At 9: 30am on July 22nd, the first batch of 25 science and technology innovation board stocks started trading on the Shanghai Stock Exchange, and science and technology innovation board officially opened.

　　Chen kangliang

　　2019 is a "big year" for China’s capital market reform, including the establishment of science and technology innovation board and the pilot registration system, and many other heavy reforms have been carried out one after another, which not only achieved phased results, but also triggered the market’s expectation on how to "continue to reform" in the next step. In this regard, the Central Economic Work Conference, which closed in Beijing on December 12th, gave the answer.

　　The meeting proposed to speed up the reform of the financial system, improve the basic system of the capital market, improve the quality of listed companies, improve the exit mechanism, and steadily promote the reform of the Growth Enterprise Market and the New Third Board.

　　Dong Dengxin, director of the Institute of Finance, Wuhan University of Science and Technology, said that the Central Economic Work Conference made clear four requirements on how to reform the capital market in China in the next step, among which "improving the basic system of the capital market" was the first one, which was the requirement of clearly promoting the modernization of the capital market governance system and governance capacity from the height of top-level design, and was in line with the spirit of the Fourth Plenary Session of the 19th CPC Central Committee.

　　Dong Dengxin further pointed out that as far as the development of China’s capital market is concerned, in the past 30 years, it has focused on the expansion of scale, from scratch, from small to large, and paid relatively little attention to the improvement of the basic system. However, it should be noted that institutional advantage is the greatest advantage and institutional development is the greatest development. It is of great significance to improve the basic system of the capital market, especially considering that China’s capital market should achieve high-quality development.

　　"Relevant systems, including information disclosure system, IPO (initial public offering) system, delisting system, etc., all need to be further improved, and the direction is to realize the marketization, legalization and internationalization of the capital market." Dong Dengxin said.

　　In order to improve the quality of listed companies, Zhang Yuewen, director of the Corporate Finance Research Office of the Institute of Finance of China Academy of Social Sciences, said that listed companies are the foundation of the capital market, and the long-term healthy development of the capital market can only be guaranteed if there are high-quality listed companies. However, in the current China capital market, the quality of some listed companies is worrying, and there are still big problems, including the decline in comprehensive financial quality and the increase in asset-liability ratio; There are defects in corporate governance, and the relationship between controlling shareholders and minority shareholders is alienated; The quality of information disclosure is not high; The protection of investors’ rights and interests is not paid enough attention, and it needs to be reformed urgently.

　　To this, Dong Dengxin also agreed. He said that in the past, market players and regulators paid insufficient attention to improving the quality of listed companies, but this year, the attention of all parties has been continuously strengthened. A few days ago, the China Securities Regulatory Commission issued the "Action Plan to Promote the Quality Improvement of Listed Companies", striving to greatly improve the overall appearance of listed companies through three to five years’ efforts. This indicates that the special reform to improve the quality of listed companies has moved from blueprint planning to construction, and the next step is to implement it, including improving the delisting mechanism.

　　Zhang Lichao, a senior researcher at Guosen Securities, also said that improving the delisting system of listed companies and strengthening delisting efforts are important components of multi-level capital market construction, which plays an important role in optimizing resource allocation, promoting the survival of the fittest, improving the quality of listed companies and protecting the legitimate rights and interests of investors. The remarkable increase of delisting companies since this year shows that the export of A-share market is gradually smooth. Only by making the delisting channels smooth can the capital market become an organic system with normal metabolism, which will also objectively promote the improvement of the quality of listed companies.

　　Li Zhan, chief economist of zhongshan securities, believes that the diversified delisting mechanism of China’s capital market will be accelerated in the future, including both compulsory delisting and active delisting, as well as restructuring delisting methods such as absorption and merger, clearing assets replacement and selling shells, and gradually converge with developed capital markets such as the United States.

　　Pan Xiangdong, chief economist of New Era Securities, said that this is an important area for deepening the reform of China’s capital market, especially the conditions surrounding the reform of the pilot registration system of GEM have become more and more mature. Growth Enterprise Market will take over from science and technology innovation board and become the main battlefield of China’s registration system reform in the future.

　　In fact, the top-level design to promote the reform of the registration system of the Growth Enterprise Market was published nearly four months ago. In August, the Opinions of the Central Committee of the Communist Party of China and the State Council on Supporting Shenzhen to Build a Pilot Demonstration Zone in Socialism with Chinese characteristics proposed that we should study and improve the GEM listing, refinancing, mergers and acquisitions, and create conditions to promote the reform of the registration system.

　　Pan Xiangdong further pointed out that encouraging science and technology enterprises to list on the GEM will help to further lower the threshold for science and technology enterprises to enter the capital market; GEM and science and technology innovation board will form an organic supplement to further improve the construction of multi-level capital markets; The implementation of the registration system for GEM enterprises can encourage more high-quality operating assets such as small and medium-sized enterprises to enter the GEM, improve the capital market structure of the GEM, and promote the healthy development of China’s capital market.

　　CCTV News:Today, the Supreme People’s Court held a press conference to issue the Opinions on Giving Full Play to the Judicial Function and Strengthening the Judicial Protection of Property Rights, which put forward clear requirements for the relevant judicial execution from three aspects: the basic principles of strengthening the judicial protection of property rights, judicial policies and mechanism construction.

　　Today, the Supreme People’s Court also issued the Implementation Opinions on Properly Handling Historical Property Rights Cases in accordance with the Law. The Implementation Opinions require adhering to the principles of seeking truth from facts, equal protection, correcting mistakes according to law and combining correction with prevention, providing equal judicial protection for all types of property rights subjects, unblocking the filing channels of property rights complaint cases, and standardizing the application of retrial procedures.

　　Equal protection of economic property rights of all forms of ownership

　　The "Opinions" require that the litigation status and legal application of all kinds of property rights subjects be treated equally, pay attention to equal protection of non-public property rights, and equally protect the litigation rights and substantive rights of Chinese and foreign parties.

　　Punish all kinds of crimes against property rights according to law, and equally protect economic property rights of all forms of ownership.

　　Yan Maokun, Director of the Supreme People’s Court Research Office:It is emphasized that crimes against state-owned and collective assets should be punished according to law, and criminal law protection for non-public property should be strengthened, and crimes against the property rights of non-public enterprises and investors, managers and employees in the non-public economy should be punished according to law.

　　The "Opinions" require an objective view of the irregularities in business operations, and acquit those who have insufficient conviction basis according to law.

　　Yan Maokun, Director of the Supreme People’s Court Research Office:It is emphasized that we should treat it objectively from the perspective of history and development, strictly follow the principles of a legally prescribed punishment for a crime, never suspecting a crime, and handling related cases fairly according to law. All kinds of economic activities, except those explicitly prohibited by laws and administrative regulations, shall not be treated as crimes; Those who violate laws and regulations but do not constitute a crime, or whose crimes and non-crimes are unclear, shall be declared innocent according to law.

