A GROUNDBREAKING study has uncovered key insights into the differing tumour rejection behaviours of chimeric antigen receptor T cells (CAR-T) targeting CD19, potentially paving the way for improved cancer treatments. Researchers compared two types of CAR-T cells: CD28.ζ-CAR-T, known for inducing rapid tumour lysis, and 4-1BB.ζ-CAR-T, which demonstrates more persistent tumour control. The study focused on the molecular dynamics occurring at the CAR T-cell immune synapse (CARIS), providing a deeper understanding of the contrasting effects these therapies have on tumour rejection.
The study found that CD28.ζ-CAR-T cells created brief, highly lethal CARIS, which allowed them to rapidly and effectively eliminate leukemic blasts through serial killing. On the other hand, 4-1BB.ζ-CAR-T cells formed longer-lasting CARIS and relied on robust expansion and cooperative killing, resulting in slower but more sustained tumour control.
One of the key findings was the behaviour of CAR molecules within membrane lipid rafts (mLRs), a crucial part of the immune synapse. Upon tumour engagement, CD28.ζ-CAR molecules quickly moved into mLRs, triggering the mobilisation of lytic granules and boosting the T-cell response. This facilitated fast recovery and sensitivity even at low tumour cell densities. In contrast, 4-1BB.ζ-CAR-T cells gradually accumulated at mLRs, leading to a more mechanical, tonic CARIS that drove chronic, Fas ligand-based tumour killing.
These findings provide valuable insights into how CAR-T therapies work at the molecular level and could guide the development of more adaptive and effective cancer treatments.
Helena Bradbury, EMJ
Reference
Gad AZ et al. Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells. Science Advances. 2025;11(2):eadq8114.
