• A UAB research team defines the criteria these immunotherapies must meet to advance both conceptually and in trials, which are still at a very preliminary stage
• They should have high selective precision and be programmable, sustained over time, and controllable throughout the pathologies. Macrophages, microglia and regulatory T cells would be appropriate effector cells for these treatments

The application of CAR immunotherapies to neurodegenerative diseases is limited by major challenges due to the complex nature of these pathologies and the heterogeneity of harmful molecules to be treated. Nonetheless, and despite uncertainties, the initial findings are encouraging to continue advancing research, still in its very early stages. This is the conclusion of a team of researchers from the Universitat Autònoma de Barcelona (UAB), in a review study published in the journal Trends in Pharmacological Sciences (Cell group).

CAR immunotherapies allow immune cells to be designed in the laboratory, with a high specificity to combat pathogenic molecules. This specificity is achieved by modifying the patient's immune cells with genetic engineering so that they express a synthetic protein on their membrane, called the Chimeric Antigen Receptor (CAR). This receptor recognises the target molecule and activates an immune response by the cell that expresses it. The modified cells also incorporate different intracellular signaling modules for their activation and safety.

In the article published, UAB researchers addressed the trials that have been carried out so far with CAR platforms for the treatment of neurodegeneration and analysed how different types of immune cells (effectors) could be used to modulate key processes, from the cleaning of toxic aggregates typical of diseases such as Alzheimer's and Parkinson's, to immune rebalancing.

This review allowed them to define what they consider to be the basic principles that these therapies should meet to continue advancing research. In addition to having high selective precision, they should be programmable, sustained over time, and controllable throughout various contexts of the evolution of pathologies. And they could be based on effector cells such as macrophages, microglia and regulatory T cells (Tregs). These cells would be more appropriate for the multifactorial and chronic nature of neurodegenerative disorders than T lymphocytes, another type of effector that is being used with CAR-T therapies in oncology to treat some types of cancer, mainly hematological, and some autoimmune diseases.

"In neurodegenerative diseases, rather than a simple and stable antigen to target, we have heterogeneous and evolving sets of aggregates and unfolded proteins of different conformations, aggregation states and toxicity, which are found in different regions of the brain and stages of the disease. These layers of complexity change the therapeutic goal of the CAR platforms we investigate, from eradication to controlled modulation", explains Salvador Ventura, professor of the Department of Biochemistry and Molecular Biology and researcher at the Institute of Biotechnology and Biomedicine of the UAB.

Key factors advancing research

Controlling the activation and inactivation of CAR platforms is emerging as a key factor in achieving high-precision 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", highlights Giulia Pesce, researcher at IBB-UAB and first author of the article.

In this sense, more and more control systems with logic gates are being designed, inspired by Boolean principles (AND, OR, NOT, etc.), but they are still in the conceptualisation phase for neurodegeneration. Platforms with on-off control and conditional secretion of therapeutic molecules seem, for now, the most appropriate architectures to address aggregates while limiting neuroinflammation and collateral tissue damage.

Another essential issue for advancing research is achieving greater molecular precision, for more robust binding of receptors to aggregates, and a better distinction between functional and toxic aggregates.

The authors also propose different approaches using effector cells depending on the stages of the disease and the objectives. Microglia and macrophages in the early stages of neurodegeneration, to clear toxic aggregates and limit their accumulation and spread, and Treg and microglia in later stages to favour immune balance and counteract inflammation. In more advanced stages, in which aggregate elimination strategies are insufficient, platforms with macrophages and microglia could be equipped with switchable systems that secrete immunomodulatory molecules or target other proteins to counteract the effects of the aggregates.

Overall, despite the preliminary nature of clinical data from in vitro and mouse cell models, "the findings made so far make immunomodulation based on CAR platforms increasingly plausible for the treatment of neurodegeneration", notes Salvador Ventura. "We are seeing that immune cell engineering, as in the case of a recent astrocyte-based CAR therapy, 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, applying more effective and durable cellular intervention strategies in the brain", he concludes.