Solving the problem of exhausted cancer-fighting cells
Chimeric antigen receptor (CAR) T cell therapy can be very helpful in treating some types of cancer when other treatments fail. However, different factors can cause these tumour-infiltrating white blood cells to reach a state of exhaustion, causing non-responsiveness to treatment and even relapses. A new study supported by the EU-funded EN_ACTI2NG, SYBILLA and EUbOPEN projects now shows how this exhaustion can be prevented, significantly improving the therapy’s effect in a preclinical model. In CAR-T cell therapy, immune cells called T cells are genetically engineered in a lab to identify and destroy cancer cells. The T cells are taken from the patient’s blood and changed by adding a gene for a receptor known as CAR, which makes the T cells bind to a specific protein, or antigen, on the cancer cells. The CAR-T cells are then readministered to the patient to wage their battle against the cancer.
Only one of four
As reported in a press release posted on the website of EN_ACTI2NG consortium partner and SYBILLA project coordinator University of Freiburg, Germany, the synthetic CAR has some elements of the natural T cell receptor. However, its structure is much simpler, possessing only one of the four different signalling chains that trigger the immune response in unmodified T cells. “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,” reports study co-senior author and University of Freiburg Prof. Dr Susana Minguet in the press release. “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.” The research team produced four types of CAR-T cells that were engineered to express a CAR with each of the four signalling chains. They then tested these cells on mice with 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 University of Freiburg Prof. Dr Wolfgang Schamel, who led the study together with Prof. Dr Minguet. So how can this outcome be explained? According to the researchers, the strong activating signal transmitted to the cell by the zeta chain quickly exhausts that cell. “It’s as if we were making the cells run an ultramarathon at maximum speed,” comments Prof. Dr Minguet. In contrast, the delta chain, which produced the best results 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,” adds the researcher. “Our results show that CARs that use one of the other signalling domains instead of the zeta chain could mitigate or prevent the disadvantages of existing therapies with CAR-T cells,” concludes Prof. Dr Schamel. The ongoing EUbOPEN (EUbOPEN: Enabling and Unlocking biology in the OPEN) project is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry. EN_ACTI2NG (European Network on Anti-Cancer Immuno-Therapy Improvement by modification of CAR and TCR Interactions and Nanoscale Geometry) and SYBILLA (Systems Biology of T-cell Activation in Health and Disease) ended in 2021 and 2013, respectively. For more information, please see: EN_ACTI2NG project website SYBILLA project EUbOPEN project website
Keywords
EN_ACTI2NG, SYBILLA, EUbOPEN, cancer, CAR-T cell, T cell, chimeric antigen receptor, tumour