13 November 2023

Researchers have made new discoveries relating to chimeric antigen receptors which could help improve therapy for blood cancer and other malignancies.

CAR-T cell therapies are created when a patient’s T cells are engineered to produce a chimeric antigen receptor (CAR) that recognises cancer cells and signals to the T cell to attack. Several CAR-T therapies have been approved for the treatment of a variety of blood cancers.

CARs are based upon naturally occurring T-cell receptors, which have intracellular signalling domains that include four ‘chains’, called zeta, gamma, delta, and epsilon.

Professor Susana Minguet from the University of Freiburg, Germany, said: “The CARs authorised by the drug authorities all use the so-called zeta chain, which triggers a particularly strong activation of the T cell as soon as the CAR binds to the surface of a cancer cell.

“Whether the other three signalling chains of the T-cell receptor – gamma, delta and epsilon – can also be used for CARs has not yet been investigated.”

In laboratory tests, Minguet and colleagues created new CARs to examine the role of each of these intracellular domains individually. They found that some that outperformed conventional CAR T cells.

Co-author Professor Wolfgang Schamel said: “Surprisingly, the zeta chain, the domain used in clinically applied CAR-T cells, showed a lower anti-tumour effect than the other three domains. These eliminated the cancer cells in the leukaemia model significantly better.”

Analysis of the RNA and proteins in these cell populations highlighted differences in their activity which explain the enhanced anti-tumour performance, the team say.

The team found that, while the zeta chain sends a strong activating signal sent to the cell, it also exhausts the cell quicker. On the other hand, the delta chain sends both activating and inhibitory signals to the T cell, which “allows the immune cell to run at its optimum speed,” according to Professor Minguet.

The work was published in Nature Immunology.

“These new insights into T cell activation could promote the rational redesign of synthetic antigen receptors to improve cancer immunotherapy,” say the authors.


Velasco Cárdenas RM, Brandl SM, Meléndez AV, Schlaak AE, Buschky A, Peters T, Beier F, Serrels B, Taromi S, Raute K, Hauri S, Gstaiger M, Lassmann S, Huppa JB, Boerries M, Andrieux G, Bengsch B, Schamel WW, Minguet S. (2023) “Harnessing CD3 diversity to optimize CAR T cells.” Nature Immunology; doi: 10.1038/s41590-023-01658-z

Link: https://www.nature.com/articles/s41590-023-01658-z

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