T cell receptor-engineered T cells

T-cells with tumor-specific T-cell receptors, TCR-Ts for short, are genetically modified T-cells with receptors that can bind certain tumor antigens. In T cell receptor gene therapy, these genetically modified T cells are used therapeutically.

In humans, T cells with tumor-specific T cell receptors (TCR) cannot develop because the corresponding antigens are typical recognition marks on the surface of cancer cells, but can also occur on other cells in the human body. T cells with a corresponding receptor are therefore eliminated by the immune system at an early stage in order to avoid an autoimmune reaction. In this respect, a detour via the immunized mouse must be found for a therapeutic principle.

T cells express T cell antigen receptors (TCR) on their surface, through which they recognize antigens. The initiation of TCR signals is based on the protein tyrosine kinases (PTK) LCK and ZAP70 and generates protein aggregates of considerable complexity. Genetically engineered TCR-Ts have receptors that recognize tumor-associated antigens (TAAs) with high specificity. They bind to the appropriate polypeptides presented by the MHC class I complex of the tumor cell and induce apoptosis. In contrast to CAR-T cells, which are directed against surface proteins, they can also recognize intracellular tumour antigens via the peptide sequences.

Mice are immunized with an antigen from human cancer cells. They produce T cells with precisely fitting receptors against this antigen. This enables the genetic blueprint of this receptor to be analyzed and cloned. During treatment, the patient's own T-cells are removed, provided with the new tumor-specific receptor and then reinfused. These T-cells with a now tumor-specific T-cell receptor can recognize cancer cells according to the lock-and-key principle and fight them in a targeted manner.

Areas of application: Solid tumors (e.g. melanomas, lung carcinomas). Initial therapy results are available for multiple myeloma.

Around 90 % of cancers worldwide are solid tumors. Most cell therapy trials for solid tumors focus on a few tumor types such as melanoma, brain tumors, cancer of the central nervous system and liver cancer. Surgical resection and radiochemotherapy are the main methods for these tumor entities. Therapy modalities with CART-T cells (Chimeric Antogenic Receptor T-Cells - these are equipped with an artificial antigen receptor - CAR) and with TCR-Ts are already being used or will be used in the near future for personalized TCR-T therapy. They open up new perspectives in the treatment of tumor entities (Li Z et al. 2024).

The transcription factor Foxp3 controls the differentiation and function of regulatory T cells Foxp3 modifies the gene expression dynamics of TCR-induced genes, which are fundamental mechanisms for Treg-mediated immunosuppression (Ono M 2020).

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