Exploring CAR NK-cell therapy for refractory lupus.

# Exploring CAR NK-cell therapy for refractory lupus *The Lancet 2025* Comment Research Projects Agency Triage Challenge; and has received equipment 4 Andolfatto G, Innes K, Dick W, et al. Prehospital analgesia with intranasal support from the United States Army Institute for Surgical Research. SGS serves ketamine (PAIN-K): a randomized double-blind trial in adults. as an Editor for Military Medicine, the Journal of Special Operations Medicine, and Ann Emerg Med 2019; 74: 241–50. PLoS ONE; and has received grant support from Seastar Medical. MDA and SGS 5 Schauer SG, Fisher AD, April MD. Deployed combat use of methoxyflurane report grant support from the Department of Defense Office of the for analgesia. J Spec Oper Med 2024; 24: 81–84. Congressionally Directed Medical Research Programs, United States Air Force 6 Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency 59th Medical Wing Research Program, and the Defense Health Agency Restoral physicians and risk of long-term use. N Engl J Med 2017; 376: 663–73. Portfolio. 7 Simensen R, Fjose LO, Thorsen K, et al. Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for Published by Elsevier Ltd treatment of prehospital acute pain in Norway (PreMeFen): a randomised, *Michael David April, Steven G Schauer non-inferiority, three-arm, phase 3 trial. Lancet 2025; published online Nov 20. https://doi.org/10.1016/S0140-6736(25)01575-2. michael.d.april@post.harvard.edu 8 Birnbaum A, Esses D, Bijur PE, Holden L, Gallagher EJ. Randomized double- blind placebo-controlled trial of two intravenous morphine dosages Department of Emergency Medicine, Brooke Army Medical Center, Joint Base (0.10 mg/kg and 0.15 mg/kg) in emergency department patients with San Antonio, TX 78234, USA (MDA, SGS) moderate to severe acute pain. Ann Emerg Med 2007; 49: 445–53. 1 Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL. Morphine use 9 Mauri L, D’Agostino RB Sr. Challenges in the design and interpretation of after combat injury in Iraq and post-traumatic stress disorder. N Engl J Med noninferiority trials. N Engl J Med 2017; 377: 1357–67. 2010; 362: 110–17. 10 Sairally BZF, De Silva PM, Smith P, Clark TJ. Inhaled methoxyflurane 2 Schauer SG, Fisher AD, April MD, et al. Battlefield analgesia: adherence to (penthrox) use in the outpatient and ambulatory setting: a systematic tactical combat casualty care guidelines. J Spec Oper Med 2019; 19: 70–74. review. BMJ Open 2025; 15: e089031. 3 Schauer SG, Naylor JF, Maddry JK, Hinojosa-Laborde C, April MD. Trends in prehospital analgesia administration by US forces from 2007 through 2016. Prehosp Emerg Care 2019; 23: 271–76. Exploring CAR NK-cell therapy for refractory lupus Published Online The treatment landscape for systemic lupus alternative.5 Building on the immune-resetting November 12, 2025 erythematosus (SLE) has shifted greatly in recent years, rationale of B-cell depletion, this approach leverages https://doi.org/10.1016/ S0140-6736(25)01949-X driven by the emergence of cell-based immunotherapies the unique biological profile of NK cells to deliver See Articles page 2968 targeting pathogenic B-cell populations. Among therapeutic benefits while avoiding some of the risks these, autologous CD19-directed chimeric antigen associated with autologous CAR T-cell therapy.6,7 CAR receptor (CAR) T-cell therapy has shown promise in NK cells induce milder immune reactions than CAR inducing remission in patients with severe treatment- T cells, with much lower rates of CRS and neurotoxicity refractory SLE.1 This innovation addresses a substantial due to their lower cytokine output and limited in- global burden of disease, with epidemiological data vivo proliferation.8,9 In addition, NK cells retain native estimating more than 3·4 million individuals affected cytotoxic abilities and can recognise and eliminate worldwide;2,3 notably, in an Asia–Pacific cohort study, at aberrant or autoreactive immune cells via stress least 14% of patients were identified as having severe ligands, offering an added mechanism of immune refractory disease.4 control that could be valuable in complex autoimmune By depleting autoreactive B cells at a tissue level, diseases such as SLE.10 CAR T-cell therapies offer a mechanistically targeted This open-label, single-arm, prospective case series approach to disease modification. However, widespread was conducted at a single centre in China (Changhai clinical implementation remains constrained by Hospital, Shanghai). The study enrolled 18 adults with challenges, such as manufacturing complexity, high relapsed or refractory SLE between August, 2023, and cost, and a risk profile characterised by cytokine release June, 2024. Eligibility required moderate-to-severe syndrome (CRS), neurotoxicity, and opportunistic disease activity (Systemic Lupus Erythematosus Disease infections. These limitations highlight the need for Activity Index 2000 [SLEDAI-2K] ≥8) and previous alternative cellular platforms with improved safety, failure of at least two standard therapies. The cohort was