A research team from the Universitat Autònoma de Barcelona (UAB) outlined on Apr. 8 the key criteria that chimeric antigen receptor (CAR) immunotherapies should meet to advance as treatments for neurodegenerative diseases, according to a review study published in Trends in Pharmacological Sciences.
The study addresses how CAR immunotherapies, which involve genetically modifying immune cells to target specific pathogenic molecules, face major challenges due to the complexity and variability of neurodegenerative disorders. Despite these difficulties and the early stage of research, initial findings encourage continued investigation into their potential applications.
UAB researchers reviewed existing trials using CAR platforms for neurodegeneration and analyzed how different types of immune cells could be engineered to modulate processes such as clearing toxic protein aggregates—characteristic of conditions like Alzheimer's and Parkinson's—and rebalancing immune responses. The team identified several essential principles for advancing these therapies: high selectivity, programmability, sustained function over time, and controllability across various stages of disease progression. They suggested that effector cells such as macrophages, microglia, and regulatory T cells may be more suitable than T lymphocytes typically used in cancer-focused CAR-T therapies.
Controlling activation and deactivation of CAR platforms is seen as crucial for precise immunomodulation. "The progressive nature of neurodegenerative diseases demands CAR systems capable of stable and sustained functionality without causing the accumulation of toxicity in the brain, an organ with low tolerance to inflammation and in which neuronal damage is irreversible," said Giulia Pesce, researcher at IBB-UAB and first author of the article.
The review also highlights ongoing development of control systems inspired by Boolean logic gates—such as AND or OR functions—to fine-tune therapeutic activity. While these are still conceptual for neurodegeneration, architectures featuring on-off switches or conditional secretion mechanisms currently appear most promising for targeting protein aggregates while minimizing inflammation.
Despite limited clinical data from laboratory models so far, Salvador Ventura said: "the findings made so far make immunomodulation based on CAR platforms increasingly plausible for the treatment of neurodegeneration." He added: "We are seeing that immune cell engineering... can open the door to intervene in Central Nervous System processes that were previously considered difficult or inaccessible to therapeutic intervention. If we manage to advance in the architecture of receptors and the safety control of CAR therapies, we could expand the therapeutic repertoire for neurodegenerative diseases beyond the limits of traditional pharmacology."
