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How to kill cancer cells and not cause a "cytokine storm"
The authors of a revolutionary method of cancer immunotherapy using T-cells received the Nobel Prize in 2018. The outstanding results were the result of understanding that our immune system plays a major role in the constant, albeit invisible, struggle of the body with malignant cells. It turned out that this natural property of immunity can be artificially enhanced and used when the tumor is stronger than natural defense mechanisms. Although not all the problems on this path have already been solved.
The immune system of a healthy person is able to detect and destroy mutated cells that can turn into cancer – this is part of its direct "duties". And the first attempts to activate the immune system to fight this disease were made at the beginning of the last century. For this purpose, "killed" pathogenic bacteria were used (as in vaccination), and in some cases the tumors completely disappeared.
One of the modern methods of activating immunity in cancer immunotherapy is the introduction of genetically modified T–lymphocytes (CAR T-cells) into the patient's body, capable of recognizing cells of a specific tumor in a specific patient. Such therapeutic lymphocytes are obtained from T cells taken from the patient himself. After the introduction of already modified T-cells into the patient's body, they begin to actively attack the tumor. Initially, this method was directed against malignant diseases of the hematopoietic system, but now they are trying to use it for the treatment of ordinary "solid" tumors.
This seemingly simple but effective method, unfortunately, can have serious side effects. The fact is that additional immune cells produce an excessive amount of biologically active molecules – cytokines, which cause a strong inflammatory reaction with a variety of symptoms, from high fever to organ failure. In many patients, such a "cytokine storm" can lead to a severe, life-threatening condition, and also reduce the anti-cancer effectiveness of therapy.
Recently, a group of Chinese scientists studied "in vitro" the process of destroying cancer cells with CAR T cells. Article by Liu et al. Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome is published in the journal Science Immunology.
It turned out that in this case, modified lymphocytes begin to release into the environment three to four times more proteins of perforin and granzyme B, responsible for the formation of pores in the cell membrane. The formation of "holes" in the membranes of tumor cells contributes to their death by pyroptosis – one of the types of programmed necrotic cell death, in which, after the destruction of the membrane, the entire contents of the cell "falls out". At the same time, molecules are released that activate immune cells macrophages, which produce substances that cause inflammation. This mechanism was confirmed in experiments on mice in which the cytokine release syndrome was modeled as a result of CAR T-cell therapy.
To remove the negative effects of immunotherapy, you can try to modify T-cells so that they cause a more environment–friendly type of programmed cell death - apoptosis, in which there is no release of immunogenic and toxic molecules. There are other options, but all this is a matter of the future. In the meantime, patients receiving CAR T-cell therapy can only hope for the best.
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