Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cell therapy faces challenges in solid tumor treatment due to targeting shared antigens on normal tissues.
• CAR T cells targeting GD2 caused fatal neurotoxicity by recognizing GD2 on normal brain tissue.

Purpose of the Study:

• To engineer CAR T cells with improved selectivity for solid tumors, minimizing off-target toxicity.
• To develop a conditional CAR expression system activated by tumor microenvironment-specific targets.

Main Methods:

• Engineered a synthetic Notch receptor for conditional CAR expression.
• Designed T cells (MEAT cells) to express CARs upon binding to P-selectin, a marker of tumor neovasculature.
• Evaluated MEAT cell efficacy and toxicity in preclinical models.

Main Results:

• MEAT cells prevented neurotoxicity by limiting CAR expression and T cell infiltration in the brain.
• Maintained significant antitumor efficacy against solid tumors.
• Demonstrated enhanced persistence and metabolic fitness of tumor-infiltrating MEAT cells.

Conclusions:

• Conditional CAR expression via synthetic Notch receptors enhances CAR T cell safety and efficacy in solid tumors.
• This approach broadens the scope of targetable solid tumor antigens by ensuring cancer cell-specific targeting.
• Provides a versatile platform for developing safer CAR T cell therapies for various solid malignancies.