This year's Nobel Prize in Physiology and Medicine was awarded to the discoverer of PD1 (Immunity Checkpoint), which allowed the immunotherapy to be cured after the cure of President Carter's melanoma. The dazzling starlight of PD1/PD-L1 even made it unclear. The public in the public equates their treatment with immunotherapy, and the clinical research direction and even clinical resources have a tendency to accumulate to PD1/PD-L1. According to statistics, nearly 60 PD-1/PD-L1 clinical trials have been publicly registered in China in 2017.
In fact, immunotherapy has a wide range of connotations. On November 26th, there were media reports on the largest clinical recruitment in the field of cell therapy in China, which was used to serve clinical trials to prevent recurrence of liver cancer after radical cell therapy. The use of immune cells and tumor cells "matching" is a clinical exploration in the field of immunotherapy in the field of scientific research.
"Tumor immunotherapy uses the body's own immune system to fight tumors, clear tumor cells, achieve the purpose of treating tumors, and maintain sustained immune memory." Wu Jianxiong, a professor at the Cancer Hospital of the Chinese Academy of Medical Sciences, who participated in clinical trials, said that tumor immunotherapy Different from the traditional three methods of surgery, radiotherapy and chemotherapy, the core is to activate the body's own "defense system" to kill tumor cells.
Activated lymphocytes have an intensive "guide system"
In this battle between humans and tumor cells, the "weapon" chosen by humans is its own lymphocytes. The method used can be roughly described as: peripheral blood (20-100 ml) is taken from the patient, mononuclear cells are isolated, cultured and activated in vitro, and lymphocytes activated by a broad spectrum are obtained, and then "returned" to the human body. In the task of strangling tumor cells.
"The peripheral blood cells derived from the patient's own body will selectively activate and grow in a specific in vitro cell culture system." Wang Wei, technical director of Beijing Yongtai Biological Co., said that during the training process, the screening of "warriors" will be synchronized. - B cells, macrophages, etc. in peripheral blood cells will die, and the final returned components are mainly T lymphocytes, with a few NK cells.
This method of "screening warriors" is called EAL (Expanding Activated Lymphocytes). According to reports, the core technology of this method won the national invention patent in 2011. "On the basis of patents, we can further improve the efficiency and achieve a thousand times of lymphocyte proliferation in a short period of time." Wang Wei said.
Both immunological checkpoint inhibitors and "CAR-T" therapies with "CAR" for T cells are designed to "recover the eye" of T cells that are enchanted by tumor cells, accurately guiding and combating tumor cells.
It can be seen that the "guide system" is excellent and is one of the key elements of the effectiveness of cancer therapy. The "guide system" that activates lymphocytes is "original" and is not artificially installed or targeted at a specific target. One of its advantages as a weapon is that its "guide" target is not unique. Wang Wei explained: "The human T lymphocytes are composed of different T cells with antigens that can identify up to 109 different 'non-self' components, including T cells with tumor target molecules."
"In cancer patients, the function of these cells is often inhibited by the immune evasion mechanism of tumor cells, and can not exert anti-tumor function." Wang Wei explained that including tumor-specific molecules that have been exposed to tumor target molecules and activated by tumor target molecules Sexually recognized and killed T cell precursors, which differ in the amount and activity of each cell. These T cells targeting tumor cells can be broadly activated in vitro by EAL technology.
Serum-free culture focuses on the safety of cell products "pain points"
Taking the body cells out to walk outside the body, the biggest risk is that it may be contaminated. The most dangerous pollution comes from undetectable viruses or other living organisms that may be present in organic cultures.
"Bovine serum is considered to be the basic substance for providing nutrients for cell culture, but it also carries a lot of risk of contamination." Wang Wei said that the team first solved the problem of serum-free culture in vitro, avoiding possible exogenous Microbial infection caused by animal or human factors. Not only that, EAL technology also has the effect of high expansion efficiency, good activity, good stability and seamless coordination with chemotherapy. The clinical approval issued by the State Food and Drug Administration in 2017 is the first individualization in China. A large number of pieces of immune cells that are not staged.
Another feature of cell therapy is that it is a "living drug." There are a lot of uncertainties, standardization is relatively difficult, and there are higher production requirements in terms of time periods.
The cells are removed and activated in vitro, and there may be many contamination risks and uncertainties during manual processing in the laboratory for several hours. Some experts have said that in the current situation of talent shortage, it is very likely that a skilled technician can achieve 90% of the activity of cell products, and a novice can only achieve 40%, this gap leads to Cell therapy cannot be industrialized or scaled up.
The standardized production process has become a "pain point" for cell therapy to finally get clinical approvals into the clinic. The person in charge of Yongtai Biotechnology, who is responsible for cell production in this clinical trial, said: "After 10 years of research, Yongtai Bio's EAL cell production process has become a standardized production process, which can achieve large-scale production and controllable production cycle. We are completely Production management is carried out in accordance with the GMP production standards. The management details are more stringent than the general production of large infusion products, and the factory pass rate of quality requirements is 100%."
The largest-scale clinical recruitment of liver cancer with a high incidence of "dead sputum"
Hepatitis B virus can induce liver cancer. In China, due to the large number of carriers of hepatitis B virus, the number of new cases of liver cancer and the number of deaths accounted for more than half of the number of new cases of liver cancer and the number of deaths in the world. According to statistics released by the China Cancer Registry (NCCR) in 2018, the number of new cancer cases in China in 2009 was 4.29 million, and the death toll was 2.81 million. Among them, the number of new cases of liver cancer is 470,000 per year, ranking fourth; the mortality rate of liver cancer is the third, and the number of deaths per year is as high as 420,000.
"This is the largest clinical recruitment in the field of cell therapy in China, to prevent recurrence after radical resection of liver cancer. The total number of recruits is 272." Wu Jianxiong said that the clinical trial was approved in October 2017. EAL technology has obtained clinical approvals for drugs. The primary objective of the trial was to evaluate the efficacy and safety of EAL in preventing postoperative radical recurrence of primary liver cancer.
"We have to answer some of the questions that are still not well understood in immunotherapy, such as whether non-specifically cultured T cells have anti-tumor effects, and whether early administration of immune cells will benefit patients." Hepatobiliary Surgery Center, Peking University People's Hospital Director Zhu Jiye said that the clinical trial is carried out by professional clinical trial service companies for project management, auditing, data statistics and CRC, as well as independent data monitoring committees and third-party image evaluation, and for follow-up scientific research. Given objective and detailed data, it may provide more ideas and basis for the application of immune cell therapy technology to solid tumors.
As people become more aware of tumors, more and more scientists believe that tumor markers can be used as the basis for the classification of tumors, rather than by the original site. "We are very keen to be able to perform molecular typing analysis of hepatocellular carcinoma. Currently, we are working with gene sequencing companies to discuss research programs, and hope to identify tumors that are sensitive and insensitive to immune cell therapy by molecular typing of hepatocellular carcinoma. Type." Wang Wei said that he hopes to find a broad-spectrum new weapon for the "tumor" in the largest clinical trial research in the field of cell therapy in China, to help more types of cancer patients.
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