Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR)-T-cell therapy shows promise for hematological malignancies but is limited against solid tumors due to poor T-cell infiltration and activation.
• Solid tumors often possess a dense extracellular matrix (ECM) that impedes CAR-T cell penetration and function.

Purpose of the Study:

• To engineer CAR-T cells capable of overcoming the physical and biological barriers presented by solid tumor microenvironments.
• To enhance CAR-T cell infiltration, activation, and antitumor efficacy against solid tumors by targeting the tumor ECM.

Main Methods:

• CAR-T cells were engineered with synthetic Notch (synNotch) receptors to induce localized secretion of ECM-degrading enzymes.
• The synNotch system enabled tumor-specific enzyme production, facilitating ECM degradation at the tumor site.
• The efficacy of synNotch CAR-T cells was evaluated in vitro using patient-derived tumor organoids and in vivo models.

Main Results:

• SynNotch CAR-T cells effectively degraded tumor ECM components, improving CAR-T cell infiltration into solid tumors.
• Engineered CAR-T cells demonstrated robust tumor killing and significant solid tumor regression with no observed toxicity in vivo.
• SynNotch CAR-T cells promoted sustained activation of T-cells within patient-derived tumor organoids, indicating enhanced persistence.

Conclusions:

• Synthetic Notch receptor engineering provides a viable strategy to enhance CAR-T cell infiltration and antitumor activity against ECM-rich solid tumors.
• This approach represents a promising advancement in CAR-T cell therapy for solid malignancies, addressing key limitations of current treatments.