent tests are carried out in GMP facilities, the quality of the gene carrier. Control is also strictly in accordance with FDA guidelines. Fresh mussels are a popular seafood product. After shelling, it can be steamed, cooked or mixed with other vegetables. Very delicious. Due to the large yield of mussels, it is not easy to store them after harvest. Most of them are cooked and processed into dried products-mussels. Mussels have high nutritional value and have certain medicinal value. 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