Safe CAR-T therapy
Scientists have found a remedy against the side effects of GM lymphocyte therapy
Daria Spasskaya, N+1
Researchers from two independent groups have discovered the cause of the development of an acute inflammatory reaction (the so-called "cytokine storm") when genetically modified lymphocytes with chimeric antigen receptors (CAR-T) are injected into the body. The discovery was made on specially designed mouse models. It turned out that the cause of the "storm" is the release by the body's own immune cells of the pro-inflammatory molecule interleukin-1 in response to the introduction of modified T-lymphocytes. The authors of the first article in Nature Medicine proposed blocking the interleukin-1 receptor during CAR-T therapy with the drug, and the authors of the second article in the same journal forced the GM lymphocytes themselves to synthesize the receptor inhibitor. Both approaches led to a decrease in the inflammatory response in the model mice.
A surface model of the interleukin-1 receptor complex with interleukin-1-beta (Vigers GP et al., Nature 1997).
Therapy with genetically modified lymphocytes with chimeric antigen receptors (CAR-T) is a promising direction in cancer immunotherapy. Two drugs of this kind approved to date – Kumriah for acute lymphoblastic leukemia, and Yescarta for some varieties of large-cell B–lymphoma - cure half of the patients considered hopeless with drug-resistant blood cancer.
Therapy consists in taking lymphocytes from patients and their genetic modification, followed by the introduction of cells back into the blood. However, simultaneous administration of a large number of lymphocytes in most cases is accompanied by serious side effects, such as neurotoxicity and "cytokine storm" (cytokine syndrome) – acute inflammatory reaction accompanied by high fever, respiratory and cardiovascular insufficiency. Despite the accompanying anti-inflammatory therapy, a "cytokine storm" can cause the patient's death. We told, for example, that because of such a death during clinical trials of "cheap" GM lymphocytes, the trials had to be curtailed.
The exact cause of the inflammatory reaction was unknown to scientists, however, it was assumed that one of the inflammatory mediators interleukin-6 (IL-6) was involved in this process. In two new articles published in Nature Medicine, the authors independently showed that the main culprit of the development of the "cytokine storm" is actually interleukin-1 (IL-1), produced by cells of innate immunity, and that the blockade of its receptor significantly weakens both the inflammatory response and neurotoxicity.
Researchers from the Sloan-Kettering Institute and Memorial Cancer Center in In New York, they achieved the development of cytokine syndrome in experimental mice by increasing the number of tumor cells against which therapeutic GM lymphocytes with a receptor against CD19 protein were directed (this effect is often observed in the clinic). Using this model, scientists found that the development of the syndrome does not depend on the GM lymphocytes themselves, but is a consequence of the release of inflammatory mediators by innate immune cells (macrophages). In particular, the cause of inflammation is IL-1, IL-6 and nitrous oxide (NO).
To suppress the inflammatory reaction, the scientists additionally modified the GM lymphocytes and forced them to produce an interleukin-1 receptor antagonist protein that blocks the action of interleukin. The introduction of such lymphocytes did not really cause an acute inflammatory reaction, despite the fact that their antitumor activity remained at the same level.
Scientists from the University of San Rafael in Milan (Italy) used a "humanized" mouse model, which managed to reproduce all the side effects of CAR-T against leukemia, including "cytokine storm" and meningitis. To do this, newborn transgenic mice of the SGM3 line expressing human blood cell differentiation factors were injected with human blood stem cells. The researchers also showed on this model that the main source of pro-inflammatory interleukin molecules are cells of innate immunity. The authors compared the effect of two drugs that block the action of interleukin-6 (tocilizumab) or interleukin-1 (anakinra). It turned out that suppressing the effect of IL-6 weakens only the cytokine syndrome, while suppressing the effect of IL-1 by blocking its receptor cancels both the cytokine syndrome and neurotoxicity, which manifested in mice in the form of meningitis.
Considering that in addition to the already approved drugs, many clinical trials of CAR-T are currently being conducted, finding out the causes of the side effects of this therapy will certainly save the lives of more than one patient. If the "improved" GM lymphocytes proposed by American scientists probably still have several tests, then the combination of therapy with an already approved anti-inflammatory drug (anakinra) may reach the clinic in the near future.
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