Chimeric Antigen Receptor (CAR) T-cell therapy is a promising treatment for Chronic Lymphocytic Leukemia (CLL), but resistance and relapse remain significant challenges. One emerging mechanism of immune evasion is mitochondrial theft ( from our own research findings), where CLL cells steal mitochondria from T-cells through tunnelling nanotubes (TNTs),
The function and persistence of CAR T-cells are heavily influenced by their costimulatory domain, typically CD28 or 4-1BB. For instance:

• CD28 CARs are highly glycolytic "sprinters," aimed for rapid, powerful attacks but prone to exhaustion.
• 4-1BB CARs are "marathon runners," with greater mitochondrial mass and a reliance on oxidative phosphorylation, which fuels their long-term persistence.

Hypothesis:
This project addresses a critical knowledge gap: Does the enhanced mitochondrial content of 4-1BB CAR T-cells make them a desirable target for mitochondrial theft by CLL?
We hypothesise that 4-1BB CAR T-cells, due to their higher mitochondrial mass and fitness, are more susceptible to mitochondrial theft by CLL cells compared to CD28 CAR T-cells.

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