1. The use of CRISPR/Cas9 technology to develop innovative strategies for cellular therapy of hematological malignancies
Supervisor: Michal Šmída, Ph.D.
T lymphocytes are a terrific weapon of our immune system able to kill non-self, infected or transformed cells. They can be genetically engineered to carry artificial chimeric antigen receptor (CAR), thereby being reprogrammed to recognize and kill tumor cells in a very specific and effective manner. CAR-T cells achieved remarkable responses in the cellular therapy of hematological B-cell malignancies, yet, CAR-T cell cancer therapy still encounters numerous problems and requires extensive development. No biomarkers predicting the response to CAR-T cells are available, failure of CAR-T cell product and treatment resistances are the major hurdle of this therapy. CRISPR/Cas9 functional screening represents a unique way of identifying genetic factors that affect the efficiency of CAR-T cell treatment.
Using genome-wide CRISPR/Cas9 knockout screening, the student will systematically interrogate cellular factors that are able to modulate and further improve the efficacy of CAR-T cells upon malignant B cells. Factors affecting the response strength of malignant B cells as well as factors influencing CAR-T cell activity or persistence will be identified. These modulating factors (genes) will be thoroughly validated and underlying molecular mechanisms elucidated. This project will propose novel specific cellular targets that can be utilized to improve the performance of CAR-T cell therapy.
Keywords: CRISPR/Cas9, CAR-T cell, B-cell malignancy, genetic screening