Restricting CAR T Cell Trafficking Expands Targetable Antigen Space.

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise for hematologic malignancies but faces challenges due to limited tumor-specific antigens.
• Targeting antigens shared between tumors and critical organs like the central nervous system (CNS) poses a significant safety concern.
• Ewing sarcoma (ES) expresses LINGO1, a potential target antigen, but its presence in the CNS necessitates strategies to mitigate off-target effects.

Approach:

• Identified a panel of surface antigens with restricted expression to cancer and the CNS.
• Engineered LINGO1-specific CAR T cells lacking integrin α4 (A4^ko) to inhibit CNS migration.
• Evaluated the efficacy and safety profile of A4^ko LINGO1 CAR T cells in preclinical models.

Key Points:

• LINGO1 is a widely expressed antigen in Ewing sarcoma.
• Engineered CAR T cells lacking integrin α4 were successfully excluded from the CNS.
• A4^ko LINGO1 CAR T cells demonstrated potent anti-tumor activity against ES.
• Altering cell adhesion properties broadens the scope of targetable antigens for CAR T cell therapy.

Conclusions:

• CAR T cells lacking integrin α4 can be safely directed against tumor-associated antigens present in the CNS.
• This strategy enhances the therapeutic window for CAR T cell treatments by enabling targeting of previously inaccessible antigens.
• Modulating immune cell migration through adhesion molecule engineering represents a novel approach to improve CAR T cell therapy safety and efficacy.