Cleavage-Responsive Biofactory T Cells Suppress Infectious Diseases-Associated Hypercytokinemia

Area of Science:

• Immunology
• Biotechnology
• Infectious Diseases

Background:

• Severe infectious diseases, including COVID-19, can cause hypercytokinemia and organ failure.
• Current peptide therapeutics face limitations like short half-life and enzymatic degradation, necessitating frequent administration.
• There is a need for advanced therapeutic strategies to manage severe infectious diseases effectively.

Purpose of the Study:

• To develop engineered T cells capable of continuously expressing therapeutic peptides for treating severe infectious diseases.
• To investigate the efficacy of chimeric T cells in preventing vascular damage and suppressing hypercytokinemia in vivo.

Main Methods:

• Engineered T cells using a lentiviral system to express multi-level therapeutic peptides on their surface.
• Incorporated matrix metallopeptidases- (MMP-) and tumor necrosis factor alpha converting enzyme- (TACE-) responsive cleavage sites for controlled peptide release.
• Assessed the therapeutic effects in tissue-engineered blood vessels and in vivo models of infectious diseases.

Main Results:

• Chimeric T cells successfully prevented vascular damage in a tissue-engineered blood vessel model.
• Engineered T cells suppressed hypercytokinemia and reduced lung tissue damage in vivo.
• The released peptides activated endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), mediating therapeutic effects.

Conclusions:

• Engineered T cells offer a novel platform for sustained delivery of therapeutic peptides against severe infectious diseases.
• This approach holds promise for treating conditions like sepsis and COVID-19 by mitigating hypercytokinemia and organ damage.
• Chimeric T cells represent a potential advancement in peptide-based therapeutics for infectious disease management.