The incidence and mortality rate of cancer in China are rising continuously, and it has become the first cause of death in urban areas and the second cause of death in rural areas. Faced with such a harsh reality, the responsibility of medical personnel engaged in cancer diagnosis and treatment can be described as arduous and sacred, with a heavy responsibility and a long way to go. At present, the main methods of cancer treatment are still surgery, radiotherapy and chemotherapy, but they all have certain limitations, such as surgery may not completely remove cancer cells, while radiotherapy and chemotherapy will damage normal tissue cells and bring certain toxic side effects. Therefore, we are committed to carry out research on biological diagnosis and treatment of tumors, hoping to open up a new effective way in addition to the three traditional therapies for tumor treatment, in order to enhance the therapeutic effect of malignant tumors for the benefit of tumor patients. Liu Ping, Department of Oncology, The First Affiliated Hospital of Nanjing Medical University Tumor biotherapy (Biotheropy) is a new therapy based on molecular biology, cell biology and molecular immunology, emphasizing the molecular basis of tumor development and regression and the targeting, specificity (targeting) and effectiveness of treatment, and applying modern biotechnology and its products for tumor prevention and treatment. It mobilizes the host’s natural defense mechanism or gives natural (or genetically engineered) targeted substances to interfere with the biological behavior of tumors and regulate the patient’s anti-tumor immune response, mobilizing the body’s defense ability to achieve the treatment of tumors. With the in-depth research on the molecular mechanism of tumor development and the development of biotechnology, biological therapy has become the fourth mode of comprehensive tumor treatment, which has received more and more attention and become the most eye-catching and promising treatment method in the field of tumor treatment today. The development of tumor is the result of the disruption of the dynamic balance between tumor and body defense. Biological therapy focuses on improving the anti-tumor immune ability of tumor patients, and plays the effect and purpose of treating and controlling tumor. Over the past half century, oncology has developed greatly in the world and in China. The integrated application of existing possible methods for tumor treatment has been deeply rooted and accepted by tumor clinical workers, and integrated treatment has become the best and most popular mode of tumor treatment. The joint cooperation between surgical treatment, radiotherapy, chemotherapy and biological treatment has achieved remarkable efficacy in the treatment of many kinds of tumors. This concept emphasizes both aspects of the organism and the disease, and stresses that biological therapy and other therapies should be combined in a planned and rational manner, with the aim of improving the effectiveness of treatment and prolonging survival time on the one hand, and improving patients’ living conditions and quality of life on the other, with the ultimate result of achieving the unity of both treatment effectiveness and quality of life. Biological treatment methods and research progress (a) somatic cell therapy and cytokine therapy Somatic cell therapy is to isolate and obtain the patient’s own immune cells, and under the induction of cytokines, a large number of immune cells with high anti-tumor activity are expanded and then infused back into the patient, such cells include LAK cells, TIL cells, CIK cells, DC cells, CD3AK cells, AKM cells, etc. These cells include LAK cells, TIL cells, CIK cells, DC cells, CD3AK cells, AKM cells, etc. This therapy is very effective for malignant melanoma, kidney cancer, non-Hodgkin’s lymphoma and other tumors and cancerous thoracic ascites, and has mild toxic side effects. Cytokines are small peptides that are synthesized and secreted by activated immune cells (monocytes/macrophages, T cells, B cells, NK cells, etc.) or mesenchymal cells (vascular endothelial cells, epidermal cells, fibroblasts, etc.) and have the functions of regulating cell growth, differentiation and maturation, regulating immune response, participating in inflammatory response, promoting wound healing and participating in tumor regression. The main ones with more clinical applications include interferon (IFN-α, IFN-β, IFN-γ), interleukins (IL-2, IL-4, IL-7, IL-12, etc.), hematopoietic stimulating factors (EPO, TPO, G-CSF, GM-CSF, IL-11, IL-3, etc.), tumor necrosis factor (TNF-α), repair factors (GM1, EGF, BFGF, etc.). BFGF, etc.). It is used for the treatment of leukemia, lymphoma, solid tumor, viral infection, hematopoietic inhibition, radiation injury, etc. (ii) Tumor vaccines and dendritic cells Influenced by the use of vaccines in the treatment of infectious diseases, tumor vaccines began to be used clinically at the beginning of this century. There is a difference: the former is generally used for prophylactic purposes, while the latter is often used for therapeutic purposes. Both vaccines use attenuated whole cells, cell walls, specific antigens or non-pathogenic live microorganisms to stimulate the patient’s immune system. The goals of active immunotherapy with tumor vaccines are: to overcome the state of immunosuppression caused by tumor products; to stimulate specific immunity to attack tumor cells; and to enhance the immunogenicity of tumor-associated antigens (TAAs). Although a lot of efforts have been made in tumor-specific active immunotherapy over the past 20 years, there is no tumor with a standard protocol for vaccine therapy. Reports from many clinical phase I and II studies have seen that this