机体免疫效应对抗在肺癌生物治疗中的应用研究(理工科一般+英文稿件)

Research on the Application of Organism Immune Response Against in the Biological Treatment of Lung Cancer Abstract: Lung cancer is one of the most malignant tumors which is harmful to human health and life. According to statistics, there are about 1.3 million new cases of lung cancer increased every year. In most cases, the patients have been treated as an incurable disease or an incurable disease in the early stage. At present, the development of biological treatment of lung cancer is very rapid, especially the immunization therapy of lung cancer, which has made significant progress and significant effect. As a new treatment mode, biological therapy plays an increasingly important role in the treatment of lung cancer. Therefore, the application of organism immune response against in the biological treatment of lung cancer is researched in this paper. Based on the summary of the biological treatment of lung cancer in recent years, the domestic and foreign researches on the status and achievements of the biological immunization therapy of lung cancer are compared, and the current most popular immunization therapies are carried on detailed exposition, including tumor vaccine, adoptive immunity therapy, cytokine therapy and so on. In addition, the effectiveness of biological immunization therapy is proved by the actual cases of lung cancer treatment. The breakthrough of biological immunization therapy has opened up a broader prospect for the treatment of lung cancer. Keywords: Lung cancer; biological therapy; immunization therapy; adoptive immunization therapy 1. INTRODUCTION Mortality rate of lung cancer is the first in all kinds of cancer in the world. In our country, the number of lung cancer patients has exceeded 1 million, China has becoming first lung cancer country in the world. According to the histopathology characteristics and clinical characteristics, lung cancer is divided into non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) two categories. NSCLC accounts for about 80% of the total number of lung cancer, SCLC accounts for 20%. The traditional treatments of lung cancer mainly include the surgery, chemotherapy, radiotherapy and traditional Chinese medicine treatment and other comprehensive treatment modes. In recent years, with the rapid development of the molecular biology of the tumor, tumor immunology and cell biology, the molecular target of tumor therapy, immunization therapy and gene therapy, and bio chemotherapy have got new breakthroughs, and have opened up broader prospect for the treatment of lung cancer. Foreign related researches started earlier, after decades of development, has formed a relatively mature biological treatment technologies and theories. Aberrant expression and potency as a cancer immunization therapy target of inhibitor of apotheosis protein family, Livin/ML-IAP in lung cancer was put forward (Hariu H et al. 2005) [1]. Active immunization therapy with 1E10 anti-Linotype vaccine in patients with small cell lung cancer: report of a phase I trial was proposed (Neninger E et al. 2007) [2]. Adoptive immunization therapy of lung cancer with immobilized anti-TCR antibody-expanded human T Cells in peripheral blood was researched (Kang N et al. 2009) [3]. Anti-tumor immune responses induced by NKT cell-based immunization therapy for lung cancer and head and neck cancer was put forward (Motohashi S et al. 2011) [4]. The blockade of immune checkpoints in cancer immunization therapy was researched (Pardoll D M et al. 2012) [5]. Nivolumab versus dovetail in advanced squamous-cell non–small-cell lung cancer was studied ( Brahmer J et al. 2015) [6]. Although domestic related researches started late, but in recent years, some progress has been made. DCIK cells used for clinical immunization therapy of lung cancer was proposed (Zhu Ning et al. 2008) [7]. Study on the biological characteristics of recombination human interconnection induced CIK cells and toxicity activity against human lung cancer cell line was put forward (Wang Shiyong et al. 2010) [8]. Tumor precise cellular immunization therapy was researched (Wu Mengchao et al. 2015) [9]. However, as a new type of treatment, tumor biological treatment has a lot of problems to be solved in front of us. Due to the high cost of biological treatment drugs and methods, the clinical research and application are limited. The effectiveness and safety of all kinds of biological treatment drugs need to be further evaluated. At present, there is no specific drug for lung cancer targeted gene therapy. There are some limitations of gene therapy, such as the low contagion efficiency, unstable expression, poor targeting and long-term safety, which restricts the development of gene therapy for lung cancer. Based on this, this paper studies the application of immune response in the biological treatment of lung cancer. The breakthrough of biological immunization therapy has opened up a broader prospect for the treatment of lung cancer. The remainder of this paper is organized as follows. Section 2 describes the general situation of biological treatment of lung cancer. Section 3 gives the study on the application of biologic immune therapy in lung cancer. Section 4 presents a real experiment to evaluate the biological treatment of lung cancer. Conclusion is summarized in Section 5. 