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CAR-ving a Path: Metalloprotease-Engineered CAR T Cells Tunnel through Solid Tumors
Alessandro Gasparetto1,2, Roberto Chiarle1,2,3
1Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Abstract:
Overcoming the physical barriers of the tumor microenvironment remains a major obstacle for chimeric antigen receptor (CAR) T-cell therapy in solid tumors. In this issue, Van Pelt and colleagues show that engineering GD2-targeting CAR T cells to express matrix metalloproteinase 7 and osteopontin-b enhances their ability to infiltrate tumors rich in extracellular matrix. These modifications improve functionality in preclinical models without increasing off-target toxicity. The findings highlight a promising strategy to design CAR T cells with extracellular matrix-remodeling capabilities. See related article by Van Pelt et al., p. 1732.
Insights
Engineering chimeric antigen receptor (CAR) T cells to remodel the tumor microenvironment improves their infiltration into solid tumors. This strategy enhances CAR T-cell functionality in preclinical models without increasing toxicity.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Solid tumors present physical barriers within the tumor microenvironment, hindering chimeric antigen receptor (CAR) T-cell therapy effectiveness.
- Extracellular matrix deposition in solid tumors impedes T-cell infiltration and function.
Purpose of the Study:
- To engineer GD2-targeting CAR T cells to overcome tumor microenvironment barriers.
- To enhance CAR T-cell infiltration and anti-tumor activity in solid tumors.
Main Methods:
- Genetic engineering of CAR T cells to express matrix metalloproteinase 7 and osteopontin-b.
- Evaluation of CAR T-cell infiltration and functionality in preclinical solid tumor models.
Main Results:
- Engineered CAR T cells demonstrated enhanced ability to infiltrate tumors with dense extracellular matrix.
- Improved CAR T-cell functionality was observed in preclinical models.
- No increase in off-target toxicity was detected with the engineered CAR T cells.
Conclusions:
- Engineering CAR T cells to express matrix metalloproteinase 7 and osteopontin-b is a promising strategy to improve solid tumor treatment.
- CAR T cells with extracellular matrix-remodeling capabilities represent a potential advancement in cancer immunotherapy.
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