scalability, and accessibility. predominantly female (17 [94%]), with a median age of The Article by Jie Gao and colleagues in 37·5 years (IQR 32·0–39·8) and median disease duration The Lancet presents the first-in-human study of of 10·6 years (4·5–14·8). allogeneic CD19-targeted CAR natural killer (NK)-cell Participants had substantial previous immuno- therapy in SLE, a potentially safer and more scalable suppressive exposure, with 14 (78%) having received 2872 Comment biological agents (belimumab and/or telitacicept) and one patient undergoing plasmapheresis. Following lymphodepleting conditioning with fludarabine and cyclophosphamide, patients received three infusions of cryopreserved, donor-derived CD19 CAR NK cells across escalating dose levels (0·75–4·5 × 10⁹ cells) and varying inter-infusion intervals (3–7 days). The primary endpoint was safety and tolerability. Secondary outcomes included disease activity indices (SLEDAI-2K, SLE Responder Index [SRI]-4, 6, and 8), lupus low disease activity state (LLDAS), and DORIS remission criteria. At 6 months, 16 (94%) of 17 evaluable patients attained an SRI-6 response, 13 (76%) reached LLDAS, and ten (59%) had DORIS-defined remission. Among nine patients with 12-month follow-up, six (67%) remained in sustained remission. Glucocorticoid tapering to 7·5 mg/day or lower was achieved in all but Nonetheless, several limitations warrant con- one patient. Improvements were also observed in siderati on. First, while the clinical improvements complement concentrations and anti-double-stranded observed are promising, the potential contribution DNA antibody titres, although changes in other of the conditioning regimen (fludarabine and autoantibodies were less consistent. cyclophosphamide) cannot be excluded. Second, As the first-in-human application of allogeneic CAR the study lacks a formal dose–response analysis. The NK-cell therapy in SLE, this study introduces a novel off- relationship between CAR NK-cell dose levels and the-shelf cell therapy platform aligned with the promise infusion intervals and clinical outcomes remains unclear, of next-generation cellular immunotherapy. CAR as is any effect on timing of B-cell reconstitution or NK-cell therapy offers potential advantages over CAR disease control. Third, as with any single-centre case T-cell approaches, including a lower risk of graft-versus- series, external validation is required to confirm the host disease, and a reduced likelihood of CRS due to generalisability of these findings. intrinsically lower cytokine production of NK cells. In this Importantly, this study offers early proof-of-concept for trial, the treatment was well tolerated: only one patient the use of allogeneic CAR NK cells in autoimmune disease. (6%) developed grade 1 CRS, and no neurotoxicity, The reported remission rates are similar to those seen in severe infections, or haematological adverse events early CAR T-cell studies.11–13 Crucially, the ability to deliver were reported. an off-the-shelf therapy without the risk of graft-versus- Profound CD19+ B-cell depletion was observed host disease or the logistical challenge of autologous in 16 (89%) of 18 patients, with reconstitution manufacturing presents major clinical and operational occurring by months 3–4 in most. While this shorter advantages, particularly in urgent or resource-limited persistence might minimise the risk of prolonged contexts. immunosuppression, it also raises important questions Key questions remain regarding optimal dosing, about the durability of remission and the potential need conditioning protocols, and the mechanisms under- for repeat dosing. Whether transient depletion alone pinning duration of immune reconstitution. Nonetheless, is sufficient to reprogramme the autoreactive immune this study marks an important step forward in the clinical network remains to be determined through longer translation of CAR-based therapies for autoimmune follow-up. At 6 months, immune profiling revealed a diseases. shift towards naive B-cell predominance and increased I have received sponsorship from AstraZeneca, UCB, and Janssen to support the B-cell receptor repertoire diversity, features suggestive Australian Lupus Registry and Biobank. I have also served on advisory boards for AstraZeneca, GlaxoSmithKline, Recordati Rare Diseases, UCB, and Janssen, and of a shift towards immunological resetting. have received research grant funding from Bristol Myers Squibb. yrarbiL otohP ecneicS/noitamina lacidem dirbyH Comment Alberta Hoi alberta.hoi@monash.edu Department of Rheumatology, Monash Health, Melbourne, VIC, Australia; School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia 1 Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022; 28: 2124–32. 2 Tian J, Zhang D, Yao X, Huang Y, Lu Q. Global epidemiology of systemic lupus erythematosus: a comprehensive systematic analysis and modelling study. Ann Rheum Dis 2023; 82: 351–56. 3 Barber MRW, Drenkard C, Falasinnu T, et al. Global epidemiology of systemic lupus erythematosus. Nat Rev Rheumatol 2021; 17: 515–32. 