Causing secondary cancers may be an acceptable risk when treating life-threatening cancers, but probably not for autoimmunity, says Matt Lunning, MD, medical director of gene and cellular therapy at University of Nebraska Medicine in Omaha. How to balance the risks between the effects of an autoimmune disease, whose severity can range widely, and the risk of future side effects or cancer that is difficult to measure, remains a major open question.
Researchers are already working on second- and third-generation versions of CAR T that they hope will be safe 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 CARs using mRNA molecules, the short-lived genetic messenger used in COVID-19 vaccines, instead of longer DNA. CAR T cells must eradicate B cells only as long as the mRNA persists, then lose their B cell-targeting capabilities. Since genetically modified T cells have no potential for long-term survival, there should be no risk of cancer.
Another plus of the Cartesian approach: Doctors infuse these T cells in sufficient numbers so that they don’t need to reproduce in the patient’s body, which Howard believes reduces the risk of inflammation. In a recent trial, 15 people with autoimmune diseases received Cartesian CAR T treatment; Two-thirds saw improvement in their symptoms, and none suffered long-term serious side effects.
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Apart from side effects, the other major challenge facing CAR T therapy is its cost, which reaches hundreds of thousands of dollars, including hospital stay, cell engineering and other expenses.
Treatment would potentially be cheaper and simpler if scientists could eliminate the need for personalized engineering of each patient’s own cells and use donor cells instead, or if they could reduce the engineering steps and grow the cells in the laboratory. Lunning says he’s keeping an eye on upcoming procedures that would modify a person’s T cells within their own body, rather than doing genetic engineering in a lab.
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