CAR-T cell therapy is a last hope for many patients with blood, bone marrow or lymph gland cancer when other treatments such as chemotherapy are unsuccessful.A limiting factor of this otherwise very effective and safe therapy is that the cells used in the process quickly reach a state of exhaustion. Researchers at the University of Freiburg have now been able to prevent this exhaustion and thus significantly improve the effect of the therapy in a preclinical animal model. The new results have been published in the journal Nature Immunology.

Using the body’s own defences against cancer
CAR-T cells are one of the personalised cancer therapies and have been used in specialised centres in Europe since 2018. In this complex treatment, immune cells, or more precisely T cells, are taken from the blood of cancer patients, genetically engineered in the laboratory with a chimeric antigen receptor (CAR) and then re-administered.

A simplified T-cell receptor
The CAR functions like a sensor with which the T cell recognises characteristic surface features of cancer cells. The synthetic CAR consists in part of elements of the natural T cell receptor, but its structure is greatly simplified in comparison. The CAR has only one of the four different subunits that transmit the signals that trigger the activation of the immune response in unmodified T cells.

Prof. Dr Susana Minguet, who led the current study together with Prof. Dr Wolfgang Schamel. Both are members of the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies at the University of Freiburg and are researching how the various subunits of the T cell receptor transmit signals in order to trigger an immune response.

For their current study, the researchers produced four types of CAR-T cells, each expressing a CAR with each of the four signalling subunits, and tested them in a mouse model of leukaemia. “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,” explains Schamel.

Strong activation is a downside
The researchers explain the result by the fact that although the zeta chain transmits a strong activating signal to the cell, this also quickly exhausts the cell. “It’s as if we were making the cells run an ultramarathon at maximum speed,” explains Minguet. In contrast, the delta chain, which showed the best efficacy in the current study, triggers an inhibitory signal parallel to the activation of the T cell. “This allows the immune cell to run at its optimum speed,” says Minguet.

Results relevant to clinical research

The researchers conclude that the development of new CAR therapies should therefore consider strategies that can achieve a more balanced immune response. (VP/Newswise)