therapy does achieve efficacy in a subset of patients and is largely free of toxic effects. It is noteworthy that some of the cases lasted for quite a long time up to several years. Hopefully, in the near future, we will see some standard treatment protocols for tumor vaccines become available. Dendritic cells (DCs) are the most effective antigen-presenting cells in the body, and in recent years, DCs have become one of the hot spots in the field of tumor biotherapy. The recent encouraging results of clinical phase I, II and III trials of DC vaccines have also demonstrated the great promise of DC vaccines in the treatment of malignant tumors. DC vaccines are prepared by direct stimulation of DCs with tumor antigen peptides or proteins, stimulation of DCs using tumor tissue protein extracts, and transfection of DCs with antigen and cytokine genes. Among them, antigen gene transfection DC or cytokine gene transfection DC can make the antigen molecules and cytokines stably expressed in DC for a long time, and thus have better stimulation effect. (iii) Molecularly targeted tumor therapy Another major progress in tumor biotherapy is the development of molecularly targeted therapy. Due to the lack of specificity of traditional chemotherapy and radiotherapy, the efficacy of these therapies is often accompanied by greater toxic side effects to patients. Therefore, it is important to select molecular targets specific to tumor cells and apply drugs targeting those targets for treatment, so as to avoid harming normal cells and achieve an efficient treatment mode with low side effects. The commonly used therapeutic targets of molecularly targeted tumor therapy are: cell receptors, signaling and anti-angiogenesis. There are two main classes of molecularly targeted therapeutic agents, monoclonal antibodies and small molecule compounds. Overexpression or over-activation of tyrosine kinase receptors is seen in many tumors, and this over-activation often leads to activation of downstream signaling pathways, ultimately leading to cell transformation, proliferation and resistance to apoptosis, which are closely associated with tumor development. Therefore, blocking the tyrosine kinase receptor signaling pathway will stop the excessive cell proliferation. Herceptin: Herceptin (Herceptin) is a human/mouse chimeric monoclonal antibody against HER-2/neu proto-oncogene product, which can specifically act on HER-2 receptor over-expressed breast cancer cells. Herceptin monotherapy is effective in the treatment of advanced HER-2/neu++ or ++++ breast cancer with 24% efficacy. Compared with chemotherapy alone, the combination of Herceptin with adriamycin, cyclophosphamide or paclitaxel significantly improved the efficacy of metastatic breast cancer. 2. IMC-C225 (Cetuximab, Erbitux): IMC-C225 is the most clinically advanced human/mouse chimeric monoclonal antibody against EGFR, which was approved by FDA in early February 2004 for use in combination with irinotecan in the treatment of EGFR-positive, metastatic colorectal cancer that has failed irinotecan-containing regimens and is used alone in patients who cannot tolerate irinotecan. EGFR-positive advanced colorectal cancer treatment with irinotecan, and some other solid tumors (lung cancer, head and neck cancer, gastric cancer, etc.) have also shown good results in clinical trials. Bevacizumab (Avastin): Bevacizumab is a novel humanized monoclonal antibody against vascular endothelial growth factor receptor, which was approved by FDA on 2004-2-26 as a first-line treatment for metastatic colorectal cancer in combination with irinotecan + 5-FU + CF (IFL). Clinical trials for the treatment of non-small cell lung cancer, breast cancer and kidney cancer have shown effectiveness. 4. Glivec, also known as Gleevec (STI571): A new anti-leukemia drug approved by FDA in May 2001 and approved by FDA in February 2003 for gastrointestinal malignant stromal cell tumors. It has also been used in the treatment of solid tumors such as glioma and small cell lung cancer, and has achieved satisfactory results. 5. Iressa (Gefitinib): an orally available small molecule inhibitor of EGFR tyrosine kinase, approved by FDA on 2003-5-5 for use as a single agent in advanced non-small cell lung cancer that has failed chemotherapy with platinum-containing or Tysodi regimens. 6. Tarceva (Erlotinib): another epidermal growth factor receptor-tyrosine kinase (EGFR-TK) antagonist, a small-molecule compound, was approved by the FDA in September 2002 as a second- or third-line treatment option for advanced NSCLC that has failed to respond to standard regimens. (iv) Radioimmune-targeted therapy With the successful application of human-derived monoclonal antibodies against tumors, radioimmune-targeted therapy using radionuclide-labeled monoclonal antibodies has also made great progress. Radioimmunotherapy uses monoclonal antibodies as carriers and radionuclides as warheads to target radionuclides generating β or α rays to tumor cells through antibody-specific binding to antigen expression-positive tumor cells and specific binding to tumor cells to achieve in-close irradiation treatment of tumors. The advantages of combining radiotherapy and immunotherapy to treat malignant lymphoma are good radiosensitivity of malignant lymphoma; the therapeutic effect is not affected by the body’s immune function; β-radiation penetrates well and can reach the deep part of the tumor; reliable efficacy and less toxic side effects. The most clinically used and successful vectors are anti-CD20 antibodies. They include human/mouse chimeric antibody Rituximab (Merova) and simple mouse-derived antibody – anti-B1 antibody (Bexxar). Radionuclides are selected based on the maximum energy, half-life, in vivo distribution, metabolism and toxicity