The 47-year-old woman was at the end of her rope.
In 2014, she was diagnosed with a rare form of anemia. Her body’s B cells, which normally produce antibodies to fight infections, had gone rogue, endlessly attacking oxygen-carrying red blood cells. Two other autoimmune disorders soon followed, one crippling her body’s ability to stop bleeding, the other increasing the risk of blood clots.
She had tried nine treatments. None helped. Her life was centered on blood transfusions, up to three daily, to keep the symptoms at bay. But constant fatigue made every day a struggle. The threat of deadly bleeding or blood clots loomed over her life.
Out of options, her care team tested an experimental treatment called CAR T cell therapy. They made a “living drug” out of the patient’s own T cells, editing the cells’ DNA so they would seek and destroy a specific biological enemy. Though CAR T is best known as a treatment for blood cancer, it’s also shown early promise in autoimmune disease. Trying to take on three conditions at the same time raised the bar, but it worked.
A single infusion of engineered cells rapidly killed off the misbehaving B cells. The woman was able to end blood transfusions within a week, and her red blood cell count was near normal in roughly a month. Her strength returned, and at the 11-month follow up, she was free of medication and able to enjoy life again.
“It was an entirely uncontrolled disease. And now she’s off any therapy. That tells you that, at least for now, we did something very right,” study author Fabian Müller at University Hospital Erlangen in Germany told Nature.
Runaway Train
The body’s B cells are powerful defenders. They watch for infections or cancer, generate antibodies to take out threats, and rally other immune cells to join the fight.
But sometimes B cells break down. Genetic mutations can lead to blood cancer. Some B cells struggle to produce antibodies, rendering them powerless to counter infection. And in autoimmune disorders, the cells mistakenly attack and damage healthy tissue—a kind of immune friendly fire—that can damage organs if left untreated.
In the woman’s case, malfunctioning B cells relentlessly attacked red blood cells, stripping them of their ability to carry oxygen. They also destroyed platelets—tiny, disc-shaped fragments in the blood that stem bleeding. The cells also attacked a protein that helps prevent clot formation.
This triple whammy ”can kill you very rapidly,” said CAR T pioneer Carl June at the University of Pennsylvania, who was not involved in the study.
Steroids to dampen the immune system didn’t work. Neither did antibodies that inhibit B cells or other classic autoimmune drugs. After attempting nine treatments and exhausting their options, the team offered CAR T cell therapy as a last resort.
CAR T drugs are usually made from a patient’s own T cells, genetically boosted to hunt down, grab onto, and destroy targets. Researchers originally developed CAR T for blood cancer, but efforts are underway to expand its use against solid cancers. In other studies, scientists have made these cancer-fighting soldiers directly inside the body to slash cost and time. Because CAR T cells can divide and replenish their numbers, a single dose could last over a decade.
The treatment is largely plug-and-play. The surfaces of all cells are dotted with protein beacons. Tumors have a unique protein signature. B cells have one too—a protein called CD19. Scientists have already had early success treating autoimmune diseases by designing CAR T cells that selectively hunt and destroy B cells.
A small CAR T trial in 2014 restored movement in patients with systemic sclerosis, a condition that causes tissue rigidity. Earlier this year, Müller helmed a clinical trial testing Zorpo-cel, T cells engineered to seek out CD19 in a variety of autoimmune conditions with promising results. Six months after treatment, all patients had ended their use of steroids and other treatments.
“For the very first time in severe autoimmune diseases, you actually have a treatment-free period,” Müller told Medscape at the time. “That is really a new perspective that has never been achieved before.”
One for All
Simultaneously tackling three autoimmune diseases was uncharted territory. Too many CAR T cells could trigger a deadly runaway immune reaction, which could risk even the brain.
The team turned to Zorpo-cel. They isolated the woman’s T cells and gene edited them to produce protein “hooks” targeting CD19 in the lab. The patient then underwent standard chemotherapy to wipe out most of her immune system. This step is obviously very tough on the body, but it’s needed to remove immune cells that would shut down CAR T.
A week after infusion, the woman’s red blood cells had rebounded, ending the need for blood transfusions. A month later, most of her disease-related blood work had improved, and she “experienced a rapid and remarkable increase in physical strength and has been able to carry out normal everyday activity,” wrote the team.
Now, a year on, she no longer needs the “two handfuls of pills” she took to manage the conditions. Her liver struggled at several points during the trial, but she avoided major immune reactions and other severe side effects. It’s not clear if the liver trouble was due to CAR T or lingering damage from earlier treatments.
Battling three autoimmune disorders with CAR T is unprecedented. But there are limitations. It’s a single-case study, and researchers will need to keep an eye on the patient’s health over time. Also, CAR T cells can dwindle and allow target cells to return. At the end of the study, the team found signs of newly formed B cells. However, they were “naïve,” in that they hadn’t learned to target normal tissues yet—and they may never learn.
Hundreds of CAR T clinical trials targeting autoimmune diseases are in the works. Multiple commercial companies have joined the race. “I think, within a year or two, there’s going to be approvals in the US,” said June.
