Kurzfassung

The CRISPR/Cas9 technology is increasingly gaining interest to be employed in reprogramming the specificity of T lymphocytes within the rapidly expanding field of adoptive cellular immunotherapy against cancer, especially for the production of genetically modified T cell receptor (TCR) or chimeric antigen receptor (CAR) expressing T cells. Efficient genomic disruption of the endogenous T-cell-receptor α or β constant (TRAC and TRBC) loci to generate non-allogeneic universal T cells from a...The CRISPR/Cas9 technology is increasingly gaining interest to be employed in reprogramming the specificity of T lymphocytes within the rapidly expanding field of adoptive cellular immunotherapy against cancer, especially for the production of genetically modified T cell receptor (TCR) or chimeric antigen receptor (CAR) expressing T cells. Efficient genomic disruption of the endogenous T-cell-receptor α or β constant (TRAC and TRBC) loci to generate non-allogeneic universal T cells from a healthy donor that express a transgenic TCR or CAR specific to cancer associated antigen or cancer neoantigens, is a very attractive strategy for cellular antitumor therapy. In this proposed study, we thus aim to generate CAR expressing T cells using the CRISPR/Cas9 technology and adeno-associated virus (AAV) vector based gene transfer to abrogate endogenous TCR expression by homologous recombination of a CAR gene construct into the genomic TCR-alpha locus of T cells. Using this approach we will focus on a CAR that recognizes the epithelial growth factor receptor variant III (EGFRvIII) as a cancer neoantigen expressed e.g. in non small cell lung cancer (NSCLC) and glioblastoma as a proof of concept study as well as on a second generation NKp30 CAR-like construct found to recognize B7-H6 positive acute myeloid leukemia (AML) for improving adoptive cellular therapy to NSCLC and AML using genetically modified 3rd. party T cells from healthy donors. This project started at the end of 2017 and is anticipated to last 3 years.
 » weiterlesen» einklappen