Kurzfassung

Down-regulation or loss of HLA expression represents an important immune-escape mechanism and is a serious limitation for immunotherapy strategies relying on HLA-restricted effectors. We have observed in patients with HLA-negative disease the emergence of HLA-independent anti-tumor αβT-cell responses. The project aims at the preclinical testing of patient-derived, HLA-independent, anti-tumor T-cell receptors (TCR) directed against tyrosinase-related protein 2 (TRP2) and the GM-CSF receptor...Down-regulation or loss of HLA expression represents an important immune-escape mechanism and is a serious limitation for immunotherapy strategies relying on HLA-restricted effectors. We have observed in patients with HLA-negative disease the emergence of HLA-independent anti-tumor αβT-cell responses. The project aims at the preclinical testing of patient-derived, HLA-independent, anti-tumor T-cell receptors (TCR) directed against tyrosinase-related protein 2 (TRP2) and the GM-CSF receptor alpha chain (CSF2RA) in mice to demonstrate their anti-tumor effects after adoptive transfer and to exclude relevant off-tumor and off-target effects applying in vivo tracking of TCR-transduced T cells and immunohistochemistry on tumor and normal tissues. In addition, we plan to identify further HLA-independent, tumor-associated T-cell targets via library expression screening with available HLA-independent antitumoral T-cell clones or T cells transduced with their TCR and via reverse targeting of promising tumor-associated surface molecules. The project´s ultimate goal is to prove both relevance and therapeutic use of the naturally occurring HLA-independent anti-tumor T-cell repertoire, to pave the way for clinical adoptive therapy studies with HLA-independent anti-tumor TCR as well as for efforts to augment such T-cell responses in patients. » weiterlesen» einklappen