Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• The αvβ6 integrin is overexpressed in multiple solid tumors, unlike its restricted physiological expression.
• Targeting tumor-specific antigens is a key strategy in cancer immunotherapy.

Purpose of the Study:

• To develop and evaluate a chimeric antigen receptor (CAR) T cell therapy targeting the αvβ6 integrin.
• To assess the efficacy and safety of this novel CAR T cell therapy in preclinical solid tumor models.

Main Methods:

• Development of a CAR using a foot and mouth disease virus-derived A20 peptide for αvβ6 recognition, linked to CD28+CD3 signaling domains.
• Co-expression of an IL-4-responsive fusion gene (4αβ) for selective ex vivo expansion of CAR T cells.
• In vivo efficacy studies in SCID beige mice bearing ovarian, breast, and pancreatic tumor xenografts.

Main Results:

• The developed CAR selectively targeted αvβ6 integrin.
• Significant in vivo efficacy was observed in ovarian, breast, and pancreatic tumor xenografts expressing αvβ6.
• Mild and reversible toxicity was noted only at supra-therapeutic doses, suggesting a manageable safety profile.

Conclusions:

• The αvβ6-targeted CAR T cell therapy demonstrates potent anti-tumor activity in diverse solid tumor models.
• The findings support the clinical investigation of this immunotherapy for solid tumors expressing the αvβ6 integrin.