mRNA-based therapy creates CAR-T immune cells within the body

A new in vivo approach to chimeric antigen receptor T-cell (CAR-T) therapy could extend the technology’s use beyond cancer, as a treatment for autoimmune disease (Science 2025, DOI: 10.1126/science.ads8473). Approved for use in 2017, CAR T-cell therapy was a breakthrough in cancer treatment, and researchers have hoped to bring that same promise to autoimmune disorders.

Current approved CAR T-cell therapy treatments rely on an ex vivo route, in which a patient’s T cells are removed, genetically engineered to target antigens, and put back into the patient. From there, the CAR T cells destroy B cells, including harmful ones like cancerous cells or those that attack the body’s own tissues. By removing such B cells, CAR-T therapy can stop disease progression or help reset the immune system. Though the therapy is approved only for cancer, research suggests that it could also help people with B cell–driven autoimmune diseases.

But the current approach of personalized CAR T-cell engineering is not practical for the much larger population with autoimmune diseases. “Some of the limitations of CAR T cells are that they’re really costly, they’re difficult to manufacture, and they're difficult to scale,” says study coauthor Haig Aghajanian, cofounder and vice president of research at Capstan Therapeutics.

Researchers hope their off-the-shelf in vivo treatment will offer a more accessible alternative. Instead of modifying T cells outside the body, Capstan uses an in vivo messenger RNA (mRNA) approach to provide a set of instructions for cells to make CAR proteins to fight cancer and autoimmune diseases.

To get the mRNA to cells, the team encased it in lipid nanoparticles (LNPs), a common delivery method. But plain LNPs administered into the bloodstream accumulate in the liver, which in the case of CAR-T therapy isn’t beneficial, as there aren’t many T cells there to be edited, and LNPs can be toxic to the liver. To avoid this buildup, the researchers designed a new lipid, L829, to steer particles away from the liver and toward T cells. They also added antibodies to target CD8+ T cells.

In mice infused with a mixed population of immune cells from people with autoimmune diseases, B cells were depleted within 24 h and remained low for 14 days after treatment.

To test whether the treatment could tackle cancer, researchers implanted human tumor cells in mice. The animals that received the in vivo CAR-T treatment had almost total tumor clearance.

Similar results were seen in monkeys, a model more closely related to humans. After two doses of the treatment, B-cell counts were almost undetectable, and the B cells that returned were naive. That result suggests a potential immune system reset—a factor that will be important for treating autoimmune diseases.

“We’re getting really high levels of [B-cell] killing within hours, which was a huge surprise to us,” Aghajanian says.

Michel Sadelain, an expert in CAR T-cell therapy at the Columbia Initiative for Cell Engineering and Therapy, says he’s excited about the study’s potential for a new way to treat autoimmune diseases. But he cautions that “the non-human primates don't have a cancer or an autoimmune disease. The question still is, Is the treatment enough to make a significant impact on the disease state? We don't know yet.”

Capstan began a Phase 1 trial this month to test the treatment against autoimmune diseases.