Immunotherapy for tumors (Section Two)

Posted by beauty33 on August 11th, 2019

Although the tumor-bearing organism can recognize, process and present tumor antigens and produce a limited immune response, it does not produce effective killer tumor cells. In addition to low immunogenicity, the body can not effectively respond to immune cells. Tumor cells can also grow and proliferate by evading the monitoring of the immune system in a variety of ways: Including: DC antigen presentation ability is reduced, making T cells unable to activate effectively; In the absence of costimulatory molecules, T cells bind to their neighboring cells or their own CDl52 by expression of the differentiation antigen cluster CD80, resulting in decreased or absent T cell response, resulting in immune tolerance; Immunosuppressive cytokines secreted by tumor cells spontaneously It can inhibit T cell differentiation and induce tolerance; The expression of MHC molecules in tumor cells is too low, which reduces the antigen presentation ability; Fas ligand (Fas-L) belongs to the tumor necrosis factor family, and the expression of Fas.L in tumor cells increases, while Fas expression Decreased or absent. Expressing Fas-L can induce apoptosis of lymphocytes expressing Fas, and due to the down-regulation of Fas expression in tumor cells, the role of lymphocytes in promoting tumor cell apoptosis is weak, which weakens the immune effect. In addition to the above mechanisms, tumor cells also secrete some cytokines or adhesion molecules to promote their own proliferation.

1. Specific Immunotherapy

 Specific immunotherapy includes phagocytic cells including monocytes and macrophages. In addition to phagocytosis and antigen presentation, various cytokines such as interleukin (IL-1 can be secreted after activation, IL-6, IL-8, IL-12. Tumor necrosis factor (TNF). Similarly, in addition to direct cell killing, NK cells can also secrete cytokines such as interferon (IFN), TNF-α, granulocyte-macro-phage colony stimulating factor (GM-CSF), IL-3 and macrophage colony-stimulating factor (M-CSF). These cytokines have a promoting effect on T cells, B cells, APC cells and the like. Therefore, the use of non-specific immune-stimulants or direct administration of related cytokines may achieve the purpose of regulating immune cell activation, proliferation and functional activity.

Non-specific immune-stimulants include endotoxin, lipid A, trehalose, thymosin, and some Chinese herbal ingredients. More successful non-specific immune-stimulants, such as BCG for bladder infusion for bladder cancer, and levamisole and 5-fluorouracil in combination with colon cancer shows a certain degree of effect. Advances in genetic engineering have made it possible to mass produce cytokines. To date, dozens of clinical studies have analyzed whether immune-stimulatory cytokines can safely and effectively activate tumor-specific immune responses, either alone or in combination with conventional chemotherapy. Recombinant cytokines are approved by the FDA for use as anti-tumor immune-stimulants, namely IFN-a2a, IFN-a2b and IL-2. In addition, granulocyte colony stimulating factor (GM-GSF) and GM-CSF are clinically used as immune-remodeling agents for transplant patients or post-chemotherapy cancer patients. The main problem is that the systemic application of cytokines has a large side effect, rapid failure, low concentration in the tumor, and poor efficacy. In recent years, attempts have been made to introduce cytokines into the body via a vector or to bind to a monoclonal antibody to enhance its targeting and reduce systemic side effects. More efforts should be made for the development of promising combination therapies, including combination with Toll-like receptor agonists, immunological checkpoint inhibitors, and immunogenic chemotherapy.

2. Cancer Vaccine

The design idea of cancer vaccine is to apply various techniques to enhance the immune system's ability to recognize tumors by introducing tumor antigens into patients, to improve the immune microenvironment, and to stimulate powerful specific cellular immunity. In recent years, with the rapid development and cross-infiltration of related disciplines such as tumor pharmacology, molecular biology and immunology, as well as the development of tumor-associated antigens, carriers and adjuvants, various forms of tumor vaccines have been developed and clinical trials have been carried out. It mainly includes the following categories: Tumor cell vaccine, which is divided into whole tumor cell vaccine and genetically modified tumor cell vaccine; Tumor antigen vaccine, which is divided into tumor associated antigen (TAA) and tumor-associated antigen ( Tumor specific antigen (TSA) vaccine, and tumor antigens include multiple layers, such as intact protein molecules, antigen peptides and purified DNA; DNA cancer vaccine, actually a kind of antigen vaccine, which is divided into naked DNA, plasmid DNA and viral vector DNA vaccine. TAAS is directly introduced into DC, which plays the role of antigen presentation, activates T lymphocytes and initiates the initial immune response; Bacterial vaccine, the earliest bacterial injection therapy is a bacterial vaccine.

In theory, tumor vaccine is one of the most effective and economical cancer treatment methods. A limited number of vaccine injections can bring long-term anti-tumor immunity effects. In fact, tumor vaccines have not been effectively confirmed in clinical studies. Has long been questioned. Until 2010, the US FDA approved the use of the Sipuleucel-T vaccine (or Provenge, manufactured by Dendreon, USA) for the treatment of asymptomatic or mild metastatic hormone-resistant prostate cancer, the first FDA-approved therapeutic tumor. The vaccine marks the official transition of the cancer vaccine from basic research to clinical application. Sipuleucel-T is an autologous cell therapy that mobilizes the patient's own immune system to fight disease. Its active component contains autologous peripheral blood mononuclear cells as well as recombinant fusion proteins of prostatic acid phosphatase and GM-CSF. The final products also include T cells, B cells, NK cells and other cells. However, existing studies have shown that the vaccine is only effective in a small number of patients, and is mainly in patients with small tumors and low-grade malignancies. The current combined application of Sipuleucel-T and other immunologic or chemotherapeutic drugs continues.

To be continued in Section Three…