Zhongsheng Kangyuan: pioneer in the industrialization of tumor new antigen DC vaccine

Many years ago, clinical trials of tumor vaccines based on tumor associated antigens have flourished For example, peptide vaccines based on tumor antigen MUC1, melanoma associated antigen 3 (magea3), epidermal growth factor receptor 2 (HER2) of breast cancer, many taa-dc vaccines, and many taas-dna and RNA vaccines based on virus, bacteria and virus like particles all failed The only approved Provenge also suffered from poor effectiveness and cost in large sample population End After 2013, the technology of individualized tumor vaccine based on new tumor antigens rose In July 2017, nature published two articles from different teams at the same time affirming the clinical application prospect of the new generation tumor vaccine in the treatment of melanoma In April 2018, Science Translational Medicine reported that the total 2-year survival rate of patients with advanced ovarian cancer treated with individualized DC tumor vaccine reached 100% In the same year, ASCO annual meeting in the United States revealed that the individualized DC tumor vaccine caused a persistent immune response in endometrial and mucinous cancer patients, greatly improving the progression free survival period of patients However, the clinical effects of these two generations of tumor vaccines are quite different, because the target (antigen) is different Tumor related antigen is regarded as its own component by the immune system of the body, and T cells have weak recognition and response ability to it However, the new anti-tumor principle is a kind of tumor antigen specific to tumor cells caused by gene mutation in cancer cells, which has a high affinity with TCR on the surface of T cells, and as the target of immunotherapy, it usually has no immunotoxic side effects In 2017, there were nearly 100 clinical trials of new generation tumor vaccines registered on clinical trials, and the number of research articles and patent applications related to new tumor antigens increased rapidly As a result, capital began to pursue the new tumor antigen project enthusiastically According to incomplete statistics, there are more than 30 companies around the world specializing in the research and development of new tumor antigens, including the new Unicorn Modena therapeutics, gritstone, neontherapeutics, etc However, since the second half of 2018, with the large sample clinical research published by head companies, especially neon, who is engaged in the research and development of tumor new antigen peptide vaccine, releasing unsatisfactory data, the outside world began to question the value of this technology, and the capital market has entered a calm and wait-and-see period High quality antigen is as indispensable as high quality antigen-presenting cells According to Dr Cheng Xudong, a distinguished professor of Beijing Academy of science and technology, tumor new antigen is a tumor cell specific antigen produced by random gene mutation in tumor cells, and is an ideal antigen for therapeutic tumor vaccine The detection and identification of new tumor antigens are complex, involving interdisciplinary fusion, such as high-throughput gene sequencing, bioinformatics prediction, gene expression analysis, immunocoprecipitation, MHC affinity test, protein mass spectrometry analysis, tumor clone subgroup status analysis and other technical means, sequencing technology, data analysis ability, protein detection technology, immune identification and even The quality of R & D and operation personnel is extremely high, with high technical barriers "However, European and American scientific research institutes and leading enterprises in the industry have done a good foundation work in this field, laying a solid foundation for the clinical application of new antigens." Dr Cheng Xudong pointed out For example, in terms of peptide and mRNA vaccines based on new tumor antigens, neon's neo-pv-01 and gristone's grant-001, early clinical trial data clearly show that the progression free survival of patients with melanoma, non-small cell lung cancer (NSCLC) and bladder cancer is prolonged Dr Cheng Xudong explained that follow-up data such as neo-pv-01 and grant-001 did not show a further significant breakthrough in clinical efficacy The reason is not the problem of the new antigen itself More importantly, they used the new antigen to solve the problem of weak antigenicity of tumor cells, but failed to solve the problem of immune cell dysfunction in tumor patients One of the main reasons is that the function of antigen-presenting cells in patients is inhibited and T cells can not be activated by antigen-presenting cells Therefore, in order to achieve the expected good clinical effect, immunotherapy should not only solve the problem of antigen, but also solve the problem of immunosuppression in tumor patients In other words, when a large number of tumor specific antigens are injected into the body, it is necessary to ensure that they are effectively ingested and presented by antigen-presenting cells in the body, and that there are enough effective T cells to be activated Dr Cheng Xudong said that this treatment technology, which came into clinical practice after decades of struggle between human beings and tumors, although many people began to be confused after the early clinical trial data was not as expected, he still believed that the application and clinical popularization of new tumor antigen therapy were the development trend of tumor immunotherapy at present and in the future "Unlike most researchers who lean on polishing the prediction technology of new tumor antigens, we have found a breakthrough in the mechanism of action of new tumor antigens in vivo We believe that DC cells can be induced directly from monocytes of patients, loaded with new tumor antigens which have been proved to be functional in vitro, cultured into highly mature healthy DC cells, and then reinfusion, which can break the immune tolerance of tumor patients and significantly improve the clinical effectiveness of the new tumor antigen vaccine " Dr Cheng Xudong told the arterial network In May 2018, Dr Cheng Xudong founded the Zhongsheng Kangyuan Biotechnology (Beijing) Co., Ltd., focusing on the research and development of a new generation of individualized tumor new antigen DC vaccine Immediately after the establishment of the company, it received tens of millions of yuan of angel investment from famous domestic venture capital institutions such as Tongchuang Weiye, Huachuang capital and Shouke Kaiyang With the help of capital, the founding team quickly broke through a series of technical difficulties