Summary

Development of Target structures for targeted T-cell therapy
T-cell therapy of malignant diseases can be directed against intracellular antigens, which are presented as epitopes by MHC class I molecules and can be targeted by T-cell receptors (TCR), and surface molecules, which can be targeted both by TCR and chimeric antigen receptors (CAR). Both strategies are using transgenic autologous T-cells from the patients, which are expanded in vitro and transferred back to the patient after lymphodepleting cytostatic treatment as an adoptive T-cell therapy.
For the selection of target proteins, the most important feature is the selective expression pattern to avoid on target/off tumor-toxicity. Other important features are functional relevance and the expression in tumor-initiating cells. After identification of a potential target protein, next relevant step is the identification and selection of the T-cell epitope. The last crucial step is the development of a TCR with high enough affinity to be used in clinic and the development of expression vectors, which can induce high surface expression and specific functional avidity in the transfected T-cells.
Main goals of our research are the identification of selectively expressed proteins in several tumor types, which can act as targets for adoptive T-cell therapy, and the application of established tumor-associated antigens in additional tumor entities including pediatric malignancies (in cooperation with A. Künkele, Berlin). We identify class I epitopes by in silico prediction and HLA stabilization or by stimulation with peptide libraries. Epitopes are vetted by affinity to the respective HLA molecule, by analysis of spontaneous T-cell responses in tumor patients, and by analysis of presentation in vivo by ligandome analysis (in cooperation with J. Walz, Tübingen). Specific T-cell clones are generated by in vitro stimulation with autologous or allogenic antigen presenting cells or vaccination of TCR transgenic mice (in cooperation with G.Willimski, Berlin). TCR of those clones are sequenced and used to generate expression vectors.