CD Laboratory for Next Generation CAR T Cells

Immunotherapy using CAR-T cells has already shown very high efficacy in the treatment of certain forms of cancer. There are therefore great expectations for its broad application in cancer therapy. This CD Laboratory is developing the basic knowledge to enable the urgently desired clinical implementation of even more potent CAR strategies.

CAR T cells are cells from the regular immune defence (T cells) that have been equipped with chimeric antigen receptors (CARs). This allows T cells to be directed against any surface antigens of cancer cells. The great potential of CAR T-cell therapy is demonstrated in the treatment of malignant B-cell diseases, such as acute lymphoblastic B-cell leukaemia. CAR-T cells are extremely effective here and have been clinically approved since 2017.

However, there have been no comparable successes for solid tumours to date. The central problem here is that, on the one hand, the effectiveness of CAR-T cells must be further increased, but on the other hand, they are already causing life-threatening side effects. Firstly, this is due to the fact that CAR-T cells proliferate after administration and their activity is not yet sufficiently controllable. The main reason, however, is that CAR-T cells attack healthy tissue, as tumour-associated antigens always occur on some healthy cells as well. This lack of tumour specificity and the inadequate control of T cell activation have so far prevented the full clinical potential of CAR T cell therapy from being exploited.

The aim of this CD Laboratory is therefore to develop new molecular tools with which the recognition of healthy tissue can be minimised and at the same time the position of CAR-T cells can be reversibly controlled by the administration of drugs. Reversible control is achieved by controlling the interaction of proteins through small molecules. In order to optimise their suitability in humans, these small molecules are selected according to their tolerability and pharmacological properties. These novel molecular switches can not only be used to regulate the position of CAR-T cells, but also open up completely new possibilities in the engineering of cells in general.

In addition, the research and development of novel CARs should enable the CAR-T cells to be activated only when they interact with antigen A and B simultaneously (on tumour cells), but not when only one of the two antigens is present (on healthy cells). If these two antigens are selected accordingly, this dependence on the simultaneous recognition of two antigens can significantly improve the tumour specificity of CAR-T cell therapies.

The development of safer and more effective CAR-T cells is located at the interface between immunology and protein engineering. The interdisciplinary collaboration between St. Anna Children's Cancer Research (CAR-T cell engineering) and the University of Natural Resources and Life Sciences (protein engineering) is therefore a key strength of this CD Laboratory.