CAR natural killer-cell therapy shows potential for treating refractory lupus

medwireNews: Allogeneic chimeric antigen receptor (CAR) therapy with natural killer (NK) cells could be “a potent option” for treating people with refractory or relapsed systemic lupus erythematosus (SLE), say Chinese researchers.

In a first-in-human investigation involving 18 adults with moderate-to-severe SLE, who were treated with CD19-targeting CAR NK-cell therapy, there were no dose-limiting toxicities and no neurotoxicity or other severe adverse events. There was one (6%) case of grade 1 cytokine-release syndrome reported in a patient who received the highest dose.

Moreover, of nine patients who had more than 12 months’ follow-up, 67% attained DORIS remission, which is defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 0 points and a Physician’s Global Assessment score (PGA) below 0.5 points. And 67% attained a lupus low disease activity state (LLDAS), which is defined as a SLEDAI-2K of 4 points or less and no major organ activity, with a PGA of 1.0 point or lower.

“This study suggests that allogeneic CAR NK-cell therapy is a potent option for treatment of autoimmune diseases,” write Dongbao Zhao (Changhai Hospital, Shanghai) and co-authors in The Lancet.

Zhao et al propose that allogeneic CAR NK-cell therapy could be a potential alternative to autologous CAR T-cell therapy and address the latter’s limitations of “manufacturing scale and time, access, safety, and cost.”

During the ongoing, open-label, prospective study, 17 women and one man with refractory or relapsed SLE were recruited between August 2023 and June 2024. The patients had received at least two prior standard systemic therapies, which included biologics in 78% of cases.

The mean age of the participants was 37.5 years, and the median duration of disease was 10.5 years. All the patients had a SLEDAI-2K score above 8 points at baseline, and severe organ involvement according to British Isles Lupus Assessment Group (BILAG) 2004 criteria.

The researchers explain that the CAR NK cells used in the study were derived from cord or peripheral blood mononuclear cells that were mismatched for human leukocyte antigens taken from healthy donors. The cells were then activated and transduced with a CAR gene-carrying retrovirus and expanded for 16 days before being cryogenically preserved to enable storage and shipment.

All patients were given daily conditioning chemotherapy consisting of intravenous fludarabine 25 mg/m² and intravenous cyclophosphamide 300 mg/m² for 3–5 days before starting the CD19 CAR NK-cell therapy.

After thawing, the CD19 CAR NK-cell therapy was given as one cycle of three sequential infusions, with participants receiving one of four different dosing levels, 0.75 × 10⁹ cells, 1.5 × 10⁹ cells, 3.0 × 10⁹ cells, or 4.5 × 10⁹ cells, at infusion intervals of 3, 5, or 7 days according to lymphocyte recovery and the pharmacokinetics of the CAR NK cells.

Long-term safety monitoring over a median of 11 months showed “no disease flares or treatment-related adverse events,” report the researchers.

At 6 months, rates of DORIS remission and LLDAS were 59% and 77%, respectively, and all 17 evaluable patients achieved SLE Responder Index (SRI)-4 criteria, 94% SRI-6, and 71% SRI-8. And at 12 months, all nine evaluable patients met SRI-4 and SRI-6 criteria, and 78% met SRI-8 criteria.

Zhao et al say that “it is critical” to acknowledge that allogenic CD19 CAR NK-cell therapy and autologous CAR T-cell therapy have different efficacy profiles. “CAR NK-cell therapy demonstrated slower kinetics in achieving [double-stranded]DNA antibody seroconversion and did not induce DORIS remission in all patients.”

In a related editorial, Alberta Hoi (Monash Health, Melbourne, Victoria, Australia) observes that the study “offers early proof-of-concept,” for a potential “off-the-shelf cell therapy.”

However, she observes: “Key questions remain regarding optimal dosing, conditioning protocols, and the mechanisms underpinning duration of immune reconstitution.”

In addition, the study “lacks a formal dose-response analysis,” and, as it involved a single-site, “external validation is required to confirm the generalisability of these findings,” the editorialist points out.

Hoi concludes: “Nonetheless, this study marks an important step forward in the clinical translation of CAR-based therapies for autoimmune diseases.”

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Lancet 2025; doi:10.1016/ S0140-6736(25)01671-X
Lancet 2025; doi:10.1016/ S0140-6736(25)01949-X