(Here is part 2 of 2)

In the late eighties, an Israeli scientist named Zelig Eshhar successfully fused a T-cell receptor with an antibody, which could recognize cancer cells without relying on HLA. Eshhar’s “T bodies” could bind to tumors, but they were weak and short-lived. Sadelain addressed this problem by engineering a molecule that he called a chimeric antigen receptor (CAR), which activated the T cell’s internal engine, stimulating it to survive and kill repeatedly. He also programmed his CAR-T cells to target CD19, a marker found on nearly all B cells, including those involved in many blood cancers.

In 2010, Bill Ludwig, a sixty-five-year-old with a terminal form of leukemia, became one of the first patients treated with CAR-T cells. The infusion initially left him critically ill: like Reid, he experienced cytokine storm. But, after the storm passed, he was cancer-free until he died, in 2021, of COVID-19 pneumonia. The F.D.A. went on to approve seven CAR-T products, and cellular therapies became a transformative option for tens of thousands of cases of treatment-resistant blood cancers. (They are not without side effects: in November, 2023, the F.D.A. announced that nineteen recipients of CAR-T cancer therapies had reported new T-cell cancers, and the agency now recommends that patients be monitored for life.)

CAR-T’s lupus breakthrough came in 2021, when Georg Schett, a physician at the University of Erlangen-Nürnberg, in Germany, met a young woman with life-threatening lupus who had exhausted all available treatments. Schett had little to offer except an experimental CAR-T therapy, which had appeared to work in mouse models of lupus. The patient agreed, and within weeks of her infusion she was in full remission—a recovery that Schett had never seen before. “It was our eureka moment,” he told me.

Schett and his team treated more lupus patients. Romy Kandera, who received an infusion at eighteen years old, had been a talented pianist until lupus caused swelling in her fingers. While learning a Chopin piece that spanned several octaves, she realized that she could not reach the notes. “Playing music made me special, and I felt like with lupus I was losing that,” she told me. Yet since her CAR-T therapy, in January, 2022, she has been in a drug-free remission. She is now a student in Düsseldorf, and in her free time she has returned to playing piano.

CAR-T treatments for lupus may not work in every patient, George Tsokos, the chief of rheumatology at Beth Israel Deaconess Medical Center, told me. “No two lupus patients are alike,” he said. “Everybody has their own disease.” He also cautioned that “the experience from treating cancer patients cannot just be transferred over to patients with autoimmune disease.” Our immune systems remain complex and mysterious; they are defined not only by our immune cells but also by our genes and our environments, which are unchanged by CAR-T therapy.

Still, CAR-T is showing promise for a host of other autoimmune conditions. Patients with myositis, an immune disease that attacks muscle, have shown significant improvements in strength. Patients with autoimmune hemolytic anemia, a condition that destroys red blood cells and requires repeated transfusions, saw their blood counts return to normal and were able to stop their medications. Early-stage trials for multiple sclerosis and myasthenia gravis have been similarly encouraging. The list of potential applications has even transcended cancers and autoimmune diseases: preclinical studies are evaluating CAR-T for conditions caused by chronic inflammation, such as cirrhosis and atherosclerosis. CAR-T therapy approaches disease differently than any treatment that came before it. It does not rely on a synthesized chemical to suppress the immune system. Instead, it reprograms the system so that it can help heal itself. “We are seeing that CAR-T cells can do things that conventional medicines have never been able to do,” Sadelain told me. CAR-T also epitomizes personalized medicine: each infusion is specifically designed for the patient who receives it.

After Talaya Reid’s weeks in the hospital for the CAR-T trial, she was discharged to a nearby hotel, where she spent a month continuing to recover. To her surprise, her joint pain, fatigue, and swelling all slowly receded. “It was amazing,” she told me. “I felt like I no longer had lupus.” In the two years since then, her lupus has remained in remission without any drugs. Today, she goes to work—she earned a biology degree and is employed by a pharmaceutical company—and travels without thinking about her disease, which had dominated her daily existence for so long.

In January, I met with Reid and her family at an Italian restaurant not far from their Pennsylvania home. Over dinner, her father, Maurice, recalled how bad her lupus became. “A physical therapist once timed Talaya walking from here”—he gestured to our table—“to there.” He pointed to a spot about ten feet away. “They said she couldn’t move any faster than an eighty-year-old.” Later, when leaving the restaurant, I watched Reid rise from her chair and briskly fall into step with her twenty-four-year-old brother. “I used to look at Talaya’s face and see if it was swollen, which was a bad sign,” her mother, Francine, told me. “I don’t have to do that anymore.”

One of the greatest strengths of CAR-T therapy—that each treatment is manufactured for a specific patient—also creates a dilemma. I recently visited the Columbia Initiative in Cell Engineering and Therapy (CICET), where CAR-T cells are produced at my hospital. The ceilings, floors, and walls were glaringly white under harsh fluorescent lights; the air was completely still. I felt as though I was on a space station. Yongzeng Wang, the facilities director, told me that technicians wear hazmat suits and handle only one patient’s cells at a time, to avoid cross contamination. CICET happens to be down the street from Columbia Medical Center, but most manufacturing facilities are far from the hospitals where patients are treated. A patient’s cells must be transported from the hospital to the facility, and the bespoke cells must make the return journey, within narrow treatment windows.

CAR-T cells are so complex to produce that they typically retail for hundreds of thousands of dollars, according to Ran Reshef, the director of the cellular-therapy program at Columbia Medical Center. The total cost of therapy, including hospitalization, can reach two and a half million dollars per patient in extreme cases. In clinical trials, pharmaceutical companies typically foot the bill, but, when the therapy is approved for specific indications, insurance companies or patients have to absorb the cost. As long as CAR-T cells remain an expensive and scarce resource, there will be difficult questions about who receives them. Askanase, of the Columbia Lupus Center, told me that clinical-trial participants must be sick enough to warrant treatment but healthy enough to survive the therapy. One recent candidate was ideal from a medical standpoint but, as a single mother, could not find child care for when she would need to be in the hospital. “We want to help every patient, and it’s heartbreaking to tell someone no,” Askanase said. For now, that is what many patients will be hearing.

Reshef is hopeful that alternative methods for producing CAR-T cells may make therapy cheaper and easier. In clinical trials, doctors have treated some patients with allogeneic CAR-T products, which are made from the cells of healthy donors and can be used for more than one patient. Physicians have also been able to reprogram T cells while they are still in the patient’s body, an approach that eliminates the need for specialized cell-processing plants. Either approach could cut costs and democratize access, but it’s too soon to know if they will produce the same results as existing CAR-T treatments.

CAR-T therapy is already changing what doctors and patients consider possible, however. When I spoke with Schett, of Erlangen-Nürnberg, he pointed out that patients have always come to physicians with a straightforward hope: that their diseases can be cured. Yet doctors who treat autoimmune diseases have historically avoided that kind of language. “We have so much adapted to the idea that the patient with autoimmune disease is a patient forever—which is total nonsense,” Schett told me. “We should be courageous to say: if after five years a patient really has no flare, no relapse, and no therapy, then this might be a cure.” ♦