On November 13, 2025, The Lancet, the world's top medical journal, published a landmark research result by the team of Professors Zhao Dongbao and Gao Jie from the First Affiliated Hospital of Naval Medical University as an original article—the world's first systemic application of off-the-shelf CD19 CAR-NK cell therapy (KN5501) in the treatment of refractory systemic lupus erythematosus (SLE). With 67% of patients achieving complete remission and excellent safety profile, this breakthrough has completely broken the long-standing treatment dilemma of the disease characterized by "refractoriness, high recurrence rate and severe side effects". It marks that China has become a global leader in the field of cellular therapy for autoimmune diseases, lighting a beacon of hope for millions of patients worldwide.
The "Immortal Cancer": The Dilemma in the Diagnosis and Treatment of Refractory Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that seriously endangers human health. Dubbed the "immortal cancer" in the medical community due to its protracted course, frequent relapses and irreversible multi-organ damage, it most commonly affects women of childbearing age between 15 and 45 years old. There are approximately 3.41 million SLE patients worldwide, with the incidence rate in women being 7 to 9 times that in men.
The core pathological mechanism of SLE lies in immune system dysfunction, where the body produces a large number of autoantibodies that mistakenly attack various organs and tissues such as the skin, joints, kidneys and blood system. This causes patients to suffer from persistent fatigue, skin rashes and joint pain, and in severe cases, can lead to life-threatening complications such as renal failure and cardiovascular diseases. Within 5 years of diagnosis, more than 40% of patients develop irreversible organ damage, and refractory cases account for about 25% of all SLE patients.
For a long time, the treatment of SLE has been mainly based on glucocorticoids and immunosuppressants. Although biological agents have been introduced into clinical practice in recent years, more than half of patients still do not respond to existing treatments or experience frequent disease relapses. More troublingly, long-term use of glucocorticoids and immunosuppressants can lead to severe adverse reactions such as avascular necrosis of the femoral head, diabetes and infections, which seriously affect patients' quality of life and work capacity, and even put some patients in a dilemma of "treatment equals harm".
The much-discussed CAR-T therapy has shown curative potential in the field of autoimmune diseases, but its "customized" nature results in complex preparation processes, long production cycles and high manufacturing costs. Additionally, it is prone to serious safety risks such as cytokine release syndrome and neurotoxicity, making it difficult to benefit ordinary patients on a large scale and becoming a major bottleneck restricting its clinical application.
Technological Innovation: The Solution of Off-the-shelf CAR-NK Therapy
Faced with the clinical predicament, the team of Professors Zhao Dongbao and Gao Jie spent two and a half years on in-depth research and innovatively selected natural killer (NK) cells as effector cells to replace T cells used in traditional CAR-T therapy, successfully developing the off-the-shelf CD19 CAR-NK cell drug KN5501, which fundamentally solves many problems of traditional treatments.
To understand the significance of this breakthrough, it is essential to clarify the core principle of CAR-NK therapy. NK cells are core members of the human innate immune system, accounting for about 10-15% of human peripheral blood lymphocytes. They can rapidly recognize and attack abnormal cells without prior identification or specific training, serving as the first rapid line of defense in the immune response. Chimeric Antigen Receptor (CAR), on the other hand, is an engineered "targeting-activation" integrated receptor that equips immune cells with a "navigation system" to precisely lock onto target cells.
CAR-NK therapy involves genetically modifying NK cells derived from healthy donors (which can be obtained from cord blood or peripheral blood) in the laboratory by introducing a CAR receptor targeting CD19, followed by ex vivo expansion and reinfusion into patients. These "upgraded" CAR-NK cells can not only precisely recognize and eliminate pathogenic B cells expressing CD19—the core cause of SLE—through the CAR structure, but also achieve efficient and multi-pathway immune regulation by virtue of the natural killing mechanism of NK cells themselves.
Compared with CAR-T therapy, KN5501 has three core advantages. First, its "off-the-shelf" feature eliminates the need for customized preparation for each patient. NK cells from healthy donors can be used for large-scale batch production and on-demand use, which greatly reduces treatment costs—its expense is only about one-tenth of that of autologous CAR-T therapy. Second, it has higher safety: NK cells have a weak ability to secrete cytokines, leading to an extremely low risk of cytokine release syndrome. Moreover, allogeneic NK cells do not cause graft-versus-host disease (GvHD) and can be safely applied without additional genetic editing. Third, it has a short preparation cycle, avoiding long waiting times and enabling refractory patients to receive treatment quickly.