of beta-rays (also gamma-rays are used). Currently approved drugs for radiolucent therapy: Zevalin ( 90Y-labeled murine-derived anti-CD20 antibody), approved by the FDA on February 19, 2002 for marketing in the United States [18]. Bexxar (131I-labeled tositumomab), approved by the FDA on June 30, 2003 for marketing in the United States. (v) Tumor gene therapy (gene therapy) Gene therapy of tumor is the use of cell engineering technology to transfer nucleotides into target cells to disrupt or correct certain pathophysiological processes or other substances and means can achieve the purpose of tumor prevention and treatment by correcting the abnormalities of genes or gene products in target cells, which is the hot spot and new hope of tumor treatment research at present. Gene therapy is a high technology intensive field of biomedicine, which integrates the latest research results of molecular biology, molecular genetics, molecular virology, cell biology and other disciplines to achieve. The first element is the target gene or therapeutic gene. One of the tasks of the completed Human Genome Project is to establish a large gene pool for gene therapy, which will provide a continuous supply of useful genes for the treatment of various diseases. The second element is the vector that carries the gene into the cell for expression, both viral and non-viral vectors. The third element is the target cell. The therapeutic gene must act through the target cell. Gene therapy strategies The current gene therapy strategies are broadly divided into the following six types: 1. gene replacement: replacing the disease-causing gene with a normal gene in situ, so that the DNA in the cell is completely restored to normal. This is the most ideal gene therapy method, but the current technology is still difficult to achieve. 2. gene correction: correcting the abnormal part of the disease-causing gene and preserving the normal part, so that the disease-causing gene can be completely restored, which is demanding in operation and difficult in practice. 3. gene augmentation: also known as gene supplementation, the target gene is introduced into diseased cells or other cells, and its expression product can strengthen or correct the function of defective cells. In this method of treatment, the defective gene is still present. Most of the current gene therapies use this approach. 4. gene inactivation: the use of antisense technology to specifically close the properties of gene expression and inhibit the expression of harmful genes to achieve the purpose of treating diseases. For example, antisense RNA, nucleases or nucleic acids are used to suppress the expression of some oncogenes, inhibit the proliferation of tumor cells and induce the differentiation of tumor cells. This technique can also close the expression of drug-resistant genes in tumor cells to increase the effect of chemotherapy. 5.Immune adjustment：Importing antibodies, antigens or cytokine genes into the patient’s body to change the immune status and achieve the purpose of preventing and treating diseases. For example, interleukin-2 (IL-2) is introduced into the body of tumor patients to increase the level of IL-2 and activate the anti-tumor activity of the immune system in the body to achieve the purpose of tumor prevention and treatment. 6. Others: To increase the sensitivity of tumor cells to radiotherapy or chemotherapy, by giving precursor drugs to reduce the damage of chemotherapy drugs to normal cells. (vi) Application of biological response modifiers Biological response modifiers (BRM) are a class of biological agents with a wide range of biological and antitumor activities, including both a large class of naturally occurring biological substances and methods and means that can alter the equilibrium state of host and tumor in vivo. Although the mechanisms of action are diverse, they are not limited to two major aspects. Direct antitumor effects by interfering with cell growth, transformation or metastasis or tumor killing or inhibition by activating effector cells of the immune system and the factors secreted by them. They mainly include cytokines, chemokines, bacterial type biological response modulators, microecological type biological response modulators, fungal polysaccharide type biological response modulators, tumor proliferation viruses, etc., which are widely used in clinical treatment. Natural or recombinant cytokines: including interleukin, interferon (IFN), tumor necrosis factor (TNF), colony-stimulating factor (CSF), etc. Certain bacteria and their active ingredients: e.g. BCG (BCG), Corynebacterium shortum (CP), Streptococcus (OK432), Pseudomonas japonicus, etc. Phytopharmaceuticals include active ingredients of traditional Chinese medicine: such as shiitake mushroom polysaccharide, yunzhi polysaccharide, astragalus polysaccharide, spikenard polysaccharide, wolfberry polysaccharide, ginseng flower total saponin, cordyceps, etc. Organic acids and small molecule synthesis agents: such as Levamisole. Problems and Prospects of Biological Therapy Tumor biotherapy as the fourth treatment mode has achieved certain efficacy, but faces more challenges. How to approach biologic therapy with a new way of thinking will help to understand the role and status of biologic therapy correctly and objectively. There are still some problems in biologic therapy itself: the main problems currently faced are the lack of suitable targets, lack of sufficient economy, irregular treatment protocols, and insufficient concepts and awareness. However, biologic therapy has become the main direction and trend of tumor treatment in the 21st century, and it should be combined with other therapies to make biologic therapy play a more important role in comprehensive tumor treatment.