2. GENERAL SITUATION OF LUNG CANCER BIOLOGICAL TREATMENT In cancer therapy, biological therapy has its unique advantages, which is different from surgery, chemotherapy and radiotherapy (Anagnostou V K et al. 2015) [11]. As early as in 1975, the biological response modifier (BRM) concept was proposed by the National Cancer Institute of the United States, based on this, the biological treatment of cancer came into being. Through 30 years of development, which has formed a more mature biological treatment technologies or theories. The principle of biological treatment is that the immune cells that have the ability to kill or inhibit the tumor are added or increased the cancer patients to adjust the patient's own immune mechanism, and enhance the immune ability of the body to resist tumor, so as to achieve the purpose of control and removal of tumor cells. Which mainly includes: Cytokine technology, tumor vaccine technology, immune active cells inherited infusion technology, monoclonal antibodies and their coupling technology, gene therapy technology and so on. The techniques used in these ways have a certain degree of overlap or overlap, and sometimes there are no clear boundaries between each other. These techniques mark the basic formation of tumor biological treatment system. Although there are many different ways and methods, but the purpose is to treat malignant tumor by furthest using or enhancing the human body itself with the ability of anti tumor. The toxic and side effects of biological therapy drugs are low, only in a large dose, there are fever, rash, low blood pressure, antigen antibody reaction and other symptoms, the incidence rate is relatively low. Clinical application of biological treatment of lung cancer mainly includes lung cancer molecular target to therapy, cytokine, adoptive immune cell therapy and gene therapy. Nowadays, there are a variety of biological agents, the multiple immune modulator agents, gene therapy and molecular targeted therapy drugs are used in clinic. Which makes some breakthroughs in the treatment of lung cancer, and provides a rich content for the future development and study of biological treatment (Rizvi N A et al. 2015) [12]. But the final evaluation of curative effect still need to be further studied.     Fig. 1 Tumor immunization therapy Cancer has become a heavy economic burden in developing countries and developed countries. And the incidence of cancer is increasing because of population growth and aging (Butts C A et al. 2013) [10]. Lung cancer is one of the most rapidly growing cancer incidence and mortality, which is the most recent epidemiological situation of human health and life threatening. According to the survey, the number of lung cancer patients in the world is growing rapidly, as shown in the following table. Fig.2 Lung cancer incidence in different regions and sex Age standardized rate (per 100 thousand people) 3. APPLICATION OF BIOLOGIC IMMUNE THERAPY IN LUNG CANCER Mortality rate of lung cancer is the first in all kinds of cancer in the world. In our country, the number of lung cancer patients has exceeded 1 million, China has becoming first lung cancer country in the world. According to the histopathology characteristics and clinical characteristics, lung cancer is divided into non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) two categories. Such as carcinoma, squamous cell carcinoma and large cell carcinoma and so on. NSCLC accounts for about 80% of the total number of lung cancer, SCLC accounts for 20%. In most cases, the patients have been treated as an incurable disease or an incurable disease in the early stage. Local advanced or general good non-small cell lung cancer patients can receive concurrent chemotherapy, and combine with or without surgical treatment. This can achieve an average of 8 months of disease progression free survival, but the overall survival rate is still less than 15% in 5 years. Patients who had been diagnosed with advanced lung cancer were treated with a new type of toxicity drug, such as the perpetrated (Beechem J et al. 2016) [13]. Or the targeted therapy for prostate cancer, such as the second generation of small molecule (EGFR) targeted drugs. Or the ALK inhibitors and so on. In spite of this, the overall survival time of the advanced disease is only limited to a limited increase. Over the past ten years, there has been a further understanding of the interaction between tumor and immune system, which has opened up a new door to tumor immunization therapy, and has helped us to break through the bottleneck of the traditional treatment strategy. Fig.3 Immune treatment strategy for non small cell lung cancer Immunization therapy strategies of two types of non small cell lung cancer are currently being tested in clinical. This includes the enhancing of the immune function of the body through the cancer immune vaccine, as well as the immune suppression of tumor by the use of the immune node inhibitors. Immunization therapy is also an effective way to treat lung cancer. It can stimulate the body's immune response through a variety of ways, enhance the body's anti-tumor ability, and ultimately achieve the purpose of controlling and eliminating the tumor. Since the concept of biological response regulation (BRM) was put forward in 1982, the immunization therapy of tumor has been paid more and more attention by scholars both at home and abroad. The immunization therapy of lung cancer mainly includes tumor vaccine, adoptive immunization therapy and cytokines therapy. In recent years, the research progress of tumor vaccine is fast. Immunization therapy is sometimes used alone, in most cases as an adjustment therapy. 