Researchers in Brazil have enhanced natural killer (NK) cells with chimeric antigen receptors incorporating the 2B4 and DAP12 signaling domains, significantly improving their ability to destroy tumor cells in preclinical models.
How the 2B4-DAP12 combination boosts CAR-NK cell activation
The Ribeirão Preto Blood Center and Center for Cell-Based Therapy (CTC) used the NK-92 cell line to test CAR designs with specific costimulatory components. Adding 2B4 and DAP12 to the chimeric antigen receptors increased the cells’ readiness to attack, enhancing their tumor-targeting efficiency. This addresses a key challenge in CAR-NK optimization: identifying internal signaling mechanisms that maximize cytotoxic function.
Why dasatinib pretreatment improves therapeutic control
Researchers tested dasatinib, a drug that temporarily suppresses NK cell activity, to evaluate reversible pharmacological control. Pretreatment with dasatinib followed by infusion of 2B4-DAP12-engineered CAR-NK cells resulted in stronger tumor growth inhibition in animal models compared to conventional approaches. This strategy combines optimized activation signals with pharmacological modulation to improve both efficacy and controllability.
Institutional support behind the Ribeirão Preto research
The Center for Cell-Based Therapy (CTC) operates as a Research, Innovation, and Dissemination Center (RIDC) funded by FAPESP and is affiliated with the Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP). The study was published in Frontiers in Immunology, contributing to ongoing efforts to advance CAR-NK therapies beyond the well-established CAR-T cell paradigm, particularly for tumors resistant to current immunotherapies.
What are CAR-NK cells and how do they differ from CAR-T cells?
CAR-NK cells are natural killer cells engineered with chimeric antigen receptors to target cancer cells; unlike CAR-T cells, which are derived from T lymphocytes and have been extensively studied, CAR-NK cells are still being optimized for signaling efficiency and safety, with potential advantages in reduced toxicity and broader applicability.
Why is the 2B4-DAP12 signaling combination significant in this study?
The inclusion of 2B4 and DAP12 costimulatory domains in the CAR design enhanced NK cell activation state and tumor-killing capacity, addressing a critical gap in understanding which internal signaling mechanisms optimize CAR-NK function, as noted by researchers at the Ribeirão Preto Blood Center and CTC.