As the second leading cause of death after cardiovascular disease, cancer has become one of the major diseases threatening human health in the world today. According to the latest data released by the World Health Organization, by 2030, the number of global cancer deaths will increase to 13 million, and new cancer cases will increase to 22 million. In China, according to the latest statistics released by the Ministry of Health, the incidence of cancer in China is in a period of rapid rise, with 2.6 million new cases of cancer each year, 1.8 million people died of tumors, and tumors have become the first among Chinese urban and rural residents. cause of death. For the treatment of tumors, almost every patient is struggling along the road of surgery, radiotherapy and chemotherapy. Although traditional treatments can temporarily curb the development of tumors, they cannot fundamentally solve the problems of tumor recurrence, metastasis and spread. At the same time, due to the huge toxic side effects, the tumor patients' own immunity decreased, and eventually the remaining tumor cells revived, which accelerated the deterioration of the disease. In recent years, with the rapid development and cross-infiltration of oncology, immunology, molecular biology and bioengineering technologies, how to prevent the metastasis and recurrence of tumors and improve the survival time of patients with malignant tumors, It has become the direction of scientists in the world to treat tumors, and it is also the fundamental way out for cancer treatment.
Tumor biotherapy is an emerging and remarkable therapeutic treatment model for cancer. It uses biotechnology and biological agents to interfere with the occurrence, growth, differentiation, apoptosis, invasion, metastasis and recurrence of tumor cells and promote the body. Reconstruction of the immune system, so that cytotoxic substances are concentrated in the tumor tissue, thereby stimulating and enhancing the body's biological response to the tumor, to achieve control and elimination of minimal residual lesions in the body, and even to achieve partial or complete remission of advanced tumors. Because of its high specificity, it has no toxic and side effects, reduces the risk of postoperative recurrence and metastasis of tumor patients, and improves the sensitivity and tolerance of patients to chemoradiotherapy, making tumor biotherapy the first step after surgery, radiotherapy and chemotherapy. Four major cancer treatment technologies. The commonly used methods including fine tumor biological therapy mainly include cytokine therapy, adoptive cellular immunotherapy, tumor vaccine therapy, tumor gene therapy, molecular targeted drug therapy, and anti-angiogenesis therapy.
According to the principle of tumor biotherapy, they can be divided into four categories (see Table 1). Among them, active immunotherapy of tumor refers to the method of inputting antigenic tumor vaccine to the body, stimulating the body's immune system to produce anti-tumor immunity to treat tumor; and passive immunotherapy of tumor refers to the immune effect of exogenous infusion into the body. The substance, which is used to treat tumors in the body by these exogenous effect substances.
Table 1 Classification of tumor biotherapy
Classification
Specific active immunity
Tumor vaccine
Antibody targeting
Non-specific active immunity
Cytokine
Bacterial extract
Specific passive immunity
Antibody targeting
Immunocompetent cells (TIL, specific TIL)
Non-specific passive immune immunization Immunocompetent cells (LAK, CD3AK, CIK)
One
Somatic cell therapy and cytokine therapy
Cytokines are synthesized and secreted by activated immune cells (mononuclear/macrophages, T cells, B cells, NK cells, etc.) and some non-immune cells (vascular endothelial cells, epidermal cells, fibroblasts). A class of small-molecule proteins with extensive biological activity as intercellular signaling molecules have the functions of regulating immune response, immune cell differentiation and development, participating in inflammatory reactions, and stimulating hematopoietic function. Cytokines have a variety of activities, such as overlap, antagonistic, pleiotropic, synergistic, etc., to adjust the body's physiological functions, stimulate cell activation, differentiation, proliferation and apoptosis, and is related to tumorigenesis and development. More clinical applications include interferon (IFN-α, IFN-β, IFN-γ), interleukin (IL-2, IL-4, IL-7, IL-12, etc.) and hematopoietic stimulating factor (EPO, TPO, G-CSF, GM-CSF, IL-11, IL-3, etc.), tumor necrosis factor (TNF-α), repair factor (GM1, EGF, BFGF), and the like.
1. Interferon: Interferon (IFN) is a glycoprotein produced by nucleated cells stimulated by an inducing agent. It can be divided into IFN-α, IFN-β, IFN- depending on cell source, physicochemical properties and antigenic characteristics. γ these three types. The biological effects of interferon mainly include inhibiting the proliferation of virus in cells, inhibiting cell division, and enhancing the activity of immune cells. It is widely used in hairy cell leukemia, chronic myeloid leukemia, multiple myeloma, non-Hodge Treatment of tumors such as gold lymphoma, kidney cancer and melanoma.
