Overview
Tumor is a serious disease that threatening human life. According to the results of the World Health Organization, cancer is a major cause of death in the world. In 2020, nearly 10 million cases (or nearly one in six) of deaths were caused by cancer, and the trend is younger.
There are as many as 19.29 million new cancer cases and 9.96 million deaths worldwide each year, of which 49.3% of new cancer cases and 58.3% of deaths occur in Asia. According to the results of our social survey, 68.84% (or 243 in 353) of the people believed that the biggest difficulty in cancer treatment was tumor recurrence, and the key to tumor recurrence was its heterogeneity. Traditional cancer therapies such as radiotherapy and chemotherapy not only cannot cure the tumor, but also cannot deal with the heterogeneity of the tumor. Their own application will cause many side effects, such as nausea and vomiting, loss of appetite, decrease of white blood cell count, immune function decline, arrhythmia, cognitive decline, neurotoxicity and so on. Cell therapy, because of its high targeting, often can precisely act on cancer cells, so there are few side effects. The reason why tumors are difficult to cure is their recurrence, which is caused by the heterogeneity of tumors.
The nature of tumor heterogeneity is the emergence of new genes and corresponding new antigens. According to the theory of clonal selection, for each old or new antigen, there are antibodies that theoretically exist and bind to it. In other words, as long as all or most of the corresponding antibodies to the old and new antigens are an element of the antibody set prepared in advance, even if the tumor antigens are thousands of changes, there is a chance to kill all the cells carrying different old and new antigens. Therefore, applying this theory to cancer treatment is our goal.
Policy analysis
On July 19, 2018, State Drug Administration of China organized a report on biotechnology drug research and development and industrial development.
The Chinese government attaches great importance to the development of biomedicine industry and has listed biomedicine as one of the country's eight strategic emerging industries in the 13th Five-Year Plan for the Development of Strategic Emerging Industries, according to the meeting. In the field of biological products, the State Food and Drug Administration has issued important regulations and rules, such as the Technical Guiding Principles for Research and Evaluation of Cell Therapy Products (Trial) and the Measures for the Administration of Batch Issuance of Biological Products, which have played a positive role in promoting the development of industrial health standards.
On September 29, 2019, the state drug administration issued "on the second session of the thirteenth session of the national committee of CPPCC proposal reply letter no. 3324", said: "our drug approval center according to the drug research and development and technical review of communication management approach (trial)", the relevant provisions of the diversified channels of communication have been established. The applicant may communicate with the Drug Review Center on the requirements of the research and development process at different stages of the research and development of cell therapy products, so as to improve the efficiency of the research and development and application of cell therapy products. We will closely cooperate with the national health committee, in accordance with their respective responsibilities, standardize the order of cell therapy research and encourage technology innovation, through the establishment of effective operation of the regulatory system, perfect the relevant management system and technical standard, regulating the development of cell therapy, promote cell therapy to clinical scientific research achievements, create a good environment for healthy development of cell therapy in our country ."
On May 10, 2021, The State Council issued the Implementation Opinions of The General Office of the State Council on Comprehensively Strengthening the Capacity Building of Drug Supervision (State Administration and Development (2021). 16), which mentioned that the drug regulatory scientific research will be included in the relevant national science and technology plans, focusing on supporting the regulatory scientific research in the fields of traditional Chinese medicine, biological products (vaccines), gene drugs, cellular drugs, artificial intelligence medical devices, new materials for medical devices, new raw materials for cosmetics, and so on, and accelerating the development and listing of new products. Therefore, China attaches great importance to and supports the development of cell therapy products, which has a role in promoting our project.
Market analysis
Since the CAR-NK product is not yet available, we use the CAR-T market to predict its development prospect, and the CAR-T product is developing rapidly in the Chinese market. The domestic CAR-T cell therapy industry is growing rapidly, with nearly 100 companies of all sizes involved in the research and development of CAR-T cell therapy. Nanjing Legend, a subsidiary of Kingsley Biotechnology, is currently in China. The company has the fastest progress in CAR-T clinical research, its "LCAR-B38M CAR-T cell autotransfusion preparation (LCAR-B38M cell preparation)" is the first CAR-T product in China to be accepted by CDE under the" Class 1 New Drug for therapeutic biological products "application, and has been granted priority evaluation qualification. On March 12, 2018, the product received CDE clinical trial approval, becoming the first CAR-T cell therapy approved as a drug in China. In April 2018, the product was approved by the Food and Drug Administration (FDA) for phase 1b /2 clinical trials in the United States. According to the clinical data of LCAR-B38M cell preparation published by Nanjing Legend,35 patients with relapsed or drug-resistant multiple myeloma had an objective response rate of up to 100% after treatment.
