An engineered T cell (center) is designed to deliver therapies to the brain. This T cell displays orange synthetic receptors on its surface that recognize components of extracellular matrix fibers that are found only in the brain. Within the cell, downstream signaling pathways are programmed to initiate transcription and release a therapeutic payload.
The central nervous system (CNS), which includes the brain and spinal cord, is notoriously difficult to treat due to the challenges of effectively delivering therapies across the blood-brain barrier.
This protective barrier shields the brain from harmful substances, but it also prevents many therapeutic molecules from reaching their target. In addition, therapies that reach the brain often affect other parts of the body, causing unwanted side effects.
To overcome these challenges, researchers are exploring a revolutionary strategy: using immune cells, particularly T cells, as delivery vehicles for targeted brain therapies.
T cells are a type of immune cell that play a crucial role in defending the body against infections and other threats. These cells are highly adaptable and can navigate through a variety of tissues, including the brain, in both healthy and diseased conditions.
T cells have the unique ability to recognize and respond to specific markers, called antigens, on the surface of cells. This ability makes them ideal candidates for delivering therapies directly to the brain, sparing other tissues from unnecessary exposure.
The research team, from the University of California San Francisco, hypothesized that it might be possible to “program” T cells to selectively deliver therapeutic molecules to the brain.
To achieve this, they identified antigens that are found exclusively or predominantly in the CNS. These antigens act as a “GPS signal,” guiding T cells to the brain. For example, one such antigen, brevican (BCAN), is a protein found exclusively in the brain’s extracellular matrix—a network that provides structural support to brain cells.
To enable T cells to recognize these antigens, the researchers engineered synthetic Notch receptors (synNotch). These receptors are designed to detect specific antigens, such as BCAN, and trigger a controlled response within the T cell.
When a synNotch-equipped T cell encounters its target antigen in the brain, it activates the expression of a therapeutic molecule tailored to treat the underlying condition. To test their approach, the researchers used these engineered T cells in mouse models of brain cancer and neuroinflammation.
1. Brain tumors:
The team programmed T cells to produce a chimeric antigen receptor (CAR) when they detect specific brain antigens. CARs allow T cells to seek out and destroy cancer cells. In mice with glioblastoma (a primary brain tumor) and metastatic breast cancer that had spread to the brain, these T cells effectively eliminated tumors without harming healthy tissue outside the brain.
2. Neuroinflammation:
Neuroinflammation plays a key role in diseases such as multiple sclerosis (MS). In a mouse model of MS, the researchers programmed T cells to release interleukin-10 (IL-10), an anti-inflammatory molecule, when they entered the brain. This targeted release of IL-10 reduced inflammation and improved symptoms, demonstrating the potential for treating inflammatory diseases of the CNS.
Programming tissue-sensing T cells to deliver therapeutics to the brain. (A) Engineered T cells that can recognize normal endogenous CNS-specific antigens using a synNotch receptor to induce production of therapeutic payloads specifically in the brain. For example, induction of a chimeric antigen receptor (CAR) could be used to target brain tumors, or induction of an anti-inflammatory cytokine such as IL-10 could be used to suppress neuroinflammation. This CNS-specific delivery system could be a general platform to treat a variety of CNS diseases without the risk of systemic toxicity. (B) When injected into a mouse, CNS-sensing T cells specifically expressed the synNotch-induced payload in the brain but not in the periphery (spleen). (C) In a mouse model of glioblastoma, CNS-sensitive T cells engineered to express an anti-ephrin type A receptor 2/IL-13 receptor α2 (EphA2/IL13Rα2) CAR efficiently and durably eliminated brain tumors. (D) In a dual-tumor model, CNS-sensitive T cells eliminated only the brain-implanted tumor (solid red line) but not a flank-implanted tumor expressing identical CAR-targeted antigens (dotted pink line). Thus, T cells are selectively primed only in the brain.
A key innovation of this strategy is its two-tiered specificity. First, the engineered T cells are activated only in the brain because they are engineered to recognize brain-specific antigens.
Second, the therapeutic molecule they deliver (such as CARs or IL-10) is highly targeted to the disease process. This dual specificity minimizes the risk of systemic side effects and increases the efficacy of the therapy at the target site.
This innovative approach demonstrates how immune cells can be harnessed to deliver therapies in a highly targeted and controlled manner. While the current focus is on CNS disorders, the concept could be extended to other tissues and diseases. By programming immune cells to integrate signals from the body and the disease environment, researchers hope to create safer, more precise and effective therapies.
This work represents a major step forward in the treatment of complex and challenging CNS disorders, offering hope for conditions ranging from brain tumors to neurodegenerative diseases. The ability to customize T cells for targeted delivery could open new doors in the fight against previously intractable conditions.
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Programming tissue-sensing T cells that deliver therapies to the brain
MILOS S. SIMIC, PAYAL B. WATCHMAKER, SASHA GUPTA,
YUAN WANG, SHARON A. SAGAN, JASON DUECKER,
CHANELLE SHEPHERD, DAVID DIEBOLD, PSALM PINEO-CAVANAUGH, JEFFREY HAEGELIN, ROBERT ZHU, BEN NG, WEI YU, YURIE TONAI, LIA CARDARELLI, NISHITH R. REDDY, SACHDEV S. SIDHU, OLGA TROYANSKAYA, STEPHEN L. HAUSER, MICHAEL R. WILSON, S. ZAMVIL, HIDEHO OKADA, AND WENDELL A. LIM
SCIENCE. 6 Dec 2024. Vol 386, Issue 6726
DOI: 10.1126/science.adl4237
Abstract:
To engineer cells that can specifically target the central nervous system (CNS), we identified extracellular CNS-specific antigens, including components of the CNS extracellular matrix and surface molecules expressed on neurons or glial cells. Synthetic Notch receptors engineered to detect these antigens were used to program T cells to induce the expression of diverse payloads only in the brain. CNS-targeted T cells that induced chimeric antigen receptor expression efficiently cleared primary and secondary brain tumors without harming cross-reactive cells outside of the brain. Conversely, CNS-targeted cells that locally delivered the immunosuppressive cytokine interleukin-10 ameliorated symptoms in a mouse model of neuroinflammation. Tissue-sensing cells represent a strategy for addressing diverse disorders in an anatomically targeted manner.
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