　　Resolutely prevent economic disputes from being treated as crimes

　　The Opinions call for a strict distinction between economic disputes and criminal offences, and resolutely prevent economic disputes from being treated as crimes. Emphasis is placed on giving full consideration to the characteristics of the non-public economy, strictly grasping the criteria for identifying criminal offences, and resolutely preventing economic disputes from being identified as criminal offences. For all kinds of economic disputes, regardless of the actual losses, we must always adhere to handling cases according to law and fair trials.

　　Use coercive measures and seizure and freezing measures with caution according to law.

　　In the past, in some places, there were some irregular problems in sealing up, distraining and freezing measures, such as mistakes, exceeding the standard, sealing up, distraining and freezing the property of outsiders, resulting in property damage and loss, and some enterprises that still have the ability to produce and operate could not produce and operate normally. The "Opinions" clearly stated that compulsory measures and seizure, seizure and freezing measures should be used with caution in accordance with the law to minimize the adverse impact on the normal production and operation activities of enterprises.

　　Yan Maokun, Director of the Supreme People’s Court Research Office:If it is required that in criminal trial, the defendant who has been arrested meets the conditions of obtaining a guarantor pending trial and monitoring his residence, the compulsory measures shall be changed; In criminal, civil and administrative trials, if it is really necessary to take measures of seizure, seizure and freezing, except for enterprises that need to be ordered to close down according to law, necessary working capital and current accounts may be reserved for enterprises as appropriate.

　　Strictly regulate the disposal of property involved.

　　The "Opinions" require strict regulation of the disposal of the property involved, and safeguard the legitimate rights and interests of enterprises and personnel involved in the case according to law.

　　Yan Maokun, Director of the Supreme People’s Court Research Office:It is required to strictly distinguish between illegal income and legal property, strictly distinguish between personal property and corporate property, and strictly distinguish between personal property and family members’ property. In accordance with the requirements of openness, fairness, standardization and efficiency, strictly implement and constantly improve the system of custody and disposal of property involved.

　　Fair trial of administrative agreement cases according to law

　　The "Opinions" require fair trial of administrative agreement cases according to law, and promote the construction of a government ruled by law and government integrity.

　　Yan Maokun, Director of the Supreme People’s Court Research Office:It is emphasized that for disputes caused by investment promotion, cooperation between government and social capital, we should carefully examine the reasons why the agreement cannot be fulfilled and the liability for breach of contract.If the government violates its commitments, especially for reasons such as the change of government and the replacement of leaders, it will resolutely support the reasonable demands of the administrative counterpart according to law.

　　Fair trial of cases of property expropriation and requisition according to law

　　The Opinions emphasize that cases of property expropriation and requisition should be tried fairly according to law and the legitimate rights and interests of administrative counterparts should be safeguarded. It is required to reasonably grasp the scope of public interests applicable to expropriation and requisition, and resolutely prevent the expansion of public interests. Follow the principle of timely and reasonable compensation, and fully protect the legitimate rights and interests of the expropriated.

　　The "Opinions" call for punishing intellectual property crimes according to law and strengthening judicial protection of intellectual property rights. Deal with historical property rights complaint cases according to law, and resolutely implement the requirement that mistakes must be corrected. It is required to establish a special working mechanism and pay close attention to screening and correcting a number of complaints about property rights disputes that have been strongly reflected by the society. If the facts are unclear, the evidence is insufficient, and the applicable law is wrong after examination, the party concerned shall be corrected and compensated in time according to law.

　　Properly handle historical property rights cases according to law.

　　The "Implementation Opinions on Properly Handling Historical Property Rights Cases in accordance with the Law" requires adhering to the principles of seeking truth from facts, equal protection, correcting errors according to law and combining correction with prevention, providing equal judicial protection for all types of property rights subjects, unblocking the filing channels of property rights appeal cases, and standardizing the application of retrial procedures.

　　The "Implementation Opinions" clearly put forward that the people’s courts should promptly review and carefully screen the effective judgments on property disputes involving major property disposal and illegal crimes committed by private enterprises and investors since the reform and opening up, and if the parties or outsiders lodge complaints; If there are mistakes, they should be resolutely corrected according to law. Focus on the screening, correction and publicity of major typical cases.

Screening and retrial of property rights complaint cases caused by government actions according to law

　　The "Implementation Opinions" stipulates that when screening and retrial property rights cases, the people’s court shall retry and revise the legal rights and interests of the investors for all kinds of contracts signed with the investors according to law in activities such as attracting investment, cooperation between the government and social capital, etc. because of the change of government and the replacement of leaders, or because of legal reasons, the government promises and contract agreements are changed, and the property losses suffered by the investors are not compensated according to law.

　　Teng Wei, Vice President of the Supreme People’s Court Trial Supervision Court:In the process of expropriation and requisition of land, houses and other property, the people’s court shall review the wrong judgment that the government failed to give fair and reasonable compensation to the expropriated person in accordance with the scope, form and standard of compensation, and initiate a retrial.In the retrial review and trial, we should pay attention to the use of administrative reconciliation coordination mechanism and civil mediation to properly resolve property disputes.

　　Carefully grasp the screening and correct the judicial policy

　　The "Implementation Opinions" also emphasizes the need to carefully grasp the judicial policy of screening and correcting, accurately identify the nature of economic disputes and economic crimes, and resolutely correct the wrong effective judgments that treat economic disputes as crimes.

　　Accurately grasp the legal boundary between crime and non-crime

　　The "Implementation Opinions" emphasizes that the boundary between economic disputes and economic crimes, especially contract disputes and contract fraud, the boundary between legitimate financing and illegal fund-raising of enterprises, the boundary between economic disputes involved in the merger and reorganization of state-owned enterprises by private enterprises and malicious occupation of state-owned assets should be strictly distinguished, and the legal boundary between crime and non-crime should be accurately grasped.

　　Teng Wei, Vice President of the Supreme People’s Court Trial Supervision Court:For economic activities in production, management, financing, etc., those that were not explicitly prohibited by laws and administrative regulations at that time and were punished as crimes, or those that were illegal but did not constitute crimes should be corrected according to law.

　　Resolutely correct the wrong judgment caused by criminal law enforcement intervening in civil disputes.

　　The "Implementation Opinions" stipulates that if the parties are forced to express their will by criminal means, which leads to the mistakes in the effective civil judgment, they must be resolutely corrected. Investors in private enterprises involved in crimes shall be guaranteed to exercise their property rights and other civil rights in accordance with the law during the period when the parties are subjected to compulsory measures or serving their sentences.

