Improving CAR-T cell function through a targeted cytokine delivery system utilizing car target-modified extracellular...

Area of Science:

• Immunotherapy
• Cell Biology
• Nanotechnology

Background:

• Chimeric antigen receptor (CAR)-T-cell therapy shows promise for B-cell malignancies but faces challenges with T-cell persistence and efficacy.
• Systemic administration of interleukin-12 (IL-12), a potent immunotherapy agent, is limited by severe toxicity.

Purpose of the Study:

• To develop a novel extracellular vesicle (EV)-based delivery system for targeted IL-12 delivery to CAR-T cells.
• To enhance CAR-T-cell function and antitumor activity while mitigating IL-12-associated toxicity.

Main Methods:

• Engineered HEK-293T cells to produce EVs displaying CD19 and/or IL-12.
• Assessed the in vitro efficacy of IL-12 EVs and CD19/IL-12 EVs on anti-CD19 CAR-T cells.
• Evaluated the in vivo antitumor response and CAR-T-cell expansion in a xenograft mouse model.

Main Results:

• IL-12 EVs significantly boosted CAR-T-cell effector functions (IFN-γ, TNF-α secretion, cytotoxicity, expansion) in vitro.
• CD19/IL-12 EVs demonstrated superior binding to CAR-T cells compared to IL-12 EVs alone.
• Intratumoral administration of CD19/IL-12 EVs in mice led to durable antitumor responses and enhanced CAR-T-cell expansion without systemic toxicity.

Conclusions:

• CAR-targeted EVs serve as an effective platform for localized IL-12 delivery to augment CAR-T-cell function.
• This approach offers a safer and more potent strategy for enhancing CAR-T-cell immunotherapy in B-cell malignancies.