Cellular therapies based on effector T cells over the past decade, particularly CAR-T therapy, have revolutionized the treatment of many types of cancer. In 2017, the FDA approved two CAR-T therapies for the treatment of certain types of cancer associated with B cells, and research in the field of solid tumors is also extremely hot.
But the next breakthrough in immune cell therapy is more likely to occur in non-cancer treatments, especially the use of Treg cells to treat autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, and after organ transplantation. Grafts are resistant to diseases such as host diseases.
Although Treg cells account for only 1-2% of peripheral blood lymphocytes, they are very effective in controlling autoimmune responses and tissue inflammation, helping to maintain long-term immune homeostasis. IPEX patients who are severely deficient in Treg cells develop severe organ inflammation and autoimmune responses. More importantly, there is already ample evidence that a decrease in the number of Treg cells or a decrease in function is associated with a variety of common autoimmune pathological processes.
In fact, in some of these types of diseases, there will be a decrease in the number of Treg cells or a functional defect, and at the same time, the levels of IL-2, IL-6, IL-12, IL-1 and other inflammatory factors will be too high, resulting in Treg cells not being Stable, inflammation can not be controlled to cause tissue damage. Therefore, there are also some drugs that have been marketed by using IL-2 or rapamycin to enhance the function of Treg cells, thereby treating diseases such as autoimmune diseases.
However, the direct application of Treg cells to treat autoimmune diseases through adoptive cell therapy (ACT) is also a very potential research direction. There is a growing body of preclinical data showing that Treg cells can reduce inflammation levels and promote tissue homeostasis by promoting various mechanisms such as the production of EGFR ligands in injured tissues.
The first proof-of-concept clinical study used polyclonal Treg cells to treat autoimmune diseases. A recent clinical study also showed that Treg ACT can reduce disease progression in patients with ALS.
Although polyclonal Treg cells have demonstrated safety and a degree of efficacy in many early clinical studies as well as preclinical studies, such as treatment for lupus erythematosus and inflammatory bowel disease, multiple sclerosis and therapeutic effects of type 1 diabetes Very poor. This is most likely due to the fact that in these diseases, the number and quantity of Treg cells that bind to pathogenic antigens in polyclonal Treg cells are rarely caused. Therefore, antigen-specific Treg cell-based therapies are likely to be safer and more effective.
The development of Teg therapy based on autoantigens is more challenging than graft antigens. Because transplant antigen-active Treg cells are orders of magnitude lower than Treg cells that bind to autoantigens. The isolated Treg cells, if repeatedly activated in vitro, affect their stability and cause their transition to effector T cells.
This problem is actually a better solution now, because the antigen specificity of therapeutic Treg cells can be achieved by introducing a CAR that targets specific antigens to Treg cells.
However, because it is still in the early stage of research, there are still some questions that have not yet been answered. For example, because the T cells in the tissue may have been repeatedly contacted with Treg cells and produced tolerance, whether Treg cell therapy alone can be effective It is still uncertain about triggering immune tolerance.
In addition, the cost of ACT therapy and related technical issues may also limit the progress of research in this area of therapy. However, advances in general-purpose CAR-T and CAR-T therapy in the field of cancer therapy can also advance research in the field of Treg cell therapy.