Kurzfassung

Targeting cancer mutations by reactivating neoepitope-specific T cells via checkpoint blockade has shown therapeutic success in solid cancers with high mutational load but is hampered in patients with tumors carrying lower numbers of mutations. Thus, for less immunogenic tumors such as pancreatic ductal adenocarcinoma (PDA) and glioblastoma, targeting mutations by T-cell receptor (TCR) gene therapy may be a more appropriate strategy. Through funding from the...Targeting cancer mutations by reactivating neoepitope-specific T cells via checkpoint blockade has shown therapeutic success in solid cancers with high mutational load but is hampered in patients with tumors carrying lower numbers of mutations. Thus, for less immunogenic tumors such as pancreatic ductal adenocarcinoma (PDA) and glioblastoma, targeting mutations by T-cell receptor (TCR) gene therapy may be a more appropriate strategy. Through funding from the Deutsche Krebshilfe (DKH Priority Program Translational Oncology), our team of DKTK partners has identified a series of HLA-A*02:01-restricted TCRs against various recurrent and patient-individual mutations. Based on in vivo anti-tumor efficacy testing in clinically relevant models, a lead TCR will be selected for GMP-compliant retrovirus production. Manufacturing of T cell products in a closed CliniMacs Prodigy system will facilitate first-in-human testing. 
In addition, we will explore SEREX antigens for recognition by MHC class II-restricted CD4+ T cells and obtain pre-clinical proof of concept for the combinatorial use of mutation-specific CD8+ T cells and tumor-specific CD4+ T helper cells. Tumor-specific CD4+ T cell help is not only important for an optimal CD8+ T cell-effector response, but also for countering tumor immune escape through loss of HLA-class I expression and/or deficiencies in antigen processing, two immune-editing features regularly encountered in human cancers.» weiterlesen» einklappen