Kurzfassung

Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, however, overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new therapies is required to improve outcome. The Kirsten rat sarcoma viral oncogene homolog (Kras) is one of the most frequently mutated proto-oncogenes found in NSCLC, and particularly the frequency of single amino acid substitutions at...Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, however, overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new therapies is required to improve outcome. The Kirsten rat sarcoma viral oncogene homolog (Kras) is one of the most frequently mutated proto-oncogenes found in NSCLC, and particularly the frequency of single amino acid substitutions at codon 12 results in e.g. a KrasG12V tumor neoantigen as an attractive therapeutic target. In this project we therefore aim to establish cellular therapeutic tools that target the G12V mutation in Kras. We have generated different TCR-like chimeric antigen receptors (CARs) directed to KrasG12V in the context of HLA-class I molecules, and functional studies on anti-KRAS driven immunity by KRASG12V CAR redirected T cells are in progress. Taking advantage of an established autochthonous lung cancer mouse model that closely resembles the development of NSCLC in humans we are currently establishing e.g. HLA-A*0201 transgenic NSCLC mice in close collaboration with the group of PD Bockamp (Institute for Translational Immunology) to explore therapeutic efficacy of KRAS CAR T therapy and evaluate different monotherapeutic or combinatorial approaches upon transfer of either KRASG12V-specific tumor infiltrating T lymphocytes or TCR-like CAR redirected T cells alone or in combination with checkpoint blockade inhibitors or TLR9 agonists. These studies might gain interesting and valuable information for redirected ACT to improve cellular immunotherapy in metastatic lung cancer.» weiterlesen» einklappen