In addition, the research team adopted a unique HTAS-RV delivery system and NK cell expansion and cryopreservation technology, which further improved the stability and efficacy of CAR-NK cells and laid a solid foundation for clinical translation. Before CAR-NK cell infusion, patients receive short-term lymphodepletion conditioning to create a "space" for the infused CAR-NK cells, reduce immune rejection and further enhance treatment efficacy.
Clinical Evidence: 67% Complete Remission and Safety Exceeding Expectations
This world's first human clinical study on allogeneic CAR-NK cell therapy for lupus enrolled 18 patients with relapsed and refractory moderate-to-severe active SLE, with a median follow-up time of more than 12 months and the longest follow-up reaching 18 months, delivering encouraging clinical outcomes.
In terms of efficacy, among the 9 patients with more than 1 year of follow-up, 6 (67%) achieved complete DORIS remission and reached a state of low disease activity of lupus without any relapses. At 6 months after treatment, the condition of all patients was effectively controlled: 13 patients maintained low disease activity and 10 achieved complete clinical remission. More importantly, patients' mental state, quality of life and work capacity were significantly improved, and some patients have resumed normal work. This indicates that the therapy can not only control symptoms but also achieve long-term disease remission through immune reconstitution, rather than just temporary symptomatic treatment.
In terms of safety, the therapy demonstrated an excellent safety profile and completely avoided the severe side effects of traditional treatments. Among all 18 patients, only 1 (6%) developed grade 1 cytokine release syndrome, manifested as transient fever that resolved spontaneously. No neurotoxicity of any grade, dose-limiting toxicity or other treatment-related serious adverse events were observed. During long-term follow-up, there were no disease relapses or treatment-related adverse events. All patients maintained normal immunoglobulin G levels without the need for immunoglobulin replacement therapy, and their white blood cell and platelet counts remained stable, fully confirming the low toxicity of CAR-NK cells.
In-depth analysis by the research team found that although CAR-NK cells exist transiently in the body after infusion and are gradually cleared within about 14 days, they still achieve profound B cell depletion—CD19-positive B cells in the peripheral blood of 89% of patients dropped below the detectable limit. Subsequently, B cells in patients gradually reconstitute, and the reconstituted B cells are predominantly naive B cells with a significant reduction in memory B cells and plasma cells, achieving the reconstitution of immune tolerance, which is the core mechanism underlying the long-term remission achieved by this therapy.
Professor Alberta Hoi from Monash University in Australia, a renowned expert in the global field of lupus, highly commented in the accompanying editorial in The Lancet: "This clinical exploration of a new off-the-shelf cellular therapy marks an important step forward in the clinical translation of CAR cell therapy for autoimmune diseases." On December 24, 2025, this achievement was also successfully selected as one of the "Top 10 Global Clinical Breakthroughs of 2025" by the medical community, winning widespread recognition from the global medical community.
Industrial Translation: The Inauguration of a Cell Therapy Center to Benefit More Patients
To accelerate the industrial translation of this innovative technology and benefit more patients with refractory lupus, Shanghai Changhai Hospital held a clinical research achievement release conference and the inauguration ceremony of a cell therapy center on November 14, 2025. A comprehensive cell therapy center integrating scientific research, clinical practice and translation was officially inaugurated and put into use.
Supported by the National Key Laboratory of Immunology and Inflammation and the Clinical Research Center, the center integrates the advantageous resources of the Department of Rheumatology and Immunology, Department of Precision Therapy, Department of Gastroenterology, Department of Hematology, Clinical Research Ward and other related disciplines. It is committed to building a high-level cell therapy platform integrating "medical treatment, teaching, research and industry", focusing on refractory diseases such as autoimmune diseases, hematological malignancies and solid tumors. The center will accelerate the phase of registrational clinical trials of CD19 CAR-NK cell drugs and develop more new cellular therapy technologies.
For the majority of patients, the establishment of the cell therapy center means that they will have the opportunity to participate in more clinical studies of innovative therapies such as CAR-NK in the future, and also receive more standardized and systematic diagnosis, treatment, long-term follow-up and continuous care, making the treatment process smoother and more reassuring. The research team stated that they will continue to explore personalized treatment regimens, optimize treatment doses and infusion frequencies, further extend patient follow-up time, improve and enhance the safety of this domestic innovative therapy, and promote its early industrialization and large-scale application to benefit more patients worldwide.