CARsgen Therapeutics, Ltd is the first company in China to conduct clinical trials of CAR-T cell therapy for solid tumors, and the world's first CAR-T clinical trial targeting GPC3 in the treatment of hepatocellular carcinoma, targeting EGFR/EGFR VIII clinical trials of dual-target CAR-T for glioblastoma, and CAR-T for Claudin18.2 for gastric tumor and pancreatic cancer. In addition, clinical studies of humanized CD19 CAR-T in the treatment of leukemia and lymphoma and whole-human BM-CACAR-T in the treatment of multiple myeloma have been carried out. As of July 2018, CARsgen Therapeutics, Ltd has already had 3 products entered the IND acceptance stage of CDE. The infusion agent targeting CD19 autologous chimeric antigen receptor T cells developed by PersonGen, a subsidiary of Anke Biotechnology, was accepted by the IND of CDE on January 8, 2018. Currently, the pharmaceutical, pharmacological, toxicological and clinical status evaluation of the product has been completed.
From the perspective of patents, China's CAR-T cell therapy technology started relatively late, and relevant patent applications were only started in 2011. In the early years, patent applications were mainly filed by foreign applicants in China. The University of Pennsylvania, Baylor College of Medicine, and the U.S. Department of Health and Human Services were the main patent applications. After 2015, with the rapid increase in the number of global patent applications, China's CAR T cell therapy patent applications have also increased to a large extent. After 2016, the annual number of patent applications exceeded 400. Since 2017, the number of Chinese domestic applications exceeded foreign applications, becoming the main force of China's CAR T cell therapy patent applications.
Thus, the development of cell therapy in our country is very rapid, and our country has a certain position in the world CAR-T market. It is reasonable to speculate that CAR-NK products will have better development after the market.
To investigate the future of CAR-NK audience, also is the public's attitude toward our products, we designed a questionnaire, in line with the random, comprehensive principle about the opinions of the respondents, the content including the public attitude to cellular immunity, concerns, etc., total recycling effective questionnaire 353, 77.05% said they are willing to accept this new anti-cancer therapy, but most of them hope Our products are safe and cost-effective and can be seen before cell therapy is applied people
SWOT analysis is based on the situation analysis under the internal and external competitive environment and competitive conditions. We list the main internal strengths, weaknesses, external opportunities and threats closely related to the research object through investigation and arrange them in the form of matrix. Then use the idea of system analysis to match and analyze various factors, so as to make a comprehensive, systematic and accurate research on the situation of the project. According to the research results, we formulate corresponding development strategies, plans and countermeasures.
Risk analysis
Safety is an important issue, the target identified in our project is uncertain, and the perfused NK-92 cells have strong proliferation ability, which is easy to destroy the balance of the immune system in vivo. A mathematical model was established to determine the safe range of a single injection. And try to ensure that the engineered cells do not harm the human body or the environment.
We fully consider the economic situation of the product audience and the profit of the drug company, highlight the characteristics of CAR-NK treatment such as off the shelf, minimize the cost of treatment, and commit to include CAR-NK treatment in the national health insurance plan.
The research and development of the project is still in the early stage and has not entered the clinical trial stage, so the investment is risky. However, we have fully understood the intention of the target audience of the product, completed the market analysis, and designed and planned the design and research and development of the product. However, the later stage of the project cannot be carried out without financial support. We are actively raising funds for the project and will continue to push forward.
As for drug supervision, we have fully understood the provisions of drug research and development and quality monitoring, so as to ensure that our products can be developed and produced smoothly if the later promotion goes smoothly.
Product design and development plan
Our program has many advantages over conventional anticancer therapies and CAR-T cell therapies
(1)The application of NK-92 cells in chassis cells does not cause graft-versus-host disease, cytokine storm, etc., and has less side effects on the body.
(2)The application of antibody library makes it possible to combat tumor heterogeneity and reduce tumor recurrence.
(3)The tumor-associated antigen is used as an inhibitory signal of suicide circuit to determine the number of immune cells by the dynamic situation of the tumor.
(4)The extraction and recovery of immune cells enriched in patients can provide a new idea for screening tumor antigens
Considering patent factors, we do not set the ultimate goal of the product as a marketed drug, because patent and market factors will cause a significant increase in price. We can set the product as an information repository, and treat the sequence information library obtained from healthy individuals or NK cell library stored in the laboratory, when the patient is willing to accept treatment, we can directly apply the sequence information storage or cell library into treatment.
We designed two plans for our project, and we list their characteristics, advantages, and disadvantages in the follow chart.
This is our initial idea. After that, we will listen to the opinions of all parties and improve the project. We have also made the improvement plan of the project
Product cost analysis
Compared with CAR-T, our product has the advantages of being more economical and easier to be accepted by the public. However, since there is no CAR-NK product on the market, it is necessary to demonstrate the cost of the product，it is also a suggest from ZJUtil iGEM. Since the project exists as a repository, the construction of sequence information database and other steps can be completed only with peripheral blood of normal people, which can be used as a common step in the treatment of all patients, embodied the characteristics of off the shelf, for individual patient treatment process, the step of cost is negligible. Defining the project in the form of the repository, can effectively avoid the patent, market and other factors lead to rising prices and uncertainty, so compared with drugs, the repository of cost analysis also has guiding significance for the final price.
To bring these highlights to fruition, we did the following planning for the course of the project, with specific timing to continue adjusting based on subsequent progress. Now, we are at the first phase and we have the opportunity to continue our project after the iGEM competition.
