Single-day nonactivated IL-18-armed CAR T cells establish a durable, stemlike state with enhanced persistence

Area of Science:

• Immunology and Cancer Therapy

Background:

• Chimeric antigen receptor (CAR) T-cell therapy has revolutionized B-cell malignancy treatment.
• Current CAR T-cell therapies face challenges like manufacturing delays, T-cell exhaustion, and limited persistence.

Purpose of the Study:

• To develop a rapid, single-day production method for non-activated CAR T-cells.
• To engineer CAR T-cells to secrete interleukin-18 (IL-18) to enhance anti-tumor efficacy and persistence.

Main Methods:

• Engineered non-activated CAR T-cells to secrete IL-18 (CART-IL18).
• Evaluated anti-tumor efficacy in xenograft models of lymphoma, leukemia, and pancreatic cancer.
• Conducted single-cell transcriptomic and metabolomic analyses to understand cellular mechanisms.

Main Results:

• CART-IL18 cells demonstrated robust anti-tumor efficacy and improved persistence across models.
• IL-18 enhanced T-cell function, metabolic fitness, and resistance to exhaustion.
• Transcriptomic analysis revealed favorable gene expression profiles, while metabolomics showed enhanced mitochondrial bioenergetics.

Conclusions:

• IL-18-enhanced, activation-free CAR T-cells offer a potent and persistent therapeutic platform.
• This approach reduces manufacturing time and improves CAR T-cell product potency.
• The findings support clinical evaluation in patients with tumors refractory to standard CAR T-cell therapy.