Immunotherapy is the most popular tumor therapy in recent years, and it is not uncommon for immunological checkpoint inhibitors (Anti-CTLA-4, Anti-PD-1/PD-L1, etc.) and cell therapy (CAR-T). Recently, the arterial network interviewed Professor Liu Gentao, a doctor-in-law of the new technology focusing on cancer treatment, and combed the latest research progress of the medical doctors. Professor Liu is an adjunct professor of Tongji University School of Medicine, an internationally renowned cancer stem cell expert, with five authorized invention patents and 50 SCI papers.
Technology frontier
1. New IL-2 mutants may become the future gospel for cancer patients
IL-2 is the first discovered leukocyte growth factor, an essential factor for the activation and expansion of T cells and NK cells, and the most important cytokine in the immune system; participating in antibody responses, tumor surveillance, etc., maintaining the immune system itself. Fine dynamic balance between immunity and tumor immunity; approved by the FDA for clinical treatment of kidney cancer and melanoma in 1992 and 1998; domestic CFDA approved interleukin 2 for the treatment of renal cell carcinoma, melanoma, breast cancer, bladder The treatment of malignant tumors such as cancer, liver cancer, rectal cancer, lymphoma, and lung cancer is used for the control of cancerous chest and ascites.
IL-2 is also used in certain viral, bacillary, and intracellular parasitic infectious diseases such as hepatitis B, leprosy, tuberculosis, and infections caused by Candida albicans.
However, long-term clinical applications have found that low-dose effects have limited or no effect: because interleukin 2 first activates and amplifies Treg (CD4+CD25+) cells, inhibiting the killing effect of the immune system on target cells (tumors). Only at high doses, IL-2 has significant anti-tumor effects, but high doses of IL-2 are associated with strong toxic side effects, including capillary leak syndrome, pulmonary edema, high fever, coma, and even death. This greatly limits the widespread use of IL-2 in the clinic. Research and discovery of new high-efficiency and low-toxicity IL-2 mutants is also a hot spot in current immunotherapy research.
The study found that IL-2 receptor (IL-2R) contains three polypeptide chains: α chain, β chain, γ chain, and has the highest affinity with IL-2 when expressed simultaneously. It is the alpha chain of IL-2R that causes IL-2 to induce regulatory T cells at low doses, and the source of serious toxic side effects at high doses. To clarify this principle, the combination of the University of Maryland and the University of Maryland and UCLA for many years of research on IL-2, through the amino acid site-directed mutagenesis, found a new high-efficiency, low-toxic IL-2 mutant. This mutant has a low binding affinity to the α-chain receptor, but the receptor binding of the β-chain and the γ-chain is not affected, thereby greatly reducing the toxic side effects of IL-2. The research results have recently been published in the Cell Death and Disease magazine of the Nature Publishing Group, and have attracted the attention of many scholars in Australia and other countries.
At present, the low-toxic new IL-2 mutant preparation technology has obtained Chinese patents. Animal experiments show that the new IL-2 mutant has high activation and promotion of cell proliferation in CD4, CD8 and NK cells, and can significantly enhance the expression of CD69, CD183 and CD54, and has strong tumoricidal ability in vitro.
"We cultured NK cells with the new IL-2 mutant technology, which significantly improved the proliferation efficiency of NK cells, and also promoted the activation of NKG2D, a higher activation factor of NK cells. The tumoricidal ability in vitro was significantly enhanced." Professor Liu Gentao Said proudly in the interview.
In addition, the medical and medical Lianchuang is studying the use of new IL-2 mutants in combination with PD-L1 therapy for cancer treatment, and is currently in the preclinical research stage.
2. Multi-target targeting tumor stem cells
In the past 20 years, a major hotspot and progress in cancer research has been the discovery and confirmation of the "tumor stem cells" hypothesis in most solid tumors, and the role of cancer stem cells in tumorigenesis, development, metastasis and recurrence. A large number of systematic studies have found that cancer stem cells not only have anti-chemotherapy and anti-radiation characteristics, but also have strong migration ability and angiogenic ability. Therefore, cancer stem cells are sometimes called "tumor-initiating cells", in the recurrence of cancer and The transfer also plays a key role.
Professor Liu Gentao began research on tumor stem cells of gliomas in 2002, and proved that CD133 is a surface marker of cancer stem cells. Subsequently, HLA-A2-restricted epitopes on CD133 were further identified and patented.
Specific effector T cells are prepared by tumor stem cell-associated antigens to treat tumors, which may fundamentally eliminate this group of cancer stem cells that are resistant to chemotherapy and anti-radiation.
"Although different types of cancer stem cells have different surface markers on their surface, almost all tumor stem cells have a set of genes that control dry maintenance." Recent studies have found tumor dry maintenance genes Oct-4 and SOX-2. "Interestingly, these genes are themselves tumor antigens that can be recognized by T cells, which provides a theoretical basis for the removal of cancer stem cells by immune cell therapy," Professor Liu said.
Based on these two principles, the combination of science and technology in vitro induces CSC-CTL, targets tumor stem cell surface antigen, and cancer stem cell dry maintenance gene, and achieves the goal of eliminating tumor stem cells. At present, the medical and medical team has discovered a target that is highly expressed in cancer stem cells. In vitro and in animal experiments, T cells prepared using this target have good antitumor activity.
In addition, the medical and medical Lianchuang is also carrying out genetic modification immunotherapy targeting cancer stem cells, such as CAR-T, CAR-NK and other research on tumor immunity.
Results and cooperation
In collaboration with EMORY University in the United States, the Physician has developed a trophoblast culture technology for five NK-activated amplification-related factors or proteins such as IL-21, which inhibits the surface immune checkpoint of NK cells, 2 to 3 weeks. It can be amplified 1000 times, and the tumoricidal activity is several times or even dozens of times that of traditional NK cells. The technology is currently used to prevent postoperative recurrence of tumors. It has been deployed in the pioneering area of ​​Boao Medical Center in Hainan and has been approved for use by Japan and Russia.
At present, the medical and medical Lianchuang is cooperating with Tongji University Affiliated Hospital, Changhai Hospital and Changzheng Hospital to carry out CAR-T therapy for malignant solid tumor research, which has entered the clinical stage and has a high remission rate in clinical application.
Science and Technology Joint Venture Development Unit
In China, the company has a subsidiary, Shanghai Branch Medical Association Medical Laboratory Co., Ltd., which is guided by molecular diagnostic technology and provides excellent medical testing, drug clinical, scientific research services, health management and pathological consultation services.
In the international market, the Medical Association has established BIOMED-JAPAN Biomedical Japan Co., Ltd., its holding hospital, Japan Hongqiao Hospital, to provide cancer immunotherapy services. The hospital is equipped with a apex CPC cell laboratory and has obtained a complete certificate of relevant certificates for the Ministry of Health and Welfare.
Founded in 2010, Science and Technology Co., Ltd. is committed to the research and clinical application of new technologies for cancer treatment and won the Shanghai High-tech Enterprise. There are more than 63 R&D personnel in the department, including Doctor of Medicine of the Second Military Medical University, Senior Engineer of Molecular Medicine, Wu Guoxiang, CEO of the Medical Union, famous cell biologist, Honorary President of Tongji University, and Academician of the Chinese Academy of Sciences. Well-known experts and professors, as well as some overseas team members. The company has 13 Chinese patents and 2 US patents. In 2015, it won the A round of financing led by the Shanghai Lotus Equity Fund.
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