The philosopher Francis Bacon (1561-1626) said that Nature, in order to be governed, needs to be obeyed. Sharp appreciation, rigorously true, although it is no less true that Nature, to be governed, needs to be understood. Only the understanding of natural mechanisms makes it possible to develop intervention systems that, by obeying the laws of Nature, nonetheless make it obey us by obeying itself.
The previous philosophical introduction comes to mind because thanks to the discovery and understanding of the mechanisms of action of cytotoxic T cells (activated CD8 T lymphocytes) and Natural Killer (NK) cells, it has been possible to develop very promising antitumor procedures that, obediently They kill cancer cells. I mean systems called T-CAR the NK-CAR.
The letters CAR correspond to the acronym in English for the words Chimeric Antigen Receptors, or chimeric antigen receptors. These receptors are completely artificial genes and proteins, the result of the union of two or more proteins – hence the name chimeric, derived from the chimeras of Greek mythology, made up of the body of two different animals – designed with the intention of that CD8 T lymphocytes or NK cells, depending on their nature, attack and kill tumor cells.
To understand how it has been possible to achieve this, it is necessary to briefly summarize the series of discoveries that have allowed it. Perhaps the most important discovery was to verify that CD8 T lymphocytes are the cells capable of killing other cells in the body that have stopped cooperating with others because they have become tumors, or because they have been infected by a bacterium or a virus. .
Activated CD8 T cells can kill other cells because—another important discovery—they have antigen receptors on their surface capable of detecting self molecules (class I major histocompatibility complex molecules, MHC-I) that have captured antigens from a foreign agent –for example, a virus–, or from a protein that has mutated –as happens in a tumor. Once the target cell is detected with the receptor, the T lymphocyte receives through it a molecular signal that allows it to adhere to the cell and release cytotoxic molecules into the adhesion space that will penetrate the target cell and trigger the process of apoptosis, or programmed cell death. Once the cell is dead, the T lymphocyte detaches itself from its “corpse” and travels in search of another rogue cell to kill.
NK cells—discovered more than fifty years ago—use a very similar mechanism to kill cells they detect as dangerous. However, the way they detect them is very different from that used by CD8 T lymphocytes. NK cells become activated when they do not detect enough molecules of MHC-I self on the surface of a cell, or detect other self molecules that cells express as a consequence of stress. Thus, NK cells act against an imbalance in the expression of self molecules that is indicative of a problem. few molecules of MHC-I or too many stress indicator molecules tip the balance from a “don’t kill me” message to a “kill me” message delivered by a cell that has become dangerous to the organism.
designed to kill
These and other discoveries and the understanding of the mechanisms of action of CD8 and NK T cells have made it possible to genetically modify them so that we can direct their action against tumor cells, particularly against the cells that cause various types of leukaemia. The idea is none other than to equip these cells with designer receptors capable of sending a killer activating signal not when they detect the molecules that activate them naturally, but when they detect molecules of our choice, such as a specific antigen of a particular tumor type to which NK or CD8 T cells do not naturally respond. These design receptors are called CAR.
Some therapies T-CAR have already been approved by the FDA American or European Medicines Agency. Hundreds of clinical trials with T-cells are currently underway.CAR. It is to be hoped that some of them will be successful and become new antitumor tools. T-therapyCARAlthough very promising, it is not without its problems. One of the most important is that it requires CD8 T cells taken from the patient himself, who, depending on his condition, does not always have a sufficient number of these types of cells. The generation of T-cellsCAR for each patient it is a laborious process that can take weeks, and is life-threatening for patients with aggressive tumors. In addition, the therapy can lead to serious side effects, such as graft-versus-host disease (known as GVHDfor its acronym in English) or even, sometimes, trigger a cytokine storm that can be fatal.
