Programming tissue-sensing T cells that deliver therapies to the brain.

Area of Science:

• Neuroscience
• Immunology
• Biotechnology

Background:

• Developing targeted therapies for central nervous system (CNS) disorders remains challenging due to the blood-brain barrier and lack of specific targeting mechanisms.
• Existing treatments often lack specificity, leading to off-target effects and limited efficacy in the brain.

Purpose of the Study:

• To engineer T cells capable of specifically recognizing and targeting antigens within the CNS.
• To program these CNS-targeted T cells to deliver therapeutic payloads, such as chimeric antigen receptors or immunosuppressive cytokines.
• To evaluate the efficacy of these engineered cells in treating brain tumors and a mouse model of neuroinflammation.

Main Methods:

• Identification of extracellular CNS-specific antigens, including extracellular matrix components and neuronal/glial surface molecules.
• Engineering of synthetic Notch receptors to detect identified CNS antigens.
• Programming T cells with these receptors to express payloads, including chimeric antigen receptors (CARs) or interleukin-10 (IL-10).
• In vivo testing in mouse models for brain tumor clearance and amelioration of neuroinflammation symptoms.

Main Results:

• CNS-targeted T cells expressing CARs effectively cleared primary and secondary brain tumors without off-target toxicity.
• CNS-targeted T cells delivering IL-10 ameliorated symptoms in a mouse model of neuroinflammation.
• The engineered tissue-sensing cells demonstrated high specificity for the CNS environment.

Conclusions:

• Engineered tissue-sensing cells provide a versatile strategy for anatomically targeted treatment of diverse CNS disorders.
• This approach enables precise delivery of therapeutic payloads directly to the brain, enhancing efficacy and reducing systemic side effects.
• Synthetic Notch receptor technology is a powerful tool for programming immune cells for targeted CNS therapies.