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Introduction to Tumor Immunotherapy—Part One

Under normal circumstances, the immune system can identify and remove tumor cells in the tumor microenvironment, but in order to survive and grow, tumor cells can adopt different strategies to inhibit the body's immune system, unable to kill tumor cells normally, called immune escape. In order to better understand the multi-step complexity of tumor immunity, the concept of tumor-immune cycle is proposed. The tumor-immune cycle is divided into the following six steps: tumor antigen release; tumor antigen presentation; initiation and activation of effector T cells; T cell migration to tumor tissues; tumor tissue T cell infiltration; T cells recognition of tumor cells. Any abnormalities in these steps can lead to an anti-tumor-immune cycle failure and an immune escape. Different tumors can suppress the immune system's effective recognition and killing of tumor cells through abnormalities in different links to produce immune tolerance, and even promote the occurrence and development of tumors.
Tumors are the products of normal proliferation and migration in the body after the normal cells of the body have undergone mutation accumulation. Conventional tumor treatment is divided into two categories: surgery, which can remove solid tumors, but usually cannot eradicate tumors, and is not suitable for hematological tumors; radiotherapy and chemotherapy, although this treatment can effectively treat a variety of tumors, it can cause damage to the normal cells; at present, immunotherapy for tumors is increasingly becoming the hope of conquering cancer. At present, the main tumor immunotherapy programs include therapeutic tumor vaccines, immune checkpoint inhibitors, adoptive cellular immunotherapy, oncolytic viruses, etc.
1. Therapeutic Tumor Vaccines
For decades, cancer vaccines in development have become a form of immunotherapy that prevents cancer from developing or killing existing tumors by stimulating or restoring the body's own immune system.
The tumor vaccine is designed by applying 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 including 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; autologous dendritic cell immunotherapy vaccine. TAAS, directly introduced into DC, which plays the role of antigen presentation, activates T lymphocytes and initiates the initial immune response. Bacterial vaccine is the earliest bacterial injection therapy.
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. 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 tumor treatment. 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 with small tumors and low-grade malignancies. The current combined application of Sipuleucel-T and other immunologic or chemotherapeutic drugs continues.
2. Adoptive Cellular Immunotherapy
The immune response produces a complex interaction between the adaptive immune system and the natural immune system. B cells and T cells of the adaptive immune system use their receptors to recognize antigens, and T cells recognize antigen presenting cells (APC) to present antigenic peptides, a major histocompatibility complex (MHC). B cells directly recognize antigenic epitopes with highly specific adaptive immunity and immune memory. Natural immunity is non-specific immunity expressed by phagocytic cells, natural killer cells (NK), etc. The recognition of receptor-derived receptors (PRRs) identifies pathogen-associated molecular patterns shared by microorganisms and their products, such as lipopolysaccharide, peptidoglycan, and mannose, regulating the initiation, strength, and type of response of specific immune responses.
Dendritic cells (DCs) are a class of non-mononuclear phagocytic cells, which are important bonds between natural and adaptive immunity and are the most powerful APCs known in the human body. The production of anti-tumor immunity depends on the DC to capture the tumor antigen, process it intracellularly, and then present the antigen information to the immature T cells in the lymphoid tissue, thereby activating the specific immune response of the body. Activated T cells release cytokines and further stimulate T cell division, proliferation and maturation. A part of mature T cells differentiate into memory T cells to retain antigenic memory and rapidly respond to re-invasion of antigens, and most of them differentiate into effector cells with immune effects, such as regulatory T cells that produce cytokine-regulated immune responses, killer T cells that target and kill foreign cells, and effector T cells that stimulate B lymphocyte proliferation and antibody production. Dendritic cell-based vaccines can present tumor antigens to achieve a durable immune response.
To be continued in Part One…
publié le mercredi 14 août à 14:41

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