2. Interleukin-2: Interleukin-2 (IL-2) is the most widely used interleukin (IL), which is an active transmitter produced by activated T cells and can induce lymphocytes. The proliferative response induces the production of LAK cells, promotes the proliferation and differentiation of B lymphocytes, and participates in various immune regulation of the body. IL-2 has a wide range of applications and is suitable for various solid tumors, malignant serous effusion, kidney cancer, melanoma and the like.
3. Erythropoietin: Erythropoietin (EPO) is a cytokine produced by renal tubulointerstitial cells that promotes the proliferation and redness of red blood cell precursor cells. It is mainly used in the treatment of renal anemia. It also has a certain effect on anemia caused by tumor radiotherapy and chemotherapy.
4. Colony Stimulating Factor: Colony stimulating factor (CSF) is a type of cytokine that promotes the formation of granulocytes and macrophages by hematopoietic progenitor cells. Granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are clinically commonly used colony-stimulating factors. G-CSF has the functions of promoting the formation, differentiation and maturation of myeloid cell progenitor cells and enhancing the function of neutrophils. It is suitable for neutropenia caused by tumor after radiotherapy and chemotherapy; GM-CSF has the function of promoting granulocyte system and mononuclear giant The proliferation of the phagocyte system activates the action of mature granulocytes and monocyte macrophages and can be used for immunotherapy of tumors.
two
Adoptive cellular immunotherapy
Tumor adoptive cell immunotherapy refers to a method in which tumor-specific immune cells expanded and activated in vitro are sequentially returned to a tumor patient for tumor treatment. Adoptive cellular immunity can be divided into specific and non-specific types. The former is obtained by injecting a lymphocyte sensitized with a known antigen into a receptor to obtain cellular immunity to the antigen; the latter is caused by a specific antigen. Sensitive normal human lymphocytes are injected into the receptor to obtain cellular immunity to various antigens. The cells used in specific adoptive cellular immunotherapy mainly include TIL and specific transgenic T cells; the cells used in non-specific adoptive cellular immunotherapy mainly include LAK, CD3AK, and CIK.
LAK: lymphokine-activated killer cell (LAK) is an effector cell that induces non-effect cytotoxicity induced by IL-2 in vitro and activates peripheral blood mononuclear cells. LAK cells have no killing effect on normal cells, and the killing effect on tumor cells is MHC non-limiting, broad-spectrum, non-specific. Because LAK is not very lethal and has limited amplification capacity, a large amount of infusion is required when clinical application of LAK, and IL-2 is required in large doses while infusion. A variety of toxic and side effects occur in the large number of applications of IL-2. The most serious is capillary leak syndrome, which is mainly characterized by systemic edema and multiple organ dysfunction, which can cause pleural effusion and lung. Interstitial edema and congestive heart failure.
2. TIL: Tumor infiltrating lymphocyte (TIL) is a large amount of T lymphocytes isolated from tumor tissues that are amplified by IL-2 in vitro and have strong killing activity against tumor cells. TIL has a certain specificity for tumors, and its killing effect is 50 to 100 times that of LAK cells. Returning TIL to the body's blood or tumor can last for two months. At present, TIL has been used in the treatment of primary or secondary tumors in the skin, liver, kidney, lung, head and neck, ovary, etc., and has great potential therapeutic value.
3. CD3 AK: anti-CD3 monoclonal antibody activated killer cell (CD3 AK) is an anti-CD3 monoclonal antibody used as a major stimulating factor to stimulate lymphocyte induction together with IL-2. Tumor-killing effector cells. The most important feature is that CD3 monoclonal antibody can stimulate the proliferation of lymphocytes in vitro, and the activation of lymphocytes can be completed in one time and maintain the proliferation and growth trend for at least 16 days. The amplification effect is much higher than that of IL-2 alone. Activated lymphocytes (LAK, TIL, etc.). CD3 AK is mainly used to remove residual tumor cells after tumor surgery, which has a certain effect on delaying recurrence and prolonging the survival of tumor patients. Since the CD3 AK was reported to be used in the treatment of tumors in 1993, the application of CD3 AK has developed rapidly. In 2008, at the American Oncology Conference, CD3 AK combined with IL-2 was successfully reported for the treatment of renal cancer. Recent studies have shown that CD28 mAb can enhance the anti-tumor activity of CD3 AK.
