Background

CAR-T cell therapy is a personalized cell therapy in which a patient's T cells are extracted, genetically modified, and cultured before being reinfused. Initially developed for cancer treatment, it is now expanding into strategies that reset the autoimmune system by eliminating B cells that produce autoantibodies or amplify inflammation.

The challenge lies in the complex ex vivo manufacturing process. From leukapheresis to gene introduction, cell expansion, and quality testing, the process requires specialized facilities, several weeks of time, and high costs. There is also a risk that sufficient T cells may not be obtained due to the patient's condition or prior immunosuppressive treatments. Antibody therapies such as rituximab can reduce B cells, but they often fail to deeply and persistently eliminate pathogenic cells in tissues.

Researchers at Tongji Hospital, Huazhong University of Science and Technology in China have moved this process into the body. They delivered genetic information directly into the patient's blood T cells, enabling them to produce CAR-T cells autonomously. The results were reported in the New England Journal of Medicine (NEJM).

Key Findings

The research team administered a single intravenous dose of a T-cell-targeting lentiviral vector to 16 patients with neurological autoimmune diseases who had not responded to previous treatments. Among them, 7 had progressive multiple sclerosis, and others had conditions causing muscle weakness or inflammation, as well as those affecting the brain, spinal cord, and optic nerve. The follow-up period was approximately six months.

The vector, designed by Shenzhen Genecuri BioTech, carried a CAR gene targeting the B-cell surface protein CD19. Once the vector entered the body's T cells, CD19-targeting CAR-T cells were generated and proliferated over time. There was no need to separately collect or culture cells and reinfuse them.

All 16 patients experienced complete depletion of peripheral blood B cells, and levels of autoantibodies attacking healthy tissues also decreased. Newly regenerated B cells did not show the presence of previous autoantibodies, suggesting the potential for immune system resetting. Patients with multiple sclerosis showed improvements in motor and cognitive function and fatigue levels, while those with muscle-invasive diseases showed improved muscle strength scores and reduced inflammatory markers. The research team evaluated the adverse effects as manageable.

While traditional CAR-T therapies require the manufacturing of cell-based drugs for each patient, this approach uses a storable vector to turn the patient's body into a production site. This is a significant difference in terms of production time and cost.

Implications and Outlook

These results represent an early proof-of-concept showing that in vivo CAR-T can induce B-cell depletion and clinical improvement in patients with refractory autoimmune diseases. If pathogenic B cells established in the central nervous system can also be eliminated, this treatment could potentially achieve long-term remission beyond repeated immunosuppression.

However, the study was non-randomized and involved only 16 patients with a follow-up period of about six months. Without a control group, it is difficult to confirm whether symptom improvement is due to the treatment. It is also too early to conclude that immune tolerance has been permanently restored. Since lentiviral vectors integrate the CAR gene into the cell genome, long-term monitoring for off-target cell transduction, insertional mutagenesis, and abnormal cell proliferation is necessary. The potential for infection or hypogammaglobulinemia due to the removal of CD19-positive normal B cells also needs to be considered.

Appropriate dosing per disease, duration of CAR-T persistence, and re-treatment strategies in case of relapse remain to be determined. Larger randomized controlled trials are needed to confirm efficacy and long-term safety before in vivo CAR-T can replace ex vivo manufactured CAR-T in practice.