4 Kandane-Rathnayake R, Louthrenoo W, Lau CS, et al. Prevalence and outcomes of a pilot definition of severe refractory systemic lupus erythematosus: observations from a multinational Asia-Pacific cohort. Arthritis Res Ther 2025; 27: 155. 5 Gao J, Li M, Sun M, et al. Efficacy and safety of allogeneic CD19 CAR NK-cell therapy in systemic lupus erythematosus: a case series in China. Lancet 2025; published online Nov 12. https://doi.org/10.1016/S0140- 6736(25)01671-X. 6 Jørgensen LV, Christensen EB, Barnkob MB, Barington T. The clinical landscape of CAR NK cells. Exp Hematol Oncol 2025; 14: 46. US CDC: a public health agency in critical condition For almost 80 years, the US Centers for Disease Control health infrastructure: chronic disease prevention, and Prevention (CDC) has been the nation’s immune environmental health, and data science. The result is a system, detecting threats early, coordinating rapid cascade of systemic failure that threatens to damage not responses, and safeguarding population health. Its only the CDC but also US public health. deep bench of epidemiologists, laboratory expertise, Severe reductions in staff and funding have support for health departments, and evidence-based caused multiple organ systems within the CDC to fail Published Online recommendations have fought threats to the public’s simultaneously. Approximately 13 500 staff were at November 26, 2025 health. During 2025 that immune system has been the CDC in January, 2025; the estimated number in https://doi.org/10.1016/ S0140-6736(25)02353-0 compromised, prompting our resignations, following October, 2025, was fewer than 10 000.3 From our own the firing of the US Senate-confirmed CDC Director experience, and from personal communication with CDC Susan Monarez on Aug 27, 2025.1 Since the start of the staff, we see these cuts having major impacts. With about new US administration in January, 2025, reductions in staff 40% of the workforce in the National Center for Chronic and programmes, abrupt lay-offs, drastic funding cuts, and Disease Prevention and Health Promotion cut, essential a disregard for scientific processes have compromised the expertise has been erased, halting oral health surveillance, agency. Each of these stressors weakens the CDC’s ability reproductive health programmes, and tobacco control to protect the nation and the world, eroding immunity and leaving people vulnerable to preventable non- to future infectious and non-infectious crises. Without communicable diseases.4 The elimination of partnerships immediate intervention, the prognosis is dire: a debilitated that strengthened health and wellness among CDC unable to protect the health of the American people. American Indian and Alaska Native communities further Under the guise of “disruptive innovation”, the US widens inequities.5 CDC injury prevention programmes Department of Health and Human Services (HHS) have been terminated for leading causes of death, such Secretary Robert F Kennedy Jr has offered a poorly as drowning, motor vehicle crashes, and firearm injuries, characterised plan for a new Administration for a which particularly affect those younger than 50 years.4 Healthy America (AHA) that focuses on chronic diseases The CDC’s environmental and occupational health and with a CDC that is downsized and restricted to capacity is collapsing. The workforce needed for radiation infectious diseases only.2 What is being promoted as emergencies is well below operational requirements, reform is, in reality, a misdiagnosis. The supposed with a CDC-funded assessment finding most organisa- cure is attacking the vital organs of the nation’s public tions do not have adequate capacity for nuclear and 2874 ytteG aiv grebmoolB/nerdneH neB segamI 7 Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 2020; 382: 545–53. 8 Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J. CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine 2020; 59: 102975. 9 Balkhi S, Zuccolotto G, Di Spirito A, Rosato A, Mortara L. CAR-NK cell therapy: promise and challenges in solid tumors. Front Immunol 2025; 16: 1574742. 10 Chen S, Zhu H, Jounaidi Y. Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. Signal Transduct Target Ther 2024; 9: 302. 11 Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-cell therapy in autoimmune disease—a case series with follow-up. N Engl J Med 2024; 390: 687–700. 12 Shu J, Xie W, Mei C, et al. Safety and clinical efficacy of Relmacabtagene autoleucel (relma-cel) for systemic lupus erythematosus: a phase 1 open- label clinical trial. EClinicalMedicine 2025; 83: 103229. 13 Morand E, Kandane-Rathnayake R, Cortés-Hernández J, et al. OP0079 Clinical, cellular kinetics, pharmacodynamics and biomarker data up to 12 months after YTB323 (rapcabtagene autoleucel), a rapidly manufactured CD19 CAR-T therapy, from an open-label, phase 1/2 study in severe refractory SLE. Ann Rheum Dis 2025; 84: 68–70. --- [PDF原文](https://sci-net.xyz/storage/8010893/0eceeff29ae5e905df9d5666b1fbca7c330f571a10d5d255713a6a56a85940ff/Exploring-CAR-NK-cell-therapy-for-refractory-lupus.pdf) DOI: 10.1016/S0140-6736(25)01949-X