3.1 Tumor vaccine As a kind of active immunization therapy, lung cancer vaccine is an important method for tumor immunization therapy. Lung cancer vaccine can induce specific cellular and hum oral immune response, so as to enhance the ability of the body to prevent cancer, prevent the growth, proliferation and recurrence of the tumor. At present, the lung cancer vaccine mainly includes the tumor cell tumor vaccine, anti prototype vaccine and anti independence Linotype vaccine, DNA vaccine, polytheistic vaccine, Kendrick cells (DC) vaccine an d so on. Most lung cancer vaccines are still in clinical trials. L-BLP25 is a lung cancer polytheistic vaccine produced by anti Mu Cl cumin and IL.2 gene. The results of the study show that the median survival time of the L-BLP25 combined support therapy group and the support group is 17.2 months and 13 months respectively. The CEA652 (which is isolated from CEA HLA-A24) is used in vitriol sensitized DC to treat the lung patients with the CEA, it can be found that the patient's condition is stable after the treatment, and the level of serum CEA is decreased. The tumor vaccines used in China mainly include anti tumor vaccine, tumor vaccine, and Kendrick cell tumor vaccine and so on. Anti carcinoma tumor vaccine and Kendrick cell tumor vaccine have certain anti metastasis effects on mice with high metastatic Lewis lung cancer. Kendrick cell vaccine can effectively remove the heterogeneous spread of lung cancer cells, and its anticancer mechanism is the formation of strong specific cellular immune response. 3.2 Adoptive immunization therapy Adoptive immunization therapy is to deceptively infusion the vitriol activated immune cells and cytokines into host cells to exert its anti-tumor effect. The IL.2 is used to induce LAK cells in the treatment of lung cancer for the first time in 1987. At present, adoptive immunization therapy currently used in clinical includes the activation of lymphocyte activated killer cells (LAK), tumor infiltrating lymphocytes (TIL), activated killer cells (AKM) and so on. LAK therapy Lymphocyte activated killer cells (LAK) is one of the most widely used methods in clinical application. The adoptive immunization therapy of LAK cells and the recombination of IL.2 has significant anti-tumor effects, but it is difficult to get enough LAK cells in clinical practice. Lymphocyte activated killer cells therapy requires the use of large doses of recombination IL.2, which leads to a large cost and side effects, the promotion of which is more difficult. The LAK/ IL-2/IN in the treatment of advanced lung cancer show that these therapies have different effects. TIL therapy Tumor infiltrating lymphocytes (TIL) immune therapy has certain specificity immunization therapy. The killing effect of tumor is higher than that of LAK 50 ~100 times. The main sources of which are fresh tumor tissue, drainage lymph nodes and cancerous body cavity effusion. The anti tumor effect of TIL is not only stronger than LAK, but also the treatment of small dose of IL-2 is small, other factors such as TNF, IFN and other factors can enhance the anti-tumor effect of TIL with the cooperation of IL-2 activation TIL, chemotherapy and radiotherapy. AKM therapy Activated killer cells (AKM) and tumor associated macro phages (TAM) have a strong anti tumor effect. The survival time of CD3AK cells in vitriol is long, the amplification rate is fast, the anti-tumor activity is high, the poisonous side reaction is small, thus which receives the widespread attention (Garon E B et al. 2015) [14]. IL-2 and CD3AK cells have a synergistic effect, small dose of IL-2 can maintain the proliferation of Kodak cells. 3.3 Cytokine therapy Cytokines makes the activity of immune affections cells increased, enhances the body's immune ability, and has different degrees of inhibition and killing effect on tumor cells, and changes tumor cell surface antigen structure, so as to improve the antigenicity of tumor cells and stimulate the proliferation of immune activity cells, mature, and enhance its activity. Interferon (IFN) Interferon (IFN) enhances tumor cells the main organization compatibility antigen expression through cells induced terminal differentiation and cell reversion of malignant phenotype, so as to enhance the NK cells, macro phages and CTL activity, and inhibit the expression of oncogene pathway and anti tumor effect. Tumor necrosis factor (TNF) TNF-13 secreted by lymphocytes has a strong direct killing effect on tumor cells and immune regulation. TNF has inhibitory effect on the proliferation of lung carcinoma cell line A549, Utilizes and TNF have synergistic anti tumor effect. Interleukin 2 (IL-2) IL-2 has the role in inducing the proliferation and differentiation of T lymphocytes, CTL (including TIL) and B cells, promoting the secretion of various cytokines, activating the NK, LAK and TIL, and enhancing the immune activity of monocles. The effective rate of clinical symptom relief in IL-2 reaches 80%. Colony stimulating factor (CSF) GM-CSF and G-CSF are closely related to the treatment of lung cancer, but don’t have direct anti-tumor effect. Which can prevent and treat the granule cells caused by chemotherapy drugs, and ensure that chemotherapy is carried out as scheduled and reduce the infection. Therefore, it has a certain value of immune therapy.  