　　Teng Wei, Vice President of the Supreme People’s Court Trial Supervision Court:The people’s court shall investigate and verify the private enterprise investors’ exercise of civil litigation rights seriously affected by the restriction of personal freedom, and after the restriction of personal freedom is lifted, they provide new evidence for the facts of the civil case, which may overturn the effective judgment. Those who meet the conditions for retrial shall start retrial according to law.

　　In addition, the "Implementation Opinions" also provides for issues that are strongly reflected by the society, such as the trial of cases, the disposal of property involved in execution procedures, and state compensation. (CCTV reporter Zhang Sai)

1905 movie network news Directed by Qiu Litao, supervised by Andy Lau, and starring Liu Qingyun and NiNi, the film has exceeded 400 million at the box office and achieved excellent results in the first weekend. It was released for 4 days, and won the box office and film arranging champion for 4 consecutive days, and broke through the box office of 100 million in a single day. The super reputation of the film continues to ferment, and the audience’s enthusiasm for watching movies is quite hot, which also makes the film’s next film arrangement and pre-sale rank first.

From the first film to Shock Wave 2, the explosion scene has always been the highlight of the film. In this movie, not only the "sum of all fears", which is rare in Chinese movies, appeared, but also the explosion scene was more realistic. The opening minute was the airport explosion, followed by a bomb attack that was more explosive than the last one. At the end, the shocking picture of the Tsing Ma Bridge being blown into two parts also made the audience feel, "Dismantling the nuclear bomb and bombing the bridge, the hairs were blown up, which is simply a famous scene of the year." A few days ago, the film also exposed an "explosion special" to reveal how the explosion scene in the film was shot.

　

The visual layers are overweight, and the explosion scene is thrilling.

Audience: Just the scene can be recorded in a Chinese film.

After the film was released, the audience mentioned the most audio-visual feeling as "explosion", and they were particularly impressed by the explosion in the film and were quite satisfied. Some viewers said, "visually, the layers are overweight, and the opening brings a climax. The explosion fragment of the airport was absolutely amazing, the fire was sky-high, and the plane was instantly reduced to ashes, and the effect was too shocking. " At the same time, some viewers said that whether it is the blasting of a big scene or the dark battle of a small pattern, "it is full of tension and extremely shocking in audio and video."

In addition to the audio-visual impact brought by the big scene, the audience felt that "the scene alone can be recorded in a Chinese film", and the story of the film was also well received by the audience. "Multi-angle narration makes the story thick, the memory complex and changeable, and also makes the characters have complex humanity." Some viewers also said, "Imagination is very bold, not only explosive drama, action drama, but also literary drama. It is a real, flesh-and-blood story."

　

The bomb becomes a nuclear bomb, and the difficulty is fully upgraded.

Even the actors felt "too shocked" when shooting.

In Shock Wave 2, the explosion scene is more spectacular than the first one, and the bomb is also upgraded to a "nuclear bomb". A few days ago, the "explosion special" revealed how the "explosion scene" that left a deep impression on the audience and received constant praise was filmed. In order to give the audience a stronger shock, the director and the whole crew made a lot of preparations, such as conceiving the fresh link of setting up the bomb, and planning the distribution map of "sum of all fears" in the film in detail.

Previously, when it was released, the big explosion in Hung Hom Tunnel left a very deep impression on the audience. In Shock Wave 2, there are more real-life shots, and they really entered the Airport Railway Station connecting Tsing Ma Bridge and Chek Lap Kok Airport. In the special edition, even the actors themselves felt that "it was really shocking to push a car full of bombs."

　　Cctv newsAccording to "Sanya Released" WeChat WeChat official account News, at about 11: 22 on January 17th, Haitang Branch of Sanya Public Security Bureau received instructions from the command center of the Municipal Bureau, and people smashed mass vehicles at the east-west Sanya Tengqiao Interchange of G98 Expressway. After receiving the report, the police immediately intervened in the investigation, and on the morning of January 18, they arrested the illegal personnel Li (male, 40 years old) and Li Mouyuan (female, 42 years old) suspected of causing trouble.

　　After investigation, on the same day, when a car driven by the masses Zhuang was slowly passing through the Tengqiao Interchange section of the G98 Expressway in the east to the west of Sanya, Li drove a blue car without a motor vehicle number plate to the emergency lane on the right side of his vehicle, trying to overtake, which caused Li and his fellow driver Li Mouyuan to be unhappy, and took the opportunity to overtake from the emergency lane into the driveway and park the vehicle in front of the car driven by Zhuang. Subsequently, Li got off the bus and knocked on the door and window of a vehicle in Zhuang. Li Mouyuan smashed the door, window and left and right side mirrors of a vehicle in Zhuang and fled.

　　At present, Haitang Branch of Sanya Public Security Bureau has imposed administrative detention on Li and Li Mouyuan for 15 days and imposed a fine of 1,000 yuan. The traffic police detachment of Sanya Public Security Bureau punished Li for three traffic violations, namely, failing to hang the motor vehicle number plate (pro), driving in the emergency lane in non-emergency situations and illegally parking in the expressway lane.

foreword　 　

At present, tumor immunotherapy is in the ascendant, and one of the most effective treatment strategies is adoptive cell transfer therapy (ACT). Chimeric antigen receptor (CAR) and engineered T cell receptor (TCR) are the main adoptive T cell immunotherapy in recent years. TCR engineering T cells express tumor antigen-specific receptors, and their α chains and β chains are produced by high-quality and high-affinity antigen-specific T cell clones.

TCR molecule belongs to a superfamily of immunoglobulin, which consists of two covalently bound polymorphic subunits, each of which is antigen-specific, and they are related to at least four different types of signal transduction chains. In order to activate T cells, there must be interaction between TCR and MHC.

The interaction between TCRs and pMHC(peptide-MHC) determines the fate of immature thymocytes, which is very important for the survival of naive T cells. Therefore, TCR-T immunotherapy technology activates the host’s immune system through effective interaction with MHC, especially class II molecules, which are specifically recognized by TCR-T cells and CAR-T cells. TCR-T cells can recognize tumor-specific antigens in cells, while CAR-T cells mainly recognize tumor-specific antigens on the surface. This makes TCR-T cells more effective in tumor treatment.

At present, some new technologies and tools are being applied to TCR-T, which is helpful to improve the efficacy and safety of TCR-T therapy. TCR-T cell therapy is showing great potential for anti-tumor therapy.

　 Comparison between CAR-T and TCR-T

In ACT therapy, TCR-T and CAR-T cells have been successfully used in the clinical treatment of solid tumors.