Advantages of NK-cellsCAR
One way to circumvent these problems is to use NK cells. The use of these cells has several advantages. First, they can kill tumor cells that do not express molecules MHC-I, what many tumor cells manage to do to escape the action of CD8 T lymphocytes. This means that NK cellsCAR can eradicate tumors in a way that is not dependent on a specific antigen, which T-cellsCAR they can’t do An additional advantage is that the longevity of circulating NK cells is significantly shorter than that of CD8 T cells, which decreases the risk of side effects, particularly graft-versus-host disease. However, this also entails efficiency problems when it comes to killing tumor cells.
Perhaps the most important advantage is that it is not necessary to use NK cells taken from the patient himself to genetically modify them to generate NK-cells.CAR. This has even made it possible to generate NK-cellsCAR universal from healthy donors or even from cell lines in culture, which can be used as a kind of generic base for the application of this therapy in any patient. These advantages have allowed the development of various NK-CAR that are being evaluated in clinical trials. The development of these trials has, in turn, enabled us to verify that NK-therapyCAR suffers from a serious problem: the process called trogocytosis.
don’t kill your sister
Trogocytosis is a process by which one cell “nibbles” another, snatching molecules from its surface that it can now express on its own. This is what NK-cellsCAR they do to the tumor cells they kill. In addition to killing them, they steal part of their molecules and place them on their surface.
The presence of tumor molecules on the surface of NK-cellsCAR converts them into target cells of their partners, that is, another NK-cellCAR it can now identify a “sister” of its own that has trogocytosed a tumor cell and confuse it with it, killing it. This leads to a rapid decline in NK-cells.CAR that kill each other, since the tumor cells cannot be completely eliminated.
Fortunately, understanding the mechanisms by which normal cells prevent NK cells from killing them also allows them to be modified to prevent them from killing each other. These mechanisms involve the expression of molecules that inhibit the activity of NK cells, of molecules that send out the “don’t kill me” message. Thus, in a recent article published in Nature Medicine, researchers from the Anderson Cancer Center at the University of Texas generate NK-cellsCAR that express inhibitory “don’t kill me” receptors. Researchers verify that these receptors prevent fratricide between NK-cellsCAR and allow them to remain active against tumor cells for longer. We will have to wait, however, for the results of clinical trials to confirm whether this new antitumor strategy is safe and successful.
References: Li, Y., Basar, R., Wang, G. et al. DID-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nat Med (2022). https://doi.org/10.1038/s41591-022-02003-x
CAR NK-Cell Therapy Is Quickly Growing in Immunotherapy: https://www.targetedonc.com/view/car-nk-cell-therapy-is-quickly-growing-in-immunotherapy
Jorge Laborda (10/17/2022)
Works by Jorge Laborda.
Your defenses against coronavirus
Your defenses against coronavirus
Deflamed immunology: An introduction to the immune system and its pathologies
Deflamed immunology: An introduction to the immune system and its pathologies
Deflamed immunology: An introduction to the immune system and its pathologies
Kilo of Science Volume XII eBook
Kilo of Science Volume XII Paper
Kilo of Science Volume I. Jorge Laborda
Kilo of Science Volume II. Jorge Laborda
Kilo of Science Volume III. Jorge Laborda
Kilo of Science Volume IV. Jorge Laborda
Kilo of Science Volume V. Jorge Laborda
Kilo of Science Volume VI. Jorge Laborda
Kilo of Science Volume VII. Jorge Laborda
Kilo of Science Volume VIII. Jorge Laborda
Kilo of Science Volume IX. Jorge Laborda
Kilo of Science Volume X. Jorge Laborda
Kilo of Science Volume XI. Jorge Laborda
Matrix of homeopathy
Chained circumstances. Ed.Lulu
Chained circumstances. Amazon
One moon, one civilization. Why the Moon tells us that we are alone in the Universe
One moon, one civilization. Why the Moon tells us that we are alone in the Universe
One Moon one civilization why the Moon tells us we are alone in the universe
The thousand and one bases of ADN and other science stories
Adenius Fidelius
The intelligence funnel and other essays
The gods have been cloned