through the combination of independent research and development and university cooperation, and built the internationally leading multi group tumor new antigen bio information prediction system, tumor new antigen function verification system and cancer big data processing platform with full independent intellectual property rights, becoming the first domestic platform able to achieve new tumor The enterprises that carry out high-precision, high-throughput, fast and low-cost identification of antigens are comparable to the leading counterparts in Europe and the United States At the same time, through strategic cooperation with such industry giants as Germany meitianni, the company has realized the production of immune cell drugs, solved the industry pain point that individual DC cell preparations are difficult to make drugs, and filled the domestic industrialization gap in this field At present, cosheng Kangyuan has established R & D bases and production centers in Beijing and Feicheng, the United States It has built the most leading DC tumor vaccine R & D platform based on new tumor antigens in China It is comprehensively promoting the exploratory clinical research of individualized DC vaccines for advanced liver cancer, pancreatic cancer and glioblastoma in China and the United States When the arterial network asked why DC cells were chosen as the delivery vector of new tumor antigens, Dr Cheng Xudong said that T cells that play an important anti-tumor role in patients can not directly recognize tumor antigens, only recognize the antigen peptide MHC complex expressed on the surface of antigen-presenting cells, which can be activated, then differentiate into effective T cells, attack and eliminate the expression of tumor antigens Primary tumor cells Dendritic cell (DC) is a kind of specialized antigen-presenting cell with typical dendritic or pseudopodoid processes, high expression of MHC molecules on the surface of membrane, migration to secondary lymphoid organs and stimulation of activation and proliferation of initial T cells It is the most powerful specialized antigen-presenting cell in human body and the only antigen-presenting cell in human body that can activate initial T cells DC cells are the core and foundation of anti-tumor immune response, and also the ideal antigen delivery carrier of therapeutic tumor vaccine The preparation of DC vaccine is very simple It is to isolate the precursor cells of DC cells in patients, culture them in vitro, load them with tumor antigen, then transport them back to patients, and then stimulate specific anti-tumor T cell response through DC cells Compared with other therapeutic tumor vaccines, DC vaccine has the following advanced clinical features: first, the removal of tumor cells is accurate and efficient, which can effectively repair, restore and enhance the patient's own cellular immune function, break the immune tolerance state of tumor patients, and achieve immune reconstruction Secondly, it can continuously mobilize all kinds of cytokines in vivo to participate in the removal of tumor cells, which greatly reduces the damage to normal cells while removing tumor cells, and has high safety; Third, the reinfusion of DC cells can activate resting T cells to produce primary immune response cells (one DC cell can activate 100-3000 T cells) Most of the T cells can directly play the role of tumor killing, and a few of them can become memory T cells that can survive for a long time The next contact with the same type of tumor cells can immediately start the high-intensity immune response Therefore, the immune protection system reconstructed by the new tumor antigen DC vaccine can continue to play a role for decades and realize the organic combination of treatment and prevention The clinical research results of hundreds of therapeutic tumor vaccines at home and abroad have proved that DC vaccine is stable, reliable and highly safe In 2010, sipuleucel-t, the first therapeutic tumor vaccine for prostate cancer approved by the US FDA, was an autogenous DC vaccine At present, among the second generation tumor vaccines in clinical trials around the world, the new tumor antigen vaccine with the fastest progress and the best effect is also the DC cell vaccine In 2019, at the 50th annual meeting of the society of Gynecological Oncology (SGO), the final result of a second phase clinical trial sov02 (nct02107950) was announced: the use of dendritic cell-based immunotherapy dcvac / OVCA in combination with standard carboplatin and gemcitabine regimens can prolong the total survival time (OS) of patients with advanced recurrence of ovarian cancer by more than one year Dcvac / OVCA will The risk of death was reduced by 62% with a significant increase in overall survival (OS) by 13.4 months and median progression free survival (MPFs) by 1.8 months The new tumor antigen sensitized DC vaccine developed by nwbio company is now widely used in the treatment of glioblastoma, advanced ovarian cancer and advanced prostate cancer In 2018, the company published the results of a phase 3 clinical trial, which showed that its dendritic cell vaccine improved the survival rate of patients with newly diagnosed glioblastoma, and some patients' survival period has exceeded the standard treatment survival period by nearly three times Relevant data was published in Journal of translational medicine "The combination of DC cells and new tumor antigens has broken the dilemma of the current clinical application of new tumor antigen technology," said Dr Cheng Xudong "Before the emergence of new tumor antigens, the biological treatment centers in many domestic hospitals have been widely carrying out clinical treatment of autogenous DC vaccines, but because of the lack of high-quality antigens such as new tumor antigens, and the production process of DC cells is uneven The clinical effect is generally poor due to the lack of strict quality control At present, tumor new antigen identification has entered the stage of commercialization At the same time, with the development of car-t industry, the manufacturing process of GMP level miniaturization and automatic production equipment for immune cell preparation is also becoming mature, which lays the foundation for DC vaccine upgrading and iteration In August of this year, COSCO signed an in-depth strategic cooperation agreement with meitianni, a world-renowned equipment and reagent manufacturer in the field of cell therapy According to the agreement, the two sides will give full play to their respective resources and technical advantages in the construction of tumor new antigen discovery platform, DC vaccine production automation and CMC system