CAR contains single chain antibody targeting tumor antigen, transmembrane domain and intracellular activation domain of CD3ζ. In this way, the engineered CAR can recognize specific tumor-associated antigens, and CAR can bind untreated tumor surface antigens without MHC treatment.

The first generation of CAR-T cells showed limited expansion and relatively short persistence, and the "second generation" CAR-T added costimulatory receptors CD28, 4-1BB/CD137 and OX40. These costimulatory receptors are added to the CD3ζ domain of CAR-T cells, thus promoting a more powerful and lasting T cell response. The third generation CARs combines two co-stimulatory signals (CD28 and 4-1BB) at the same time, which has better amplification and longer persistence than the second generation CARs.

On the contrary, TCR is an α/β heterodimer that binds to MHC antigen complex. Compared with TCR, CARs has some disadvantages in identifying tumor antigens, such as extratumoral toxicity. Compared with CARs, TCRs has some structural advantages in T cell-based therapy, such as more subunits (10: 1) in its receptor structure, more tyrosine-based activation motifs (ITAMs) in immune receptors (10: 3), less dependence on antigens (1: 100), and more costimulatory receptors (CD3, CD4, CD28, etc.). TCR with a low MHC affinity range (104-106M-1) can effectively activate T cells, whereas CARs needs a higher affinity range (106-109M-1).

Therefore, CAR-mediated cytotoxicity depends on higher density of cell surface antigens. In addition, T-cell/antigen interaction IS initiated in the structure of immune synapse (IS), in which TCR presents an annular region with peripheral LFA-1 adhesion, while CAR presents a diffuse LFA-1 distribution without annular region. Therefore, TCR-IS is slower but lasts longer than CAR-IS. At the same time, CAR-T cells show faster killing function and migrate to the next tumor target (serial killing), which is in sharp contrast to TCR-T cells’ prolonged signal transduction and killing time.

Recombination TCRs 　

TCR is one of the most complex receptors in human body. It contains six different receptor subunits, which have a very wide range of functions in T cells. The change of TCR of tumor infiltrating lymphocytes (TILs) significantly affects tumor-specific T cells. Among them, the change of TCR is helpful to the proliferation of T cells, and the diversity of TCR is related to the anti-tumor effect.

TCR engineering of TIL is one of the best treatment methods for tumors. TCR consists of α chain and β chain bound to peptide -MHC ligand, signal subunits (,γ and δ) of CD3 complex and CD3ζ homodimer. Except CD3ζ, all subunits have extracellular immunoglobulin (Ig) domain. Based on these structures, new technologies using engineering TCR include ImmTAC, TRuCs and TAC.

Immune mobilization monoclonal t cell receptor (ImmTAC)

ImmTACs is designed using engineered, soluble and affinity-enhanced monoclonal TCRs(mTCRs). ImmTACs is basically a fusion protein, which combines the engineering TCR targeting system and single chain antibody fragment (scFv) effector function. In the construction of ImmTACs, TCR can recognize peptides from intracellular targets presented by human leukocyte antigen (HLA).

ImmTAC specifically targets HLA- peptide complexes on the surface of tumor cells, and promotes T cell-mediated effector function through the interaction between scFv antibody fragments and CD3. ImmTAC also activates CD8+T cells in a dose-dependent manner, and can effectively redirect and activate CD8+ and CD4+ cells. ImmTAC shows multifunctional reaction by secreting various cytokines, such as TNF-α, IFN-γ, IL-6, MIP1α-β and IFN-γ inducible protein 10.

In addition, selecting the appropriate target antigen is the key to ImmTACs, and mass spectrometry and MHC polymer technology are helpful to identify the appropriate antigen. It is worth noting that TCR engineered T cells also show unexpected targeted toxicity. Generally speaking, ImmTACs has been proved to enhance the anti-tumor response of TCR-T cells, but its safety needs further study.

T cell receptor fusion structure

T cell receptor fusion structure (TRuCs), an antibody binding domain fused with T cell receptor subunits, is designed to effectively recognize tumor surface antigens. TRuCs is composed of specific antibodies targeting tumor-associated antigens fused to the extracellular N- terminal of five TCR subunits (TCRα, TCRβ, CD3, CD3γ and CD3δ), which provides new targeting specificity and HLA-independent target cell clearance for engineered T cells and can be activated by corresponding target cells.

Compared with the second generation of CAR-T cells, this method shows better anti-tumor effect. In addition, TRuCs dominates all the signal mechanisms of TCR complex, while CARs only uses the limited signal of the isolated intracellular segment of CD3ζ.

T cell antigen coupling agent (TAC)

T cell antigen coupling agent is another engineered TCR cell, which can induce more effective anti-tumor response and reduce toxicity in an MHC-independent way. TAC chimeric protein can form TCR/CD3 complex and get more T cell responses by binding to CD3 domain.

The activity of TAC receptor is closely related to the selection of CD3 binding domain. For example, a single chain antibody from OKT3(muromonab-CD3) has lower cytokine production and cytotoxicity compared with UCHT1, which may lead to substantially different functional results. Compared with the second generation of CARs, T cells engineered with TAC gene are not only beneficial to the greater infiltration in solid tumors after adoption, but also reduce the expansion and extratumoral toxicity of T cells in healthy tissues expressing antigens.

Workflow of TCR-T cell therapy 　

In order to isolate therapeutic TCR, antigen-specific T cells must be isolated from the blood of patients or healthy blood donors and amplified in vitro with specific peptide antigens and cytokines (such as IL-2 and IL-15). This process needs to determine the specific tumor-related peptide targets that can be safely targeted to patients in advance. After selecting the target antigen, different methods can be used to screen TCR with the required high affinity and tumor specificity. Pre-clinical safety testing is also necessary to ensure the minimum off-target effect and cross-reactivity of isolated high affinity TCR. Viral vectors are usually used to genetically modify autologous patient T cells to express the proven therapeutic TCR, and then transfuse it back into patients.

Determine the target antigen

Melanoma antigen 1(MART-1) recognized by T cells is the first tumor-related antigen targeted in TCR-T clinical trials. After this breakthrough, TCR-T therapies for various tumor antigens have been developed, including TCR-T therapies for MAGE-A3, MAGE-A4, GD2, mesothelin, gp100, MART1, AFP, CEA, NY-ESO-1 and viral peptides derived from HPV and EBV. Among them, NY-ESO-1 has been proved to be one of the most promising targets of TCR-T cells, and it has achieved success in the treatment of synovial sarcoma, with an objective effective rate of 67%.

The ideal TCR-T target antigen shows the following characteristics: (1) the ability to induce immune response; (2) It is related to driving tumor phenotype (such as oncogene) to reduce the risk of antigen loss and tumor immune escape; And (3) expression on tumor stem cells to promote permanent tumor eradication.

