Kurzfassung

T cells can be retrovirally equipped with T cell receptors (TCRs) that are able to recognize tumor- antigens (TA) with high affinity and thereby redirected to kill tumor cells in vitro and in vivo. In the first funding period we have identified novel and highly promising strategies to increase the robustness and activation of TA-reactive T cells to combat tumor immune escape.
TCR-gene therapy can potentially be also associated with off-target toxicity due to TCR mispairing. We have generated...T cells can be retrovirally equipped with T cell receptors (TCRs) that are able to recognize tumor- antigens (TA) with high affinity and thereby redirected to kill tumor cells in vitro and in vivo. In the first funding period we have identified novel and highly promising strategies to increase the robustness and activation of TA-reactive T cells to combat tumor immune escape.
TCR-gene therapy can potentially be also associated with off-target toxicity due to TCR mispairing. We have generated and demonstrated in the first funding period improved safety and therapeutic efficacy of a high-affinity single-chain (sc)TCR specific for a non-mutated HLA.A*02:01-restricted antigen (p53aa264-272) as a broad-spectrum TCR for cancer immunotherapy (PR5). Fitness of infused tumor antigen receptor-engineered T cells and their capacity to resist the suppressive tumor microenvironment (TME)-driven T cell exhaustion or senescence is key for a durable effective cancer immunotherapy. We have demonstrated that the tumor suppressor TP53-derived p53 isoform 133p53 functions as a novel transcriptional enhancer of metabolic and cellular resilience of TCR-engineered T cells in vitro and in a xenograft tumor model (PR1). A heterogeneous population of granulocytic myeloid-derived suppressor cells (G-MDSC) as well as conventional polymorphonuclear neutrophil granulocytes (PMN) can inhibit antitumoral TA reactive T cells. In a therapeutic approach of concurrent granulocyte arginase 1 (Arg1) inhibition, we identified a highly potent T cell immunostimulatory activity within the secretome of human granulocytes (PR3). Both strategies promote an effective T cell phenotype, the expansion and cytotoxic properties of TA-specific T cells.
We now want to identify the molecular correlate of the extraordinarily potent PMN-derived hyperstimulatory activity (PMN metabolomics and proteomics) and fully characterize the hyperactivated T cells (gene expression: RNA seq, signalling: phospho-proteomics, T cell metabolism). Its therapeutic potential will be analysed in conjunction with 33p53 isoform-modified TA-reactive T cells in vitro and in appropriate tumor models in vivo. Crucial aspects of the immunological composition of the TME will be analysed: subsets and phenotypes of tumor-infiltrating lymphocytes (TiLs), polarization of tumor-associated macrophages (TAMs), analysis of the cellular immune landscape, the tumor stroma and cancer-associated fibroblasts (CAF), gene signatures of TiLs and MDSCs/PMN as well as their dynamic cross-talk in vivo (multiphoton microscopy). In collaboration within our CRC, we will extend our TCR/tumor models to chimeric-antigen receptor (CAR)-T and/or CAR-NK cell models. We will also investigate the proposed therapeutic approach in chronic infection models. » weiterlesen» einklappen