4. CIK cells: Cytokine induced killer cells (CIK) are a new class of tumor killing cells prepared on the basis of CD3 AK. They are mainly CD3 + and CD56 + cells. Suppress the cell population. CIK can dissolve a variety of tumor cells, showing non-MHC-restricted killing, and has a good killing effect on drug-resistant tumor cells sensitive to chemotherapeutic drugs. CIK's anti-active agent is superior to LAK and CD3 AK. Because CIK can maintain the tumoricidal activity of cells for a long time, it has great clinical application value. At present, the anti-tumor mechanism of CIK cells has not been fully elucidated. The possible mechanisms are as follows: (1) CD3 + and CD56 + T cells in CIK cells kill the residual tumor cells in vivo by MHC non-limiting mechanism and pass LIF-1/ICAM- 1 system binds to target cells, releasing granzyme and perforin to perform MHC non-limiting killing on target cells; (2) CD3 + CD8 + T cells and CD3 + CD4 + T cells in CIK cells have immunomodulatory effects, which can indirectly kill Tumor cells; (3) through the deformation and trending movement close to the adherent target cells, releasing some chemical media such as perforin and granzyme, so that the target cells undergo lysis and necrosis and apoptosis, thereby killing the target cells.
5. γδT cells: γδ T cells are a special type of immune cells between specific and non-specific immunity. They are mainly distributed in skin and mucosal tissues, and do not exceed 5% of the total number of T cells in humans. . In the early stage of anti-tumor immunity, γδT cells have the functional characteristics of DC vaccine and NK cells, and have strong specific and non-specific tumor killing ability. However, due to the low content, the role of γδT cells is very limited.
6. Combined cell therapy
(1) DC-CIK cell therapy
DC and CIK are two important cells in tumor immunotherapy. DC recognizes antigen and activates the acquired immune system. CIK can achieve the purpose of killing tumor cells by means of its own cytotoxicity and secreting cytokines. It can construct an efficient and stable immune system, which can play a better tumor killing effect. Mixing DC cells with tumor antigens with CIK cells can enhance the release of cytokines and cytotoxicity, greatly enhance the proliferation and killing activity of CIK cells, and stimulate the specific anti-tumor immune effect of the body to achieve tumor Long-term control of the kill target. The DC vaccine technology in CIK-DC tumor therapy is the only high-tech tumor biotherapy method that has been approved by the state to enter the clinic and obtain national certification. At present, CIK-DC cell therapy has been widely used in various clinical system diseases, especially in the removal of minimal residual leukemia and treatment of malignant tumors, and has achieved an ideal therapeutic effect.
(2) CLS multi-cell immunotherapy
CLS multicellular immunotherapy adds three anti-tumor immune cells to CD-AK cells, NK cells and γδT cells based on DC-CIK cell therapy. NK cells can effectively kill cancer stem cells, and also have the function of killing mature tumor cells; γδT cells can complement DC cells while killing tumor cells, and labeling and killing tumor cells that are not recognized by DC; CD3AK cells target Viral cancer cells are extremely lethal. On the one hand, the newly added immune cells have their own unique killing ability, the range of killing is expanded, and the specific anti-tumor ability of the therapy is enhanced. On the other hand, the γδT cells complement the DC cells while killing the tumor cells, and DC Unidentified tumor cells are labeled and killed, which not only enhances the specific anti-tumor ability, but also enhances the ability to recognize tumor cells, which is beneficial to completely eliminate tumor cells and become the first solution for cell biological therapy.
7. Adoptive immunotherapy based on chimeric antigen receptor-modified T cells: Chimeric antigen receptor T-cells (CAR-T cells) are capable of encoding single-chain antibody-costimulatory molecules. A special genetically modified T cell produced by the fusion gene of a chimeric molecule of an immunoreceptor tyrosine activating motif to modify T cells. The expression of the single-chain variable region of the monoclonal antibody that specifically recognizes the target antigen is coupled to the activated proliferation signal domain in the T cell by means of genetic modification. CAR-T cells combine the specific recognition of a monoclonal antibody with a target antigen with the function of a T cell to produce a specific killing effect, and can kill target cells in a manner that is not restricted by a predominantly compatible complex. The current research on CAR-T is in full swing.
three
Tumor vaccine treatment
The principle of tumor vaccine is to induce the body's specific cellular immunity and humoral immune response, enhance the body's anti-tumor effect, thereby inhibiting the growth, metastasis and recurrence of tumor cells. At present, there are many researches such as tumor cell vaccine, tumor polypeptide vaccine, tumor genetic engineering vaccine, tumor nucleic acid vaccine and anti-idiotype antibody vaccine.
1. Tumor cell vaccine: treatment of intact tumor cells by physical irradiation, grinding, heat inactivation, etc.
