Published On June 18, 2018
AFTER NEARLY TWO DECADES OF CLINICAL TRIALS, the first gene therapy was approved in the United States in August 2017. It is a landmark in immunotherapy, which enlists the body’s own immune cells to fight disease (“Kept at Bay,” Fall 2015). The new treatment, chimeric antigen receptor (CAR) T-cell therapy, was developed at the University of Pennsylvania and uses modified immune cells to treat blood cancers. It has succeeded in some cases where standard methods have failed.
“People who were on their deathbeds with no chance of survival now have an 80%, even 90% chance,” says Samuel Katz, a hematopathologist researching CAR T cells at the Yale School of Medicine. But these new treatments are far from perfect, he says, and new methods are needed to head off dangerous side effects and to bring down costs.
In CAR T therapy, physicians remove some of a patient’s T cells—a type of immune cell—and rewrite the cells’ DNA by means of a disarmed virus. This causes the cells to begin producing CAR proteins. The cells are then returned to the patient’s body, where those proteins lock on to cancer cells so that T cells can finish them off.
While the therapies are effective, they have drawbacks. CAR T therapies are costly, at more than $475,000 per patient. And even after the cancer has been eradicated, the CAR T cells continue to reproduce and may attack healthy cells. This creates a risk of autoimmune disease, which can cause fevers, neurological damage and other organ dysfunction.
But gene editing isn’t the only way to get T cells to make CAR proteins, says Katz. The current approach changes the cell’s DNA “blueprint,” ensuring that it will always produce CAR. A less permanent solution would be to send a one-time message to the ribosome, the part of a cell that creates proteins. This message would be in the form of mRNA—a type of cellular communication that Peter Rabinovich, Katz’s colleague at Yale, learned to forge in the early 2000s.
An mRNA message would last only about an hour, after which the cell would stop producing CAR proteins. The proteins produced in that short time would stay on the outside of the cell, doing their job, until they degraded in three to five days, at which point the cell would return to normal.
This temporary approach could prevent CAR T cells from overstaying their welcome. “If you have any toxicity from the mRNA treatment, you’d expect that it would be very short-lived,” says Nabil Ahmed, who researches CAR T therapies at Baylor College of Medicine in Houston.
Using mRNA reprogramming also has potential cost advantages. The virus-infected CAR T cells needed for today’s treatments must be custom designed, tested and manufactured for each patient, a cumbersome process that has halted the development of some gene therapies and slowed others down by years.
In contrast, synthetic mRNA is relatively cheap and easy to manufacture, requiring little in terms of specialized equipment or ingredients. It could be mass-produced and used on a wide range of patients. Ahmed explains, “mRNA is a drug. It can be made and put in a bottle.”
While using mRNA to make CAR T cells might take a few days, says Katz, “virus-reprogrammed CAR T cells take weeks or even months to prepare. And sometimes patients don’t have that kind of time.”
Some experts are skeptical about an mRNA approach, however. “My concern would be that it wouldn’t last long enough,” says Helen Heslop, president of the American Society of Gene & Cell Therapy. “Short-term persistence may not be sufficient to control the cancer.”
The scientific jury is still out regarding how long CAR T cells need to remain in the body, says Katz, although multiple doses of mRNA-reprogrammed cells might be given until the cancer is eradicated. Neither he nor Ahmed, however, can say whether multiple doses of mRNA cells would be as effective as the existing approach to gene therapy.
Other methods for making safer CAR T cells are also under way, so if the promise of mRNA isn’t borne out, alternatives are in the wings. “The CAR T cells we’re using today are going to be viewed as primitive in fewer than five years,” predicts Michael Bishop, who oversaw early CAR T clinical trials as director of the cellular therapy program at the University of Chicago Medical Center: “With the next generations in development, we’ll be able to turn them on and off, enhance them and have greater efficacy in treating cases that we once viewed as hopeless.”
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