Thymine al (Ta1) Tal is main active component of a group of Thymine 5 (TF5). Studies show that tal can promote the maturation of T cells, enhance antigen or mitotic original sensitized T cells, and secreting interferon and other lymph factors, which has the function of improving cellular immune  and other important biological functions (Ditlev J et al. 2016) [15]. Clinical report shows that Tal has auxiliary chemotherapy and radiotherapy effect in a wide range of NSCLC with, it is good for improving the cellular immune function of the patients, it also can improve survival and disease-free survival, and reduce III ~ IV bone marrow toxicity. 4 EXPERIMENTAL ANALYSIS 4.1 Experiment Lung cancer often has a relapse after surgery, and it is fatal. Adoptive immunization therapy has the against effect in anti cancer. This study is to evaluate whether immunization therapy can reduce the recurrence rate of lung cancer after operation. This paper carries on the randomized trial of 150 patients with lung cancer undergoing radical operation. Which is divided into adoptive immunization therapy group (n=76) and control group (n=74). Tautological lymphocytes are activated in vitriol by combination interleukin -2 and CD3 antibodies in vino, and the first 6 months input 5 times. As the primary end point of this study, the recurrence free survival time is analyzed statistically. The experimental results are as follows. Fig. 4 Comparison of postoperative recurrence rate in two groups Fig. 5 Comparison of the first recurrence time in two groups Experimental results show that 76 patients received a total of 370 times lymphocyte input (the average number of cells per patient input is 7.1 × 1010[SD2.1]. Among them, CD3+ and HLA-DR+ cells accounts for 78%, 3 or 4 grade side reactions are not observed. After following-up 4.4 years, compared with the control group, the recurrence rate of adoptive immunity therapy group decreases 18%, the risk of recurrence reduces 41%. The first recurrence time of immune treatment group is later than that of the control group, the relapse free survival rate is 38% in 5 years. The relapse free survival (p=0.01) and disease specific survival (p=0.04) in the  immunization therapy group are significantly longer than those in the control group. There was no significant difference in overall survival between the two groups (p=0.09). In short, adoptive immunization therapy is a safe and feasible therapy that can reduce the recurrence rate and recurrence risk of lung cancer, and prolong the survival time without recurrence.　 4.2 Analysis of biological immunization therapy for lung cancer Normal human survival and tumor patients with low expression of biological cytokines are used to mobilize the body's own immune force to achieve anti-tumor effect, compared with radiotherapy and chemotherapy, the side effects of which are very small. The anti-tumor effect can be induced by active immunity, which is more extensive, especially for multiple lesions or malignant tumors with extensive metastases. The molecular target principle therapy is used to carried on the treatment, the objectives are clear, which has no effect on outside of the tumor cells and normal cells, in addition, which can significantly suppress tumor progression and prolong life to the inoperable advanced cancer patients. 5. CONCLUSION Over the past ten years, there has been a further understanding of the interaction between tumor and immune system, which has opened up a new door to tumor immunization therapy, and has helped us to break through the bottleneck of the traditional treatment strategy. Based on this, the domestic and foreign researches on the status and achievements of the biological immunization therapy of lung cancer are compared on the basis of the summary of the biological treatment of lung cancer in recent years in this paper, and the current most popular immunization therapies are carried on detailed exposition, including tumor vaccine, adoptive immunity therapy, cytokine therapy and so on. In addition, the effectiveness of biological immunization therapy is proved by the actual cases of lung cancer treatment. The breakthrough of biological immunization therapy has opened up a broader prospect for the treatment of lung cancer. The treatment strategy using the immune system is a feasible method. However, the understanding of the complexity of the immune system is rapidly improving in this rapidly changing era, the application of immunization treatment technology is developing, and the vaccine and immune node inhibitors of lung cancer are constantly reforming. 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