DESCRIPTION:

Central nervous system (CNS) disorders are leading cause of global disease burden and high economic cost, estimated at $800 billion per year in the US. Current systemic treatments have poor CNS penetration at therapeutic doses and numerous side effects. An ideal treatment should localize its action to the affected area. Immune cells could be engineered to deliver therapeutic payloads to specific tissues, such as the CNS. To engineer immune cells that target the CNS, we identified extracellular CNS-specific antigens, including unique components of the CNS extracellular matrix and neutral/glial cell surface molecules. We engineered synNotch receptors to detect these antigens and used them to program T cells that induce the expression of diverse payloads. CNS-targeted T cells inducing chimeric antigen receptor (CAR) expression efficiently cleared primary and secondary brain tumor xenografts, without killing cross-reactive cells outside the brain. Conversely, CNS-targeted cells delivering immune-suppressive payloads, such as the cytokine interleukin-10 (IL-10), ameliorated symptoms of a mouse model of neuroinflammatory disease. Thus, CNS-sensing cells provide a flexible new platform to address diverse CNS disorders in a precise and anatomically targeted manner.

LEARNING OBJECTIVES:

• Explain why CNS-targeted cell therapy is needed – Describe the limitations of current systemic CNS treatments and the rationale for localizing therapeutic action to the brain.
• Describe how synNotch circuits enable CNS-specific immune cell programming – Explain how CNS antigen sensing drives conditional payload expression in T cells.
• Compare oncologic vs. neuroinflammatory applications of this platform – Contrast CNS-targeted CAR T cells for brain tumors with IL-10-secreting cells for neuroinflammatory disease.