Overcoming stromal resistance in solid tumors with MMP2-engineered CAR-T cells.

Area of Science:

• Immunotherapy
• Oncology
• Biochemistry

Background:

• Chimeric antigen receptor (CAR) T-cell therapy faces challenges in solid tumors due to extracellular matrix (ECM) stromal barriers.
• Previous strategies using multiple matrix metalloproteinases (MMPs) increased complexity, while single MMP7 overexpression showed limited efficacy.

Purpose of the Study:

• To identify a single enzyme for effective ECM remodeling to enhance CAR T-cell therapy in solid tumors.
• To evaluate the efficacy of matrix metalloproteinase-2 (MMP2) in overcoming ECM-mediated resistance.

Main Methods:

• Engineered CAR T-cells (targeting mesothelin and B7H3) to co-express MMP2.
• In vitro assessment of ECM traversal, T-cell fitness, and cytotoxicity.
• In vivo evaluation in a cancer-associated fibroblast (CAF)-enriched xenograft model.

Main Results:

• MMP2 co-expression enhanced CAR T-cell infiltration and cytotoxicity by facilitating ECM traversal.
• MMP2's effects were confirmed by inhibition with the pan-MMP inhibitor GM6001.
• MMP2-engineered CAR T-cells demonstrated increased intratumoral accumulation and durable tumor control in vivo.

Conclusions:

• Matrix metalloproteinase-2 (MMP2) is a potent single enzyme for ECM remodeling in solid tumors.
• MMP2-based strategy offers a simple, scalable, and clinically translatable approach to overcome stromal resistance in CAR T-cell therapy.