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Nowadays, cancer is a global problem, after years of experience in fighting cancer, there have been various ways to fight cancer such as traditional surgical treatment, radiotherapy, chemotherapy, targeted therapy, and immunotherapy.
Currently, immunotherapy for tumors is increasingly becoming the hope for overcoming cancer, because traditional surgery can remove solid tumors, but usually cannot eradicate them, and does not apply to blood tumors, while radiotherapy and chemotherapy can effectively treat many kinds of tumors, but also have greater damage to the normal cells of the body.
Although the healthy body has a series of immune surveillance mechanisms, it is still difficult to stop the occurrence and development of tumors because a small number of tumor cells do not easily elicit the body's immune response, and during the growth process, tumor cells can escape and avoid the body's immune system surveillance by reducing the immunogenicity of their antigens or inducing immune suppression in the body. Tumor immunotherapy is a treatment method to control and clear tumors by restarting and maintaining the immune system's recognition, killing tumor cells, and restoring the body's normal anti-tumor immune response.
Tumor immunotherapy has become an indispensable link in the clinical treatment of tumors. For example, the CAR T-cell therapy currently used in cancer treatment is powerful immunotherapy, which transforms the patient’s own immune T cells into chimeric expression antigen receptors (CARs). A large number of tumor-specific CAR T-cells are generated by in vitro culture and returned to the patient to achieve the purpose of effectively identifying and killing tumor cells.
CAR-T cell therapy, i.e. chimeric antigen receptor T cell immunotherapy, is a cell therapy method, which adds a "chimeric antigen receptor" to T cells, and the "chimeric antigen receptor" is navigated by "GPS". The "chimeric antigen receptor" consists of a "GPS navigation" (extracellular antigen recognition region) and an "activation button" (intracellular signal transduction region), while CTL019 or CAR-T 019 adds an antigen receptor that recognizes "CD19" on the surface of tumor cells. "When the "GPS Navigation" locates the tumor antigen and binds to it, the "activation button" starts to activate the T cells to kill the tumor.
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Traditional tumor treatment modalities: chemotherapy, radiotherapy and the recent development of monoclonal antibodies and small molecule inhibitors are facing a serious challenge due to the huge difference in the treatment of tumor patients and the high recurrence rate.
The first use of T-cell-relay therapy for human tumors was the application of donor lymphocyte (DLI) transfusion back to a patient with myeloid hematologic tumors that had relapsed after bone marrow transplantation. Further studies demonstrated that expanded tumor-infiltrating cells (TIL) could lead to complete and sustained remission of large vascular metastatic melanoma, and monitoring of circulating tumor cells (CTCs) in the blood also showed that ACT Monitoring of circulating tumor cells (CTCs) in the blood has also demonstrated clinical efficacy of ACT therapy, however, such therapy is largely dependent on the endogenous T-cell component. Recent technological developments are manifested in the use of genetically engineered T-cell technology modified by retroviral or plasmid vectors to attack tumor cells through the generation of large numbers of targeted T cells (CART or TCRT).
CAR-T cell therapy has a target that is not restricted by MHC. Today we will briefly understand what MHC is.
MHC molecule is a glycoprotein distributed on the surface of cells, but it has polymorphisms and is the most complex polymorphic gene system in mammals. MHC has important biological functions, including participation in the selection of thymus on thymocytes, genetic control of the body’s immune response, participation in mutual recognition of immune cells, and genetic restrictions on the interaction of immune cells. MHC-1 and MHC-2 are two common types of MHC, and they can be distributed on different cell surfaces.
The classic TCR-antigen-MHC molecular binding model believes that if T cells want to recognize different cells, they need to rely on the combination of the T cell receptor (TCR) on the T cell and the antigen presented by the MHC molecule on the cell to play a recognition role. . Histocompatibility antigens (MHC) play an essential regulatory role in the body’s immunity. All antigens must be MHC processed and combined with MHC to be expressed on the cell surface to be recognized by T cells. However, the T cell costimulatory signal factor CD28/CD80 Deletion makes T cells unable to differentiate, activate, proliferate, and inactivate T cells. MHC function is inhibited during tumor metastasis, and the cell costimulatory signal is weakened, which leads to tumor cell immune escape. It is an essential reason for tumor metastasis.
Tumor immunotherapy is currently a popular tumor treatment method, and CAR T-cell therapy is one of the methods of tumor immunotherapy. Medicilon has rich experience in in vitro pharmacodynamic research, in vivo pharmacodynamic research, pharmacokinetics research and safety research of CAR T-cell therapy. At the same time, Medicilon has a strong grasp of immunotherapy and targeted tumor therapy. Trend, continue to develop and improve the pre-clinical research platform for emerging tumor treatment.
Medicilon has built a one-stop research platform for the preclinical R&D of cellular immunotherapies, covering a variety of immunotherapy methods including CAR-T, TCR-T and CAR-NK. Using a wealth of animal models and a variety of advanced analysis techniques, comprehensively considering the characteristics of different research projects, Medicilon has completed numerous pre-clinical projects for clients worldwide.
Tumor immune escape believes that the body’s immune system can monitor “non-self” mutant cells, and can be specifically eliminated through cellular immune mechanisms to maintain the stability of the body’s environment. However, when the mutant cells escape the surveillance of the body’s immune system under the action of various factors, they can rapidly divide and proliferate in the body, accelerating the deterioration of the tumor.
Tumors can evade the specific immune recognition of T cells by down-regulating the expression of tumor-specific antigens or related antigens. For example, tumor-specific CD8+ T cells are activated by recognizing tumor antigens. The specific killing of tumor cells depends on the specific recognition and binding of TCR to the MHC-I-peptide complex. To effectively escape immune recognition, tumor cells can Change the interaction between MHC molecules and antigen peptides affecting the recognition of MHC molecule antigen peptide complexes by TCR.
The lack of presentation function of MHC class I molecules is often one of the main reasons leading to tumor immune escape. The expression of MHC class I molecules in tumor cells is reduced to varying degrees, the expression of MHC I in poorly differentiated tumor cells is weaker, and metastatic tumors are the weakest or even disappear. In addition, most solid tumors do not express MHC molecules and therefore cannot effectively activate T helper cells.
Tumor cells are a very cunning type of cell. They can reduce or lose the expression of MHC to avoid the recognition of T cells and escape the killing effect of T cells. To avoid the restrictive effects of MHC, Israeli scientist Professor Zelig Eshhar developed the first generation of CAR-T therapy. Later, the second-generation CAR-T therapy was developed on this basis. At present, third and fourth-generation CAR T-cell therapy has been developed.
CAR-T therapy overcomes the MHC limitation of tumor-specific TCR targeting tumors in the past and solves the problem of immune escape caused by the down-regulation of MHC expression by tumor cells. Moreover, both protein antigens and glycolipid antigens can act as target antigens, expanding the range of tumor molecular targets.
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