A new experimental immune treatment produced remission in several patients with systemic lupus erythematosus, raising hopes that doctors may eventually have a simpler alternative to highly specialized CAR-T cell therapy for some people with severe autoimmune disease.
The treatment, called A-319, is designed to redirect a patient's own T cells toward B cells, which play a central role in lupus. Results from the small Phase 1 clinical trial were published September 10 in Nature Medicine.
Researchers treated 12 patients with active systemic lupus erythematosus, commonly known as lupus, and followed them for 52 weeks. The study was primarily designed to evaluate the safety and tolerability of the experimental therapy rather than determine whether it is effective in a large population.
Despite the study's small size, researchers reported encouraging signs of improvement. Of the 10 patients who could be evaluated for effectiveness at 12 months, eight reached what researchers call a Lupus Low Disease Activity State. Six of the 10 met established criteria for lupus remission.
Patients also experienced sustained reductions in measures of lupus activity, autoantibody levels and protein in the urine, an important marker of kidney involvement in lupus.
A-319 belongs to a class of treatments known as bispecific T-cell engagers. The drug is designed to attach to CD3, a molecule found on T cells, while simultaneously targeting CD19, which is found on B cells. That connection effectively directs T cells to attack and eliminate the targeted B cells.
B cells normally perform important functions in the immune system, including producing antibodies. In lupus, however, abnormal B-cell activity can contribute to the production of antibodies that mistakenly attack the body's own tissues.
At higher doses in the trial, A-319 produced complete depletion of circulating B cells. Researchers later observed what they described as a near-complete reconstitution of the B-cell population, suggesting that the immune system may be able to rebuild a healthier population after the abnormal cells are removed.
That possibility is particularly interesting because researchers have already seen dramatic responses in some patients with severe autoimmune diseases who receive CD19 CAR-T cell therapy.
CAR-T therapy involves removing a patient's T cells, genetically modifying them in a laboratory so they recognize a particular target and then returning those cells to the patient. The approach was originally developed to treat certain blood cancers but has more recently been investigated in severe lupus and other autoimmune diseases.
The process can be complicated, expensive and time-consuming. Patients generally require specialized medical facilities and typically receive chemotherapy to reduce their existing immune cells before the engineered CAR-T cells are infused.
A-319 could potentially avoid some of those complications.
Rather than creating an individualized cell therapy for each patient, A-319 is a manufactured drug that can be given intravenously. Researchers describe the approach as "off-the-shelf" because the same drug can potentially be administered to many different patients without first collecting and engineering their cells.
The patients in the trial initially received small priming doses of A-319, followed by treatment three times a week for three weeks. Researchers studied doses ranging from 0.3 to 1.2 micrograms per kilogram of body weight.
Safety was the primary focus of the study.
No treatment-related serious adverse events or deaths were reported, and researchers saw no severe cases of cytokine release syndrome or neurological toxicity. Cytokine release syndrome is an inflammatory immune reaction that can occur when T cells are strongly activated and is a known complication of some CAR-T and other immune therapies.
Eleven of the 12 patients did develop cytokine release syndrome, but the cases were predominantly classified as Grade 1, the mildest level. Researchers also reported minimal blood-related toxicity.
Laboratory analysis provided additional evidence that the treatment was doing more than simply suppressing symptoms.
Researchers performed detailed single-cell RNA sequencing of patients' immune cells and found widespread changes in immune activity following treatment. Some of those changes resembled the immune-system changes previously observed after CD19 CAR-T therapy for lupus.
The treatment reduced lupus-associated inflammatory signals across several types of immune cells, including B cells, T cells and myeloid cells. Researchers described the findings as evidence that the treatment may be capable of producing a broader "immune reset."
That idea could be important for the future treatment of autoimmune diseases.
Many current lupus medications work by continuously suppressing parts of the immune system. An immune-reset strategy instead attempts to eliminate the immune cells driving the disease and allow a healthier immune population to return.
Whether A-319 can reliably produce that effect remains uncertain.
The trial involved only 12 patients, and only 10 were included in the 12-month effectiveness analysis. There was also no placebo group, making it impossible to determine from this study alone how much of the improvement was directly caused by A-319.
Phase 1 trials are also generally too small to identify uncommon but serious side effects that might appear when hundreds or thousands of patients receive a drug.
The study was conducted by researchers associated with Union Hospital, Tongji Medical College at Huazhong University of Science and Technology and other institutions. The investigational drug and technical support were provided in part by iTabMed Ltd. Two researchers disclosed employment and equity interests in the company, and one is an inventor on a patent covering A-319. The academic investigators reported that they retained control over the analysis, interpretation and publication of the study.
A-319 remains experimental and has not been established as a standard treatment for lupus. The ongoing clinical trial is registered with ClinicalTrials.gov as NCT06400537.
Still, the results provide early evidence that it may be possible to reproduce some of the powerful B-cell-depleting effects seen with CAR-T therapy using a treatment that is considerably easier to manufacture and administer.
If the findings hold up in larger controlled trials, bispecific T-cell engagers could eventually offer researchers another way to pursue long-lasting remission in lupus without requiring a personalized cell therapy for every patient.