Despite significant advances, most patients treated with chimeric antigen receptor (CAR) T cells remain incurable. To systematically enhance the potency of CAR-T cells, Dr. Dennis Harrer and his team at UKR/LIT have developed an innovative “stress test” system that involves repetitive stimulation with pancreatic carcinoma cells. “Using this system, we tested how various modifications to T cell biology could impact CAR T cell performance. By downregulating the transcription factor IRF4—a central regulator of T cell activation—we achieved a remarkable increase in CAR T cell functionality, longevity, and sensitivity,” explains Dr. Harrer.

Additionally, the researchers demonstrated that targeted overexpression of the transcription factor PU.1 equips CAR-T cells with unique properties reminiscent of innate immune cells. “This acquisition of innate immune-like functions allows CAR-T cells to launch a multi-faceted attack on tumors, blending aspects of both acquired and innate immunity,” Dr. Harrer adds.