The path of the non-canonical NF-kB helped CAR-T cells to survive

Comparing CART-cells with different structures of the receptors CD28 or 4-1BB molecules — researchers have found that the latter are more likely to engraft in a patient. Their activation is a bit different, and as a result, they accumulate less pre-apoptotic compositions produced protein Bim, which regulates the survival and proliferation of cells. The paper was published in the journal Science Signalling.

Therapy CAR-T cells is very promising and shows good results for a number of diseases, but has problems whose solution will help to expand the applicability of this technology and improve its efficiency. One of the parameters that require optimization, it is the survival of CAR-T cells: the higher it is, the more effective their fight against cancer. For example, blood cancer shows that the number of regressions after treatment is directly related to how well the transplanted cells could multiply.

Benjamin Philipson (Benjamin I. Philipson) from the University of Pennsylvania and his colleagues have figured out why different engineered CART-cells persist in the patient’s body different times. Chimeric receptors composed of the outside of the T-cell piece of the antibody, connected to the intracellular domain. Latest assembled from parts of an ordinary T-cell receptor and complemented by amplifying molecules CD28 or 4-1BB.

Over the last couple of years, there is evidence that the survival of CART-cells depends, in part, from the fact of what kind of amplifier will be used. A new study has confirmed it: when modeling the treatment of leukemia ex vivo the cells with 4-1BB to live longer and better bred.

According to the authors, the reason for this lies in the fact that by using CD28 and 4-1BB includes alternative signaling pathways of NF-kB. Transcription factor NF-kB plays a key role in signal transmission from the T-cell receptor and activation of immune cells. There are two versions of this pathway, canonical and noncanonical, and they found that in the case of 4-1BB runs just a second, related — judging by the works on mice — with the best survival of CART-cells.

For myeloma and normal T-cells it is shown that the noncanonical path NF-kB (ncNF-kB) helps cells to survive by inhibiting the synthesis of pre-apoptotic compositions produced protein Bim. A comparison of the amount of this protein in normal 4-1BB CART-cells and cells with broken ncNF-kB showed that this is true for them. The failure ncNF-kB in CD28 cells had no effect on protein Bim. Thus, they showed that the best survival of 4-1BB CART-cells is associated with activation ncNF-kB and decrease in protein level of Bim.

In addition, therapy based on the use of CAR-T cells requires the optimization of other parameters. So, we recently talked about the technology of “sleeping beauty”, which will allow in the future to make the process of transformation of T-cells neater and more efficient.

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