Identification method of tumor-associated antigen

High-resolution mass spectrometry (MS) has been proved to be the most powerful Qualcomm method to promote the direct identification of HLA-I binding peptides from tumor cells. In this method, HLA-I/ peptide complexes are separated from tumor tissues or cell lines by immunoprecipitation (IP), and then the binding peptide antigens are separated from HLA-I molecules and antibodies for IP by fully washing and applying acidic elution buffer. This strategy allows each tumor sample to identify thousands of validated peptide targets, and has been used to identify HLA-I ligands of glioblastoma (GB), melanoma, renal cell carcinoma (RCC) and colorectal cancer (CRC).

Identification method of new tumor antigen

Although MS-based technology can be used to identify new antigens, it is more difficult to identify them, especially for tumor samples with limited size, because of their relatively low abundance and limited sensitivity of MS. However, the development of new generation sequencing technology is helpful to identify and locate such tumor targets. All-exon DNA sequencing, combined with computational prediction algorithm, allows to identify specific genetic changes in cancer cells, which can produce mutant peptides and present them on tumor HLA-I molecules.

All somatic mutant genes can be analyzed by computer to predict the potential high affinity epitopes that may bind to HLA-I molecules of patients, so as to be recognized by T cells. With the use of large MS elution peptide database, HLA-I peptide binding prediction algorithm is constantly updated and improved, and other prediction algorithms try to consider biological variables related to the complexity of intracellular processes.

Another commonly used method is tumor RNA sequencing, which allows the selection of new antigens with the highest transcriptional expression. It is worth noting that although these prediction methods usually show very good accuracy in identifying presented and highly immunogenic new antigens, the number of new antigen targets they usually predict is 1 to 2 orders of magnitude higher than the actual number of real targets.

Discovering new antigens by trogocytosis is a new method in recent years. Trogocytosis is a biological phenomenon in the process of cell combination, in which cells share and transfer membrane and membrane-related proteins. Li et al. found that T cell membrane proteins were specifically transferred to tumor target cells, which presented homologous HLA-I/ peptide complexes. Using these T cell-target cell interactions, they created a new antigen discovery system by incubating T cells expressing orphan TCR with homologous target cells. By transferring fluorescent markers from T cells to target cells, this method can isolate these target cells and sequence homologous TCR ligands, thus establishing a new antigen library.

Isolation of tumor-specific T cells and TCR

Using HLA-I polymer, single cell TCR sequencing or antigen-negative humanized mice, tumor-reactive T cells and TCR can be identified from autologous, allogeneic or xenogeneic cell banks.

Using HLA-I multimer method, antigen-specific CD8+T cells can be directly separated by multimer staining and flow cytometry. Before isolating the paired full-length TCR sequences, these polyclonal T cells were tested for homologous peptide recognition and anti-tumor function. TCR with high affinity and specificity can be obtained by using a highly sensitive PCR-based single cell TCR analysis method (TCR-SCAN).

Another method uses humanized mouse TCR gene bank, which will not cause T cell clone deletion or tolerance in humans. Therefore, Li et al. used the whole human TCRα/β gene locus and chimeric HLA-A2 transgene to construct transgenic mice to isolate human TCR against human TAA.

Single cell sequencing method represents a more promising method to isolate tumor-specific TCR coding genes by Qualcomm method. Using RNA bait libraries targeting each individual V and J element in TCRα and TCRβ loci, TCR coding genomic elements can be selectively isolated from excised genomic DNA(gDNA) fragments for subsequent paired terminal deep sequencing. This makes it possible to identify antigen-specific TCR from human materials or oligoclonal T cell populations of TCR humanized mice.

Infantile T cells can also be used as TCR sources for TCR-T therapy. TAA and new antigen-specific T cells can be derived and amplified from low-frequency precursors in peripheral blood of cancer patients, and can be reinfused or used as the source of antigen-specific TCR. Because cancer patients usually show immunosuppression or dominant T cell tolerance, the original sequence of HLA-I matched healthy donors also represents a reliable source, because it has a huge diversity of TCR sequences, and theoretically T cells have any antigen specificity, including new tumor antigens. A Qualcomm-quantity technology platform has been developed to find the original sequence, so as to quickly and effectively identify the rare but valuable TCR for personalized adoptive T cell therapy.

Cloning of TCR

Most TCR-based gene therapy methods rely on in vitro transduction of T cells with viral vectors, and adenovirus is the earliest vector used for gene therapy. However, due to their inability to integrate transgenes into the host genome, TCR expression will be lost during T cell proliferation. In addition, the immune genetic characteristics of adenovirus also limit its application as a gene therapy vector. In contrast, retroviruses show greater prospects as gene transfer vectors, because they can infect a variety of cells and have the ability to insert transgenes into the host genome, thus making the ectopic TCRα/β chain stably expressed.

Retroviral vectors derived from γ -retroviruses such as mouse leukemia virus (MLV) have been widely used for gene transfer into human T cells. This method has been used to transfer various genes, including suicide gene, TCR and CARs. The main disadvantage is that they cannot transduce non-proliferative target cells, which excludes the application of resting T cells in TCR-T therapy. In addition, retrovirus insertion mutation may cause potential side effects.

Recently, lentiviral vectors (LV) have attracted more attention as gene transfer vectors, because they can transfer genes into mitotic and non-splinter cell. Various techniques, such as Golden Gate cloning and LR cloning, are usually used to construct a vector for inserting TCRα/β gene.

Adeno-associated virus (AAV) is another widely used virus vector. Compared with adenovirus vector, AAV has lower immunogenicity and wider cell tropism, so it has been widely used in tumor gene therapy. In order to promote the integration of transgenes, people have developed self-complementary AAV vector (scAAV) to make AAV independent of the complementary strand synthesis of host cells. scAAV is more effective than traditional AAV in preclinical model.

At the same time, some non-viral gene editing methods have also been developed. MRNA electroporation has been proved to achieve transient expression of TCR and CAR, thus minimizing the risk of persistent virus components. Clinical data show that both TCR-T and CAR T cells modified by mRNA are feasible and safe, and there is no obvious evidence that they have non-targeted toxicity to normal tissues. However, the lack of continuous TCR expression may limit the curative effect and require repeated infusion. In addition, the non-viral sleeping beauty retrotransposon system is also used for the transduction of TCR and CARs.

Gene editing can insert large gene fragments into target cells specifically and efficiently through homologous directional repair (HDR). TCR-T cells developed by CRISPR/CAS9 have been proved to specifically recognize tumor antigens in vitro and induce a productive anti-tumor response in vivo.

Verification method of TCR

After TCR cloning, extensive preclinical verification is needed to prove the specificity and safety of engineered TCR-T cells. Verification includes evaluating the affinity of TCR by titration of homologous peptide antigens and measuring the killing effect of a group of HLA-I matched tumor cell lines. If there is no such tumor cell line, the target cells can transductively express related antigens and related HLA-I molecules. The new antigen can also be expressed in autologous antigen presenting cells to evaluate the antigen reactivity of TCR.

The safety test includes testing the ability of candidate TCR-T to identify HLA-I matching primary tissues, so as to ensure that there is no normal tissue as the target, which may lead to non-targeted toxicity. In at least two clinical trials of TCR-T cell therapy, there was a cross reaction between normal brain cells and heart cells, which led to the death of patients. These test results emphasize the importance of extensive safety tests before TCR enters clinical trials.

Safety of TCR-T 　

The ACT of TCR-T cells showed high tumor killing, but some serious adverse events also appeared in some clinical studies. It is very important to optimize TCR affinity in engineered T cells, and receptor affinity can determine the safety and effectiveness of T cell therapy. In terms of curative effect, affinity TCR interaction is enough to activate T cells, but strong affinity is needed to maintain the expansion of T cells.

In phase I/II ACT clinical trials, engineered T cells with low affinity show safer characteristics, but their anti-tumor response is weak. By identifying the TCR-pMHC interaction of T cells, engineered T cells can be divided into high affinity type and low affinity type. In addition, some technologies have been developed to improve the safety of TCR-T.

The safety switch mechanism based on engineered T cells is an attractive strategy. Thymidine kinase gene from herpes simplex virus type I (HSV-TK) is one of the most common suicide genes.

Although HSV-TK shows safety in cell-based immunotherapy, it is necessary to introduce phosphorylated nucleoside analogues. Another safer induced T cell safety switch is called inducible caspase-9(iC9). IC9 is a modified human FK binding protein, which can be activated by a small molecule compound AP1903, and this process depends on the mitochondrial apoptosis pathway.

The immunogenicity of iC9 suicide gene is low, and the immune response to transgenic cells is reduced. IC9-based safety switch has been proved to be more potential for cell therapy than previous suicide genes.

Clinical status of TCR-T cell therapy 　

As of August 9, 2021, there are 175 studies using TCR-T therapy in ClinicalTrials, 71 of which are specific TCR for specific TAA or new antigen, and 32 studies have been completed. NY-ESO-1 is the most common targeted antigen, which is expressed in many cancers, including myeloma and melanoma. Other tumor testis-associated antigens, such as PRAME and MAGE proteins, melanoma differentiation antigens MART-1 and gp100, and recent cancer drivers, such as WT1, KRAS and TP53, are also popular TCR-T targets.　 　 　 　 　 　 　 　 　 　 　

　　　　

A total of 83 sponsors/collaborators initiated or participated in the research of TCR-T cell therapy, including the National Institutes of Health (NIH), government organizations, industries and universities/academic institutions. At present, the National Cancer Institute (NCI) has supported 53 TCR-T projects, accounting for 20% of all ongoing projects.

Among the 29 pharmaceutical companies developing TCR-T therapy, GlaxoSmithKline and Adaptimunime initiated the most clinical trials, with 11 and 7 respectively. Recently, a phase 1 clinical trial (NCT02858310) of TCR-T cells targeting human papillomavirus (HPV)-16 E7 protein in the treatment of metastatic human papillomavirus-related epithelial cancer was reported. In this study, 6 of the 12 patients who received treatment showed objective clinical response and observed steady tumor regression. This is a landmark clinical trial of TCR-T cell therapy, which proves that targeted virus antigen has good clinical effect on patients with virus-related cancer. Other viral antigens explored as TCR targets include HPV-E6 protein, antigens from Epstein-Barr virus (EBV) and human endogenous retrovirus (HERV) targets, such as Herv-E.

MART-1 and NY-ESO-1 TCR-T therapy targeting TAAs also showed clinical efficacy in advanced melanoma, myeloma and non-small cell lung cancer. The total effective rate (ORR) of TCR-T clinical trial is between 0 and 60%. It is worth noting that most of these TCR-T clinical trials only enrolled a small number of patients (2 to 25), so ORR may not be statistically accurate. Therefore, larger-scale phase II and III clinical trials are needed to confirm the actual clinical efficacy of these TCR-T therapies.

Challenges and potential solutions of TCR-T cell therapy 　

Although immunotherapy based on TCR-T cells has shown certain clinical efficacy in most patients receiving treatment, it still faces many challenges in many fields. These challenges include: (1) Immunotoxicity caused by targeting normal tissues; (2) The expression of TCR in engineered T cells is insufficient or transient; (3)T cell exhaustion and dysfunction; (4) tumor immune escape, and (5) most cancer patients lack effective tumor-specific antigens as targets. Overcoming these challenges will be the key to greater clinical success in the future.　 　 　 　 　 　　

　 　 　 　 　 　

Discovery of new targets

At present, the target of peptide antigen for effective and safe immunotherapy of TCR-T is very limited. At present, most of the targets used are TAA. Although it is up-regulated in tumor tissues, it still maintains a low level of expression in normal tissues, which may lead to autoimmune toxicity. Therefore, the new antigen seems to be the safest target for TCR-T cancer treatment. However, the main challenges of developing new antigens in TCR-T clinic include: (1) the mutation of new antigens is individualized to a great extent, and there are differences among cancer patients, so it is difficult to develop widely used immunotherapy products; (2) The expression of new antigens in tumor tissues is often heterogeneous.

Nevertheless, recent reports have highlighted the emergence of new immunogenic antigens widely shared by tumor cells, including mutated KRAS and TP53. Many other studies have also demonstrated the immunogenicity of shared new antigens that can be used to generate potential therapeutic tumor-specific TCR. With the development of next generation sequencing technology, especially single cell DNA sequencing, transcriptome sequencing and mature in vitro verification methods, TCR-T immunotherapy targeting personalized new antigens may become a popular cancer treatment method in the next few years. In addition, the emerging TAA class, such as carcinoembryonic antigen, may also constitute a feasible target for the future development of TCR-T.

Maximize therapeutic TCR expression

The correct pairing of transgenic α and β chains is one of the main challenges that hinder the development of TCR-T cells. Since each transduced T cell includes two endogenous TCR chains and two transformed TCR chains, heterodimers with unknown specificity can lead to potential autoimmune consequences. Another related problem is that improper α/β chain TCR pairing will compete for CD3 complex, thus reducing the surface expression and signal transduction of therapeutic TCR.

There are several methods to properly pair the transduced TCR chains, including: (1) the constant region of partially murine TCR; (2) adding cysteine residues to promote the introduction of disulfide bonds in TCR chains; (3) changing the secondary structure of the constant region of endogenous TCR; (4) adding a signal domain to the intracellular part transduced with TCR; (5) Introducing TCR-α/β chain into substitute effector cells or constructing single-stranded TCR.

