Causing a secondary cancer may be an acceptable risk when treating a life-threatening cancer, but probably not for autoimmunity, says Matt Lunning, medical director for gene and cellular therapy at Nebraska Medicine in Omaha. How to balance the risk between the impacts of an autoimmune disease, which can range widely in severity, and the difficult-to-quantify risk of future side effects or cancers remains a major open question.

Researchers are already working on second- and third-generation versions of CAR T that they expect to be safer for both cancer and autoimmunity. For example, James Howard, a neuromuscular neurologist at the University of North Carolina at Chapel Hill, is testing a technology from a company called Cartesian Therapeutics that encodes the CAR using molecules of mRNA, the short-lived genetic messenger used in Covid-19 vaccines, instead of long-lasting DNA. The CAR T cells should wipe out B cells for only as long as the mRNA persists, then lose their B cell-targeting abilities. With no chance for genetically modified T cells to hang around long-term, there should be no cancer risk.

Another plus of Cartesian’s approach: Physicians infuse these T cells in sufficient numbers that they don’t need to reproduce in the patient’s body, which Howard thinks reduces risk for inflammation. In a recent trial, 15 people with autoimmune diseases received the Cartesian CAR T treatment; two-thirds saw their symptoms improve, and none suffered long-term serious side effects.

Treating CAR T sticker shock

Beyond side effects, the other major challenge facing CAR T therapy is its price tag, which reaches hundreds of thousands of dollars including hospital stays, cell engineering, and other expenses.

The treatment would likely be cheaper, and simpler, if scientists could eliminate the need for personalized engineering of each patient’s own cells and instead use donor cells, or if they could cut out the step of engineering and growing the cells in a laboratory. Lunning says he is eyeing up-and-coming procedures that would modify a person’s T cells within their own body ­instead of doing the genetic engineering in a lab.