CAR without brakes
For patients with lymphoma, multiple myeloma and some types of leukemia, treatment with T-lymphocytes with chimeric antigen receptors (CAR T-therapy) is sometimes the only chance to recover. Treatment involves taking T cells from the patient's blood and adding artificial receptors (CAR) to them in the laboratory. As guardians of the immune system, T cells constantly patrol in blood vessels and tissues and track down foreign structures. Equipped with CAR, T cells can find and bind very specific surface structures on cancer cells. As soon as CAR T cells enter the patient's body, they circulate in the body in search of tumor cells and destroy them.
CAR T cells remain in the body forever and multiply. If the tumor recurs, they take effect again. At least that's the theory. But in practice, many patients still have relapses. This happens because tumor cells are able to outwit CAR–T cells by producing more inhibitory protein - associated with the fragment of the estrogen receptor antigen 9 (estrogen receptor–binding fragment-associated antigen 9, EBAG9) – and forcing T cells to produce it. EBAG9 inhibits the release of cytotoxic enzymes by lymphocytes, which weakens the desired response.
A month earlier, a group led by Dr. Armin Rehm and Dr. Uta Hepken from the Max Delbrück Center for Molecular Medicine at the Helmholtz Association showed that disabling the EBAG9 gene in mice led to a sustained increase in the immune response to the tumor. The mice also developed more memory T cells. These cells are part of the immunological memory that allows the immune system to respond to the cancer antigen upon repeated collision. In a new study, the group demonstrated this effect in vitro on human CAR T cells.
As soon as the EBAG9 gene was discovered, researchers recognized that it plays an important role in the development of malignant blood tumors. But it took time to determine what that role really was. When Rehm and Hepken's group started working on this in 2009, they found that mice without the EBAG9 gene coped much better with bacterial and viral infections than control mice, and that they formed more memory T cells, which are of particular interest to tumor biology.
Then, in 2015, Dr. Anthea Virges managed to control the synthesis of the EBAG9 protein using microRNAs. In a subsequent study, she used microRNA to culture CAR-T cells with an "EBAG9 silencer" against various human leukemia or lymphoma cells. Just as in mouse models, silencing EBAG9 significantly reduced tumor growth. Relapses also developed much less frequently.
This proved that disabling the immune brake – EBAG9 – allows genetically modified T cells to secrete more cytotoxic substances. However, they do not cause a cytokine storm, which is usually a side effect of CAR therapy. On the contrary, the risk is minimized because fewer immune cells are used. Disabling the immune brake works on all types of CAR T cells, regardless of which type of blood tumor it targets.
Chemotherapy remains the first-line therapy for blood tumors, since many patients respond very well to it. CAR T therapy comes into play only if the tumor recurs. A single infusion of this product can save a life.
The results obtained in animal models and in vitro experiments using human cells have proven that disabling the EBAG9 brake effectively and without side effects enhances standard CAR T therapy. The researchers intend to present their concept to the Paul Ehrlich Institute, the German agency for the approval of biological drugs, in November. If successful, it may be available to patients in two years.
Disabling EBAG9 will allow the body to destroy tumor cells earlier and more radically. In addition to achieving longer-term therapeutic success, it can also give a real chance of a cure.
Article A.Wirges et al. EBAG9-silencing exerts an immune checkpoint function without aggravating adverse effects published in the journal Molecular Therapy.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on EurekAlert: Strengthening the immune response to cancer.