Innovative Genetic Screening Enhances CAR T Cell Therapy Effectiveness

Recent advances in genetic screening have led to the development of enhanced CAR T cells, a groundbreaking approach in cancer immunotherapy. CAR T cells are immune cells derived from patients that have been genetically engineered to better recognize and attack cancer cells by attaching a chimeric antigen receptor (CAR). This strategy has revolutionized treatment options for certain blood cancers, demonstrating remarkable remission rates in otherwise untreatable cases.

However, many patients do not respond to CAR T cell therapy, often due to intrinsic dysfunction within the T cells themselves. To overcome this limitation, researchers at CeMM Research Center for Molecular Medicine and the Medical University of Vienna have created a novel system called CELLFIE. This platform uses genome-wide CRISPR screening to systematically modify CAR T cells, identifying genetic factors that boost their therapeutic potential.

A key discovery from this research was that knocking out the RHOG gene significantly increased CAR T cells' ability to fight leukemia in preclinical models. Unlike natural T cells, which have evolved over millions of years, CAR T cells are engineered with new functions that are not always optimized. Some natural immune genes, such as RHOG, can inadvertently weaken CAR T cell effectiveness. Removing these genes with CRISPR technology enhances the cells' expansion, persistence, and ability to resist exhaustion.

Furthermore, the research demonstrated that combining knockouts of RHOG with FAS resulted in synergistic effects, making the CAR T cells even more potent. These gene-edited cells proliferated faster, remained more active longer, and successfully cured mice of aggressive leukemia. The CELLFIE platform’s flexibility enables the systematic exploration of gene combinations to develop next-generation immunotherapies, with potential applications extending beyond blood cancers to solid tumors, autoimmune diseases, and regenerative medicine.

This innovative approach not only deepens understanding of T cell biology but also opens new avenues for creating more effective and durable CAR T cell therapies. The findings highlight a promising path toward overcoming current challenges in immunotherapy and expanding its benefits to a broader range of patients.