CAR T-Cell Therapy: How Does It Work?
If immune T cells work properly, the immune system will able to kill cancer cells. The major function of immune system is to create an army of T-cells to patrol our body from signs of infection and other diseases. The T cells suspect suspicious cells and when they find abnormal one, immediately lead an attack on it, while limiting the damage to healthy cells. The way they do that is elegant. T cells have protein receptors on their surface. The receptors are claw structures latch onto antigens, which protein structures found on the surface of all cells. When a receptor latches onto an abnormal antigen like the one found only on the diseased cells, the T cell turns on and releases toxic chemicals that damage the abnormal cell and recruit other immune helpers to the area. Sometimes cancer cells cheat the immune system either by disguising themselves as healthy cells, or by sprouting so many antigens on their surface, which stymied the effective action of T cell.
One innovative way to see through the deception is CAR T-cell (Chimeric Antigen Receptor-T cell) therapy. There are mainly two different kinds of immune cells: T cells and B cells. T cells and B cells take in charge of cellular immunity and humoral immunity respectively. Among T cell, they are also two subtypes CD8 T cells and CD4 T cells. CD8 T cell known cytotoxic T cell, which directly recognizes tumor cells and secret cytokines that cause tumor cells damage or cause programing tumor cells death. CD4 T cell knows T helper cells, which helps B cells activation and differentiation into plasma cells. Plasma cells play important role in producing antibodies that eliminate tumor cells by phagocytosis or antibody-dependent cell-mediated cytotoxicity (ADCC) effect.
The idea of immunotherapy is to create antitumor monoclonal antibody conjugated drugs as well as chimeric antigen receptor to natural killer cells NK cells. Although the immune system has
the mechanism to surveillance and clear tumor cells, people are still getting cancer. The tumor cell has multiple methods to avoid immune surveillance and escape from being eliminated by the immune system. Actually immune escape mechanism is very complex to discuss such as immune suppress of tumor microenvironment, antigen presenting cells disable down modulating of surface antigen presentation CD4 positive T cell tolerance and CD8 positive T cell dysfunction all could be involve in tumor survival and tumor escape process. However, to understand how tumor cells cause T cell immune dysfunction, we must know the immune recognition mechanism of T and tumor cell. Firstly, there are two different types of antigen presented on tumor cells surface: membrane protein antigens, which could be target by B cells and antibodies, and peptide antigens that presented with major histocompatibility complex MHC-complex and can be recognize by T-cell. In general, successful T cell immune recognition is based on the presenting MHC-complex, peptides antigen along with co-stimulation molecules like CD28 and B7. However, tumor cells also have response action such as downregulating of MHC-complex molecules and downregulating of B7 molecules to inhibit T cell immune attacks.
It is well know that antibodies are broader than T cell recognition process. Antibody recognition is MHC independent and its binding affinity could be operated by antibody optimizing screening process. In this case, combining antibody recognition domain with T cell signaling motif to form a chimeric T cell receptor may form a more robust antigen receptor that has no only tumor recognition capability, but also the ability to trigger T cell cytotoxicity effect. This genetically engineered T cell what we call Chimeric Antigen T Cells (CAR T-Cells).
There are several steps to construct CAR T cells: first choosing an ideal target tumor antigen that optimize the antibody and obtain gene sequence of that antibody. Secondly, synthesize and package the CAR gene into viral victors. Third, CAR gene delivers into patient T cell through
virus transfection. Then, culture the transfected T cells and select those cells with stable CAR gene expression. Finally test the viability and quality of the newly transfected T cells or CAR T cells, and qualify their anti-tumor ability in vivo and in vitro before it can be used in clinical trials.
Therefore, CAR T cells technology is one of the most promising weapons to fight against cancer. It is significant advantages to strengthen antitumor immune response.
