The daring doctor behind a world-first treatment for autoimmune disease
Huji Xu is part of Nature’s 10, a list of people who shaped science in 2024
Huji Xu’s team was on tenterhooks after delivering the first treatments. “We couldn’t sleep, because all these cases are very sick patients,” says Xu, a rheumatologist at the Naval Medical University in Shanghai, China, who published the first results of a revolutionary cellular therapy for autoimmune diseases in September (X. Wang et al. Cell 187, 4890–4904; 2024).
Two weeks after receiving engineered immune cells, the first patient — a woman with a debilitating disorder characterized by extreme muscle weakness — told nurses that she had regained enough strength to lift her arms and comb her hair. Two other recipients, both men, with a different condition, said that their symptoms began fading within days. More than six months later, all three recipients were in remission, according to Xu. “We are a little bit more relaxed” now, he says.
The engineered cells are known as chimeric antigen receptor (CAR) T cells and have been designed to hunt down and eliminate B cells, a type of immune cell that sometimes runs amok in people with autoimmune disorders. CAR-T-cell therapy is widely used to treat blood cancers involving malignant B cells, but it has also shown some promise for autoimmune diseases.
Last year, teams in Germany revealed that they had used CAR T cells to treat at least 15 people with several autoimmune conditions, with stunning success. Xu’s trial differs from these because it used cells taken from an independent donor, whereas the German teams used cells taken from the person being treated. If successful, the donor strategy could allow for mass production of CAR-T-cell treatments, reducing their costs and extending their reach.
Xu trained as a medical doctor in Shanghai. In 1990, he moved to Adelaide, Australia, to start a PhD in immunology and rheumatology, looking at the role of a specific antibody in rheumatic diseases — inflammatory conditions that affect the joints, muscles and bones. Xu went on to research a broad range of subjects, from the biological mechanism of lupus and several types of arthritis, to sudden infant death syndrome (SIDS) and malaria vaccines.
In 2008, he returned to Shanghai and established a large clinical and research centre for rheumatology. The CAR-T-cell trial was a good fit, says Xu, because of his interest in the underlying causes of rheumatic disease. The woman his team treated had refractory inflammatory myopathy. The men had a type of systemic sclerosis that causes the skin to harden and affects many organs.
“He is very brave,” says Du Bing, an immunologist at East China Normal University in Shanghai, who was part of the team that developed the cells used in the trial. Du and his colleagues used the CRISPR–Cas9 gene-editing tool to knock out five genes from donor T cells to prevent the grafted cells from attacking or being rejected by the host’s body. Du says they approached several doctors, asking them to try the cells for autoimmune disease. No one would take the risk, except Xu.
Xu’s willingness comes from his clinical experience and his familiarity with the background research, says Xin Lin, an immunologist at Tsinghua University in Beijing. Lin, too, has developed donor-derived CAR T cells and is collaborating with Xu on a similar trial to treat lupus. “He’s a very knowledgeable physician,” says Lin.
For the three people treated, the results were “beyond our imagination”, says Du. The cells took to their new hosts, and the recipients did not experience any of the dangerous side effects associated with CAR-T-cell therapy, such as cytokine-release syndrome, sometimes observed in people with cancer.
“It is an important and significant finding,” says Georg Schett, an immunologist at University Hospital Erlangen in Germany, who was involved in testing the patient-derived CAR-T treatments for autoimmune disorders.
Donor-derived CAR T cells are preferable to patient-derived cells, but they have shown only limited success in cancer treatment, probably because they don’t persist as long in the body as do those derived from the recipients themselves. Xu’s paper suggests that donor cells might work better in autoimmune disease, but as Schett points out, Xu and his colleagues have reported on only a small number of treated individuals and for only a short amount of time. For the donor-derived treatment to be valuable, the effect needs to be sustained, he says.
Xu’s team has since given similar treatments to another two dozen individuals with autoimmune diseases. He hopes that such treatments will become available to people even with mild forms of those diseases. “We have a plan,” Xu says. “We really want this to be widely used.”
doi: https://doi.org/10.1038/d41586-024-03895-0
This story originally appeared on: Nature - Author:Smriti Mallapaty
