A risky cancer treatment can be modified to treat immune diseases

Immunotherapy—cajoling the body’s immune system into attacking cancerous cells it might otherwise ignore—has, over the past decade, joined chemotherapy, radiation, targeted drugs and surgery as one of the pillars of cancer treatment. But tinkering with the immune system has other uses. They may include treating the immune system itself.

In a paper in The Lancet Neurology, James Howard Jr of the University of North Carolina at Chapel Hill and Tahseen Mozaffar of University of California, Irvine, describe how immunotherapy might be used to correct an immune system that has itself gone haywire. The researchers aim to use it to battle myasthenia gravis, an auto-immune disease that causes a sufferer’s immune system to attack the connections between nerve cells and muscles, resulting in weakness and frailty.

Known as CAR–T therapy, the technique in question aims to replace a chunk of a patient’s immune system with an artificially enhanced substitute. It targets T-cells, one of several different types of cell that make up the human immune system. These are removed from the patient’s body, modified to more aggressively attack cancerous cells, and reintroduced. But the procedure is risky. Patients are given chemotherapy to wipe out their unmodified T-cells, in order to help the tweaked ones proliferate when they are put back. With the immune system deliberately suppressed, acquiring even a mild infection can be dangerous.

And although the modified cells reliably kill their targets, they also release lots of immune-signalling chemicals called cytokines, which can trigger inflammatory responses, from mild fevers to difficulty in breathing. The responses can occasionally be fatal. And the procedure is designed to be permanent. Once a patient’s natural T-cells have been replaced with the modified sort, the replacements will persist for life. These drawbacks limit the use of CAR–T therapy to only the most lethal cancers.

But Drs Howard and Mozaffar think they may be able to have the benefits without the drawbacks. The key is to make the reprogramming temporary. Standard CAR–T therapy involves modifying the DNA that resides in a T-cell’s nucleus. When the engineered T-cells reproduce, their new instructions are reproduced with them.

The researchers made use instead of messenger RNA (mRNA). Ordinarily this molecule conveys instructions from the DNA in a cell’s nucleus to the ribosomes, cellular machines that use that information to assemble whichever protein the nucleus has ordered. Being a mere messenger molecule, mRNA is never integrated into a cell’s genome. That means that a modified cell’s descendants will not inherit the new instructions that the parent was given. And since the treatment is designed to be temporary, there is no need to destroy a patient’s existing T-cells to make room for the modified ones.

The researchers gave their therapy to 12 patients over the course of three to six weeks and monitored them for another six months. The treatment seemed to be both safe and well tolerated. The engineered T-cells also seemed to be attacking the rogue immune cells. Three patients dropped out of the trial. Of the nine remaining, eight saw meaningful decreases in the severity of their illnesses. In three, symptoms vanished entirely.

And what is good news for sufferers of autoimmune diseases may well be good news for cancer patients, too. If the drawbacks of CAR–T can be mitigated, then it may make sense to expand its use to other cancers. Whether that would require patients to be periodically topped up with modified T-cells isn’t yet clear. But given the choice between additional visits for long-lasting efficacy or chemotherapy and risk of cytokine over-reactions, most would probably plump for the former. ■