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Updated: Jun 10, 2025
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis
Jihane Frikeche1, Marion David1, Xavier Mouska1
1Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.
Abstract:
Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.
Insights
Researchers developed a novel Chimeric Antigen Receptor (CAR) T cell therapy using regulatory T cells (Tregs) targeting myelin oligodendrocyte glycoprotein (MOG) to treat multiple sclerosis (MS). This MOG-CAR Treg therapy shows promise for inducing long-lasting tolerance in MS patients.
Area of Science:
- Immunology
- Neuroscience
- Cell Therapy
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by immune-mediated myelin sheath destruction and neuronal damage.
- Current disease-modifying therapies for MS offer limited efficacy and do not halt disease progression, necessitating the development of personalized, long-term treatment strategies.
- Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a powerful tool in cancer treatment, offering high specificity and controlled cell administration.
Purpose of the Study:
- To adapt CAR T cell technology for autoimmune diseases by engineering regulatory T cells (Tregs) to induce tolerance in patients with multiple sclerosis.
- To develop and evaluate a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy as a potential treatment for MS.
- To assess the functionality, potency, and efficacy of MOG-CAR Tregs in preclinical models of MS.
Main Methods:
- Development of a second-generation CAR construct incorporating an anti-MOG single-chain variable fragment (scFv) screened from a human library.
- Engineering of autologous regulatory T cells (Tregs) with the MOG-specific CAR.
- In vitro characterization of CAR-dependent functionality and in vivo efficacy assessment using a passive experimental autoimmune encephalomyelitis (EAE) mouse model.
Main Results:
- Demonstrated CAR-dependent functionality of MOG-CAR Tregs in vitro.
- Showcased significant efficacy of MOG-CAR Tregs in a preclinical EAE mouse model.
- Confirmed low tonic signaling and a favorable signal-to-noise ratio, indicating a highly potent CAR construct.
Conclusions:
- The developed MOG-specific CAR Treg cell therapy represents a promising new therapeutic approach for multiple sclerosis.
- This CAR Treg strategy has the potential to induce long-lasting tolerance in MS patients by targeting a key autoantigen.
- Further investigation into MOG-CAR Tregs could lead to more personalized and effective long-term treatments for MS.
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