Methods to enhance the expression of therapeutic TCR include: (1) codon optimization of TCR-α and TCR-β chain transgene, and (2) changing the configuration of TCR-α/TCR-β vector to optimize expression.

Reduce adverse events

Usually, targeting non-tumor toxicity is the main key obstacle of TAA, and this risk urges researchers to study common new antigens more carefully. At present, several oncogene hot spot mutations are being studied as potential TCR targets, such as phosphoinositide -3- kinase (PI3K), KRAS and TP53. In addition, genetically engineered TCR-T cells with suicide genes are an important safety measure. Obviously, it is very important to develop reliable, identifiable, personalized, highly specific and immunogenic tumor antigen targets to reduce adverse events related to TCR-T cell therapy.

Graft-versus-host disease of allogeneic T cells

Using allogeneic T cells is a very promising scheme, which can overcome manufacturing problems, patient-related immune cell defects and treatment delays. In order to use allogeneic T cells, it is necessary to control graft-versus-host disease caused by transduced allogeneic reactive lymphocytes and rejection of engineered lymphocytes by host immune system.

The deletion of endogenous TCR gene, HLA-I locus or CD52 molecule is one of the strategies to avoid the failure of TCR-T transplantation, which can be achieved by many methods, such as gene editing or using siRNA. In addition, pluripotent stem cell technology is also considered as a potential solution.

　 summarize

In recent years, engineered T cells have shown excellent curative effect in the treatment of hematological tumors. TCR regulation is very important for T cell reactivation, immune response and its clinical effect on foreign antigens. TCR-T cells have incomparable advantages over CAR-T cells, and show great potential in preclinical and clinical research.

However, there are still several key challenges to improve the anti-tumor efficacy of TCR-T immunotherapy, including how to safely increase the affinity of therapeutic TCR, how to identify the common tumor-specific antigen and TCR in the patient population, and how to regulate the expression of TCR and achieve the best function. The solution of these problems will help to give full play to the potential of TCR-T cell therapy and bring hope to cancer patients to relieve their pain.

References:

1.Engineered TCR-T CellI mmunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol.　2021; 12: 658753.

2. Evolution of CD8+　T Cell Receptor(TCR) Engineered Therapies for the Treatment of Cancer. Cells.　2021 Sep; 10(9): 2379.

　　
The People’s Liberation Army (PLA) has accumulated rich operational experience after a year and a half of fighting, especially since it turned to a strategic offensive. Mao Zedong made a systematic and scientific summary of these experiences. From December 25th to 28th, 1947, the Central Committee of the Communist Party of China held an enlarged meeting in Yangjiagou, Mizhi County, northern Shaanxi, at which Mao Zedong made a report on "Current Situation and Our Tasks". In this report, the famous "Ten Military Principles" were put forward. The main contents are: fight scattered and isolated enemies first, and then fight concentrated and powerful enemies; Take small cities, medium-sized cities and vast villages first, and then take big cities; The main goal is to annihilate the enemy’s effective forces, not to preserve or seize cities and places; Concentrate absolute superior forces in each battle, surround the enemy on all sides, and strive to wipe out the enemy, so as not to escape the net; Don’t fight unprepared battles, don’t fight uncertain battles; Carry forward the style of fighting bravely, not afraid of sacrifice, not afraid of fatigue and continuous fighting; Strive to annihilate the enemy in the movement, while paying attention to position attack tactics; On the issue of siege, all enemy strongholds and cities with weak defenses are firmly seized, all enemy strongholds and city cameras with medium defenses are seized, and all enemy strongholds and cities with strong defenses are seized when conditions are ripe; Replenish ourselves by capturing all the enemy’s weapons and most of their personnel. The source of our army’s manpower and material resources is mainly at the front. Be good at using the gap between the two campaigns to rest and train troops.
The full text of the top ten military principles is 593 words. In incisive language, Mao Zedong made the strategic and tactical principles of the People’s Liberation Army clear, which is both easy to understand and easy to remember. It is completely different from his opponent Chiang Kai-shek’s long speech. In the later stage of strategic decisive battle and strategic pursuit, the People’s Liberation Army flexibly applied ten military principles, further enriched and developed this theoretical treasure, and finally relied on this treasure to completely defeat eight million Kuomintang troops.
From the sixteen-character formula to the ten military principles, it marks the improvement of the strategic and tactical theory of the people’s army, and marks that Mao Zedong’s military thought reached an unprecedented height during the War of Liberation. Therefore, it is not difficult for people to understand why Chiang Kai-shek, who was an excellent cadet studying in the Japanese military academy and the president of the Whampoa Military Academy, was finally defeated by Mao Zedong, who had never been to a military academy for a day. Batman, a British military expert, commented: "Mao Zedong is an era figure who holds all the keys to unlock the military mysteries of this era." (Xinhua News Agency)

Editor: Cao Jin

Since the Eighth Five-Year Plan, the Tobacco Monopoly Bureau of Hanshou County, Changde has actively explored and innovated the ways, contents and forms of popularizing the law, carried out in-depth publicity for consumers, retailers and minors, and promoted the effectiveness of tobacco publicity and education under the rule of law.

Explain the law to consumers and improve the awareness of consumer rights protection.

(The staff of Hanshou County Bureau introduces the identification skills of true and false cigarettes to consumers)

"This is a fake cigarette? What do you think is no different from real cigarettes? How can you tell? "

As soon as the publicity booth of Hanshou Tobacco Monopoly Bureau was set up, enthusiastic people gathered around to ask questions. The staff of the county bureau gave patient answers to the preaching, while making detailed comparisons with the real and fake cigarette exhibits, and carefully answered the knowledge points of identification of real and fake cigarettes for the onlookers by means of "you ask me and answer me".

Over the years, Hanshou County Bureau has taken various effective forms to carry out regular publicity on legal popularization. In 2024 alone, it has held similar legal popularization activities for more than 10 times, distributed more than 300 tobacco monopoly legal popularization brochures printed by the county bureau, such as "Quick Identification of True and False Cigarettes", "How much do you know about the harm of fake cigarettes? Stay away from new disguised drugs-"E-cigarettes on the top ",and printed QR codes on brochures and exhibition boards to realize the popularization and dissemination of legal popularization audiences.

Send it to French retailers to improve the standard operation level.

(The staff of Hanshou County Bureau gives publicity to retailers)

"Grandma Liu, you are going to be demolished here. I have prepared some materials to facilitate your application!" Xiao Xie, a monopoly worker of the county bureau, walked into Grandma Liu’s shop and said enthusiastically.

