Therapeutic time-out
A group of researchers from Stanford University has found a way to reactivate depleted engineering CAR-T cells, giving them time to recover.
Chimeric antigen receptor (CAR-T) T cells are lymphocytes genetically modified for therapeutic purposes, in particular, to attack cancer or virus-infected cells. Constant stimulation of viral or tumor-specific T cells can lead to a progressive loss of effector function – a phenomenon called functional depletion. This leads to a decrease in the processes of expansion and lysis of target cells and, consequently, to a weakening of the therapeutic effect.
In this paper, the researchers studied the factors that contribute to the depletion of CAR-T cells, and how they respond to temporary rest.
Previous studies have shown that depletion of CAR-T cells occurs due to continuous stimulation through antigenic receptors. By studying this process, the Stanford team found that continuous cell stimulation induces epigenetic, functional, and transcriptional changes in CAR-T cells. Moreover, periodic short-term blocking of signals produced by cells reversed these changes. This can be achieved in two ways: the first involves making changes to the metabolism of the cells themselves, and the second involves the introduction of the drug dasatinib.
Testing both approaches, the researchers found that the temporary pause caused by them leads to activation of CAR-T cells. They found that the recovery is mainly due to the methylation of histone proteins, not DNA, although they could not find an explanation for this mechanism. The researchers suggest that periodic inhibition of CAR-T cell signaling may be beneficial for patients receiving CAR-T cell immunotherapy, although more research will be needed to determine the best of the two methods.
Articles with the results of the work are published in the latest issue of the journal Sciense: Weber et al., Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling and Mamonkin & Brenner, Reversal of exhaustion in engineered T cells.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru .