CAR-Ts sweep into autoimmunity

The promising results and the safety profile demonstrated in preliminary clinical studies are driving several biotech companies and academic centres to explore CAR-T cells to target autoimmune disorders, rather than just blood cancer. Indeed, in March 2024, the first clinical results demonstrated the ability of modified CAR-T cells to reduce pathogenic B cells in multiple sclerosis patients. Moreover, a phase 1 trial revealed that CAR-T therapy completely eradicated all autoantibodies in 11 out of 12 treated patients with systemic lupus erythematosus (SLE). Interestingly, individuals who responded to the treatment went on to remain medication- and disease-free for up to 4.5 years.

CAR-T therapy – how does it work?

CAR-T treatments are biologic drugs, based on T-lymphocytes genetically engineered to produce chimeric antigen receptors (CARs) that identify a specific target. After being reinfused in the patient, they detect and eliminate their antigen by activating the immune system’s response. Nowadays, CAR-T cells offer a treatment option for patients suffering from oncohaematological diseases by successfully eliminating pathogenic B cells responsible for leukemias. Considering that B cells are key drivers of autoimmune disorders, clearing out B cells of autoimmune patients could provide a potential therapeutic approach also for this condition. In order to remove disease-causing B cells, CAR-T lymphocytes are engineered to address B cells that express CD19 or B cell maturation antigen (BCMA). Although, these are the same targets recognized by monoclonal antibodies, the chronic administration of antibody-based therapies put patients at a persistent risk of serious infection.

Current CAR-T cells targeting autoimmunity

In this context, Kyverna has explored the possibility of safely eliminating B cells from the central nervous system using autologous CAR-T cells to treat multiple sclerosis. Their medication KYV-101 was administered to patients whose condition did not improve with Ocrevus (ocrelizumab). When compared to conventional monoclonal antibodies, KYV-101 truly exhibits a unique impact on this condition. Kyverna is undertaking its own phase 2 trial in the US and Europe and collaborating with academics from Stanford University on a phase 1 trial in the US. Alternatively, Cartesian Therapeutics is creating T cells that are only transiently expressing BCMA-directed CARs. This methodology allows to overcome patients tedious lymphodepletion and hospital stays prior to infusion, obstacles that have impeded the use of CAR-T for larger patient populations. The product Descartes-08 is in phase 2 trials for SLE and the muscular weakness disorder myasthenia gravis. Researchers at Columbia University are developing CAR-engineered T cells, named chimeric auto-antibody receptor (CAAR) T cells, able to address only B cells producing autoantibodies. Indeed, CAR-T therapy deplete all B cells expressing that target, although just a tiny fraction of the B cells is misbehaving, leaving patients at risk of infection until B cells are regenerated. This approach could maintain the lasting efficacy of standard CAR-T cells removing the side effects of global immunosuppression.

By Ramona Stringhi, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan

Source:

Link: https://www.nature.com/articles/s41587-024-02321-0

Doi: https://doi.org/10.1038/s41587-024-02321-0