Hanshou County Bureau earnestly implements the responsibility system of "whoever enforces the law will popularize it", integrates the popularization of law into market inspection and daily visits, turns static popularization of law into dynamic popularization of law, and turns the law on paper into a sensible law. The county bureau integrates law enforcement with service, and inspectors and city managers walk into cigarette retailers’ shops to carry out face-to-face publicity and one-on-one explanation on the legal issues involved in the standardized operation of retailers, so as to popularize the law in real time and accurately. To explain the case, publicize the tobacco monopoly law and its implementation regulations, help retailers to calculate the "legal account" and "economic account", warn retailers with real cases in their jurisdictions, and advise retailers to operate in good faith and abide by the law, and not to sell cigarettes and e-cigarettes to minors. Using online forms such as WeChat group and Tencent conference live class, the common illegal acts of tobacco monopoly law are interpreted for retailers in easy-to-understand language, so that retailers can understand the law and know awe, keep the "high-voltage line" of standardized cigarette operation, enhance the pertinence and effectiveness of law popularization, and maintain the market order of standardized cigarette operation.

Popularize law into campus and care for students’ healthy growth

(Hanshou County Bureau staff carry out activities of popularizing law into campus)

Hanshou Tobacco Monopoly Bureau strengthens the propaganda of tobacco hazards, makes great efforts to build a smoke-free campus environment, and forms the joint efforts of the whole society to protect the healthy growth of minors. Union County Education Bureau and Market Supervision Administration went into primary and secondary schools to carry out legal publicity activities with the theme of "protecting the future with children". By playing warning videos and explaining in kind, the staff preached to primary and secondary school students the dangers of traditional tobacco products, e-cigarettes and new illegal e-cigarettes such as "milk tea cups" and "coke cans", and resolutely resisted the temptation of tobacco. Combined with the recent popular "cigarette card" game among primary school students, the potential harm of "cigarette card" is emphasized, and students are warned not to be curious, not to follow the trend, not to be contaminated with tobacco, to stay away from Internet cafes, bars, KTV and other entertainment places that are not suitable for minors to enter, and to resolutely say "no" to cigarettes, e-cigarettes, etc. Widely publicize and publish the telephone number of complaints about selling cigarettes to minors, encourage teachers and students to actively report relevant information clues, and guide all sectors of society to protect the physical and mental health of minors.

In the next step, Hanshou County Bureau will normalize, institutionalize and carry out long-term publicity of law popularization, promote the effectiveness of the eighth five-year plan, and hand over socially satisfactory answers.

(Image courtesy of Cao Libin Guan)

The above contents are promotional information, and the contents involved do not represent the views of this website, and do not constitute investment suggestions or consumption suggestions.

　　Cctv newsOn the evening of 25th local time, a snowstorm started from southern Wyoming and headed for central Colorado. At present, the snowfall has exceeded 30cm, and the gust speed has reached 72km/h.. Up to now, this winter storm has caused hundreds of flights to be cancelled at Denver International Airport in Colorado, and more than 1,000 passengers stayed overnight at the airport. Another interstate highway was closed due to snowstorm.

　　According to the National Weather Service, the storm will then cross Nebraska and Kansas eastward, bringing 15.2~30.5 cm of snowfall to the areas along the way. At the same time, the National Weather Service also said that another snowstorm, which started on the night of 26th local time, is expected to bring heavy snow to parts of the northwest Pacific coast and reach the snowstorm level in Oregon and northern California. As two snowstorms occurred during Thanksgiving, it is expected to disrupt the plans of tens of millions of Americans to travel during the Thanksgiving holiday. (CCTV reporter Xu Wei)

　　According to reports, on 26th, US President Trump said in an interview that the US and China have exchanged views on economic and trade issues in the past few days, and the two sides may reach an agreement during the G20 summit. If no agreement can be reached, he will impose additional tariffs on China. At today’s (27th) regular press conference of China’s Foreign Ministry, Geng Shuang, a spokesman, said that the US threat could not scare the people of China, and a trade war would harm others and harm themselves, which could not solve the problem at all.

　　Foreign Ministry Spokesperson Geng Shuang:China has always advocated resolving Sino-US economic and trade frictions through dialogue and consultation, but at the same time it will firmly defend its legitimate rights and interests. The US threatened to impose additional tariffs on China, which did not scare the people of China. Chinese believes in no evil and is not afraid of pressure. He never buys it. I would like to advise the US side once again that a trade war and tariff increase will not solve the problem at all. I hope that the US side will listen carefully to the opposition of different groups and the general public in the United States to trade wars and tariff increases in recent days, and also listen carefully to the resistance of the international community to unilateralism, protectionism and bullying during the G20 summit.

　　Geng Shuang expressed the hope that the US and China will move in the same direction, take care of each other’s reasonable concerns on the basis of mutual respect, equality and mutual benefit, and strive for mutual benefit and win-win. This is not only in the interests of China and the United States and the two peoples, but also the general expectation of the international community.

Nowadays, the first thing for consumers to buy a car is to see whether this car is rich in configuration, and it is no exception to nature. Let’s look down with Xiaobian.

Let’s take a look at Komik’s appearance first. Komuk’s front face looks very clean and refreshing as a whole, and the air intake grille uses a straight waterfall shape, which is very recognizable. Coupled with fashionable headlights, it has a great visual impact. The car is equipped with LED daytime running lights, automatic opening and closing, delayed closing and so on. Coming to the side of the car body, the size of the car body is 4409 mm * 1781 mm * 1606 mm. The car adopts fashionable and dynamic lines, and the side circumference looks very sharp. With large-sized thick-walled tires, the shape is quite simple. In the design of the rear end, the rear end looks very comfortable, the taillights look very simple, and with the unique exhaust pipe, it is very simple and fashionable.

Coming to Komuk, Komuk’s interior looks solid and the visual effect is very good. The car looks very good outside the steering wheel, made of plastic, and looks a little more unique. Let’s take a look at the central control. The design of the center console is reasonable, which makes the interior design quite layered and conforms to the mainstream aesthetics. The dashboard and seats are equally eye-catching, and the car is equipped with a stylish dashboard with excellent display effect. The car adopts imitation leather seats, which are wrapped in place, with exquisite materials and comfortable ride.

Komik is matched with an automatic manual transmission (AT) gearbox, with a maximum power of 80KW and a maximum torque of 141N.m, with good power performance.

The car is equipped with driving mode selection, remote control key, rear wiper, engine start and stop, traction control (ASR/TCS, etc.) and other configurations, which greatly improves the convenience of using the car.

The car introduced today is remarkable in terms of space, configuration and power, and home travel is also a good helper. If you are interested, you might as well experience it.