The efficacy of CD19 directed chimeric antigen receptor (CAR)-T-cell therapy in different hematological malignancies has put cell therapy as a novel treatment option on the map. However, CAR-T treatment for solid tumors has so far been unsuccessful. Solid tumors differ from hematological malignancies, as these present physical barriers against infiltration, contain a highly immune-suppressive environment, and harbor an unfavorable metabolic milieu. Therefore, new approaches are required to tackle these hurdles. The host lab was the first to identify an unconventional CD8 T cell (uT) population in humans. These cells are naturally tissue-homing and seem to perform an immune surveillance function. In this project, CAR-T cells will be generated using these uTs (CAR-uTs). To optimize this CAR-T cell product, the optimal costimulatory signal and growth factors to be provided to the cells will be determined using several in vitro and in vivo assays. Using single cell analysis on the immune infiltrate of peripheral blood derived CAR-uTs in patient derived xenografts (PDXs), the uT clones associated with tumor rejection will be characterized in depth. This project will give deeper insights into an uT cell population in peripheral blood with great potential to control and eradicate solid tumors.