Faulty immune cells that could not distinguish friend from foe and kept sniping at their own side were wiped out by immune sheriffs made inside the body. Genetically modified T cells subdued B cells that had been attacking healthy cells instead of external pathogens.
A team led by Professor Dai-Shi Tian of Tongji Hospital at Huazhong University of Science and Technology in China said on the 2nd (local time) in the New England Journal of Medicine (NEJM) that "patients with a range of autoimmune diseases, including multiple sclerosis, produced their own CAR-T cells and restored their immune systems to normal without serious side effects."
Multiple sclerosis is an autoimmune disease that occurs when antibodies secreted by B cells attack myelin, the protective sheath around the spinal cord and nerve cells, instead of targeting invaders. As a result, nerve signals fail to transmit properly, the whole body stiffens, and even vision is damaged.
◇ Producing cell therapies inside the body
CAR-T cells means "T cells with chimeric antigen receptors (CARs)." Like a chimera, a mythical beast with traits of multiple animals, it means genes enabling T cells to find antigen proteins on cancer cell surfaces are combined with them. CAR-T cells have already been commercialized as treatments for blood cancers.
The team induced patients' bodies to produce CAR-T therapies directly, rather than making them in the lab as before. It is an "in vivo strategy." First, they loaded the genetic information to make CAR-T cells into a lentivirus and injected it into patients. The virus delivered DNA to patients' T cells to identify rogue B cells.
The clinical trial enrolled 16 patients with various autoimmune diseases, including seven with multiple sclerosis, as well as myasthenia gravis and neuromyelitis optica spectrum disorder. It included patients with diseases that weaken muscles and cause inflammation, or in which the immune system attacks the brain, spinal cord, and eyes. The researchers gave patients a single injection of the viral vector carrying the CAR-T gene and followed them for six months.
As CAR-T cells formed in patients' bodies, the levels of B cells that had been attacking normal cells and the antibodies they secreted decreased. Patients with multiple sclerosis showed improved motor and cognitive function and reduced fatigue. Patients with other autoimmune diseases affecting muscles also saw their muscle strength scores improve and inflammation decrease.
The risk of side effects appeared manageable. Mild inflammatory responses occurred but mostly did not persist for more than two weeks. Three patients had mild to moderate drops in white blood cell counts, which later returned to normal. Notably, when CAR-T cells eliminated rogue B cells, B cells that do not attack normal cells increased. This means the immune system was reset to normal.
◇ Shorter production time and lower costs expected
Once infused, CAR-T cells proliferate and keep killing cancer cells, earning nicknames such as "living drugs" and "serial killer" of cancer cells. The U.S. Food and Drug Administration (FDA) has approved seven CAR-T therapies, from Novartis' Kymriah in 2017 to Autolus' obecabtagene autoleucel last year. All were authorized to treat blood cancers in which B cells that should protect the body become cancerous.
Following blood cancers, CAR-T therapy is being tried on solid tumors in organs, such as breast and lung cancers. Recently, there is hope that CAR-T cells can even treat autoimmune diseases, which are intractable chronic conditions. In June, University College London (UCL) Hospital said it had cured lupus, an autoimmune disease that causes skin rashes, with CAR-T cells.
The problem is time and money. Existing CAR-T therapies cost an average of $500,000 because they are made through complex processes at specialized facilities. CAR-T therapy starts with collecting a patient's blood and extracting T cells. Then DNA is delivered to T cells to produce proteins that bind only to antigens on B cell surfaces. At this point, a harmless virus is used as a gene delivery vector. When these genetically modified CAR-T cells are massively expanded and reinfused into the patient, they bind to and eliminate rogue B cells.
The clinical trial results showed that the complex CAR-T production process can be handled entirely inside the body. In other words, it is like building a factory right where the medicine is needed to see therapeutic effects sooner and drastically cut production and logistics costs.
Professor David Simon of Charité – Universitätsmedizin Berlin said it was "a very encouraging proof-of-concept study for in vivo CAR-T therapy," adding, "Compared with lab-made CAR-T therapies, the in vivo approach is cheaper and faster to produce." Immunologist Bing Du of East China Normal University said, "Developing in vivo CAR-T therapy is a major achievement," adding, "These results compare well with ex vivo CAR-T therapy outcomes."
Scientists have broadened the treatment range of CAR-T therapies while advancing manufacturing technologies. Last year, Du used donor T cells engineered into CAR-T cells to treat a lupus patient who had not responded to existing drugs. Also last year, a team led by Professor Carl June at the University of Pennsylvania's Perelman School of Medicine presented a new method of delivering messenger RNA (mRNA), which is a copy of DNA information, directly to T cells in the body to produce CAR-T cells in vivo. The mRNA approach has already proven effective in coronavirus vaccines and has the advantage of not needing viral vectors.
References
NEJM (2026), DOI: https://doi.org/10.1056/NEJMc2603114