CHICAGO—At a Sunday, Oct. 26, session of ACR Convergence, Joan T. Merrill, MD, overviewed the current research landscape of chimeric antigen receptor (CAR) T cell therapies for systemic lupus erythematosus (SLE), raising important scientific questions about these emerging treatments. Dr. Merrill is the director of clinical projects in the Arthritis & Clinical Immunology Research Program at Oklahoma Medical Research Foundation, Oklahoma City.
Background
In CAR T therapy for SLE, a patient’s T cells are removed and genetically modified to target an antigen found on B cells, CD19. After receiving some sort of chemotherapy treatment (e.g., cyclophosphamide and fludarabine), the patient is reinfused with their own modified T cells. In early studies, this has led to rapid and deep reductions in circulating B cells and B cell tissue reservoirs, with consequent impressive improvement in SLE symptoms, even as the B cells repopulate.1,2
Dr. Saira Sheikh
Saira Sheikh, MD, director of the University of North Carolina Rheumatology Lupus Clinic at Chapel Hill, introduced the session. “What began as a targeted approach for B cell malignancies is rapidly evolving into a precision tool, potentially capable of inducing deep, treatment-free remission in refractory lupus. The excitement is palpable, but there is much to learn.”
Throughout her lecture, Dr. Merrill also maintained a careful balance of hopeful enthusiasm and healthy, rigorous skepticism with respect to these therapies.
Efficacy
Dr. Joan Merrill
Although the area is still incredibly young, multiple centers have now administered CAR T therapies in SLE patients. Dr. Merrill discussed results of a recent systematic review of 16 case series studies of CAR T in SLE, with 145 patients in total. Protocols differed somewhat and included 12 autologous and four allogeneic CAR T studies; 13 studies targeted the marker CD19 and three targeted both CD19 and B-cell maturation antigen (BCMA; a marker associated with plasma cells).1
From a baseline median Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of 13.1, the median score dropped to 2.3 after six months and 1.4 after 12 months. Looked at another way, 84% achieved drug-free remission, and 89% had low disease activity (as quantified by Lupus Low Disease Activity State criteria).1
“These are phenomenal results,” said Dr. Merrill, “really remarkable.”
Side Effects
Dr. Merrill put in context some of the key adverse events in patients receiving CAR T therapy for SLE, many of which have been previously described from the oncology literature. However, fully understanding the nature of these events is challenging, as they might result from CAR therapy itself, from the chemotherapy used as part of CAR T protocols, from other potent treatments for SLE or from actual disease symptoms.
A key concern has been cytokine release syndrome (CRS), known to commonly cause fever and organ dysfunction from CAR T and less often from other types of immunosuppressants. This was reported in 56% of patients, although it may sometimes be difficult to distinguish from actual disease flares.1
Scientists anticipated that the impact of CRS might be less severe in SLE patients receiving CAR T compared to those receiving it for malignancies, due to the greater numbers of cells targeted in the latter. Consistent with this, Dr. Merrill noted that 98% of these cases in CAR T for SLE have been either grade one or grade two, transient but manageable with therapies such as tocilizumab.1 “Most of our lupus patients have experienced worse symptoms when they flare,” she said.
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a poorly understood side effect of CAR T and sometimes other immunosuppressives that might occur with or without CRS. Dr. Merrill shared that these symptoms, reported in 3% of patients, all resolved with steroid treatment, and only one was a grade four event.1
Some patients had cytopenias, although generally not as severe as those in the hematology literature, Dr. Merrill noted. Relatedly, about 8% of patients developed a serious infection, with one case of fatal pneumococcal meningitis.1 From Dr. Merrill’s perspective, these numbers are not especially high given rates in previous SLE trials, especially given that patients chosen to receive CAR T may be an especially sick population.
Dr. Merrill also discussed a recently described side effect of CAR T therapies in patients with autoimmune diseases: local immune effector cell-associated toxicity syndrome (LICATS). LICATS symptoms are mild and transient symptoms occurring after CAR T therapy which mirror those from the original disease (e.g., lupus-type symptoms for an SLE patient versus those of a patient with systemic sclerosis).2,3
Although the authors made several arguments that these symptoms constitute true CAR T side effects and not just mild symptom flares, Dr. Merrill argued that it’s impossible to completely know this now.3 How scientists define these symptoms—as flares vs. adverse events—may impact how study results are reported and interpreted.
Lack of True Comparators & Needed Research
Dr. Merrill also emphasized the need for true comparators to fully understand the results of these studies. “I think there is a fundamental kind of skepticism that we need to maintain when we look at data from trials that are not controlled with placebo,” said Dr. Merrill, “because we’re not 100% sure of what we’re looking at.”
For example, she contrasted the phenomenal results of a case series studies included in the systematic review with results from a much earlier study of SLE patients and rituximab, a B cell-depleting monoclonal antibody.2,4 Unlike the way rituximab is usually administered today, these patients received two doses of cyclophosphamide and oral corticosteroids with their rituximab treatment. At six to 88 months’ follow-up, 42% of patients were in full remission and 47% were in partial remission, and the majority had stopped immunosuppressive therapy.4
Although not nearly as high as the rates reported for CAR T, these sorts of relatively high remission rates are not what most rheumatologists would associate with rituximab for SLE. Dr. Merrill noted that this study provides a closer (though imperfect) comparator to recent work in CAR T and SLE: CAR T protocols include chemotherapy such as cyclophosphamide and fludarabine, with some patients also receiving tocilizumab and potentially corticosteroids.
In essence, Dr. Merrill noted that one can’t fairly compare CAR T treatment to other earlier B cell-depleting options without also considering the potential impact of chemotherapy. It’s unclear if early chemotherapy would make a long-term difference, she said, but it’s worth considering.
For example, a study analyzed differences in molecular gene expression in SLE after CAR T with treatment after rituximab alone or treatment with cyclophosphamide alone. This revealed differences, such as changes in type 1 and type 2 interferon pathways.5
“What would happen if you did add chemotherapy to rituximab?” asked Dr. Merrill. “What would the differences be then? This is the kind of work we need to see done before we really understand what we’re looking at with CAR T.”
Thus, much work lies ahead to move the field forward. Part of that will mean innovations to help make these therapies potentially safer, cheaper, faster and more accessible. These might include innovations such as CAR using natural killer cells, other targets such as BCMA, in vivo CAR T, bispecific cell engagers or other approaches. But it will also necessitate employing basic principles of controlled trials and placebo groups and doing the deeper work to truly understand these processes at a molecular level.
“When something new comes along, there’s a tendency to try to explain it before we understand it,” said Dr. Merrill. “It’s exciting, but we have a lot of science to do.”
Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.
References
- Nordmann-Gomes A, Khalili L, Tang W, et al. CAR T-cell therapy in SLE: A systematic review. Semin Arthritis Rheum. 2025 Oct;74:152786.
- 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 Feb 22;390(8):687–700.
- Hagen M, Müller F, Wirsching A, et al. Local immune effector cell-associated toxicity syndrome in CAR T-cell treated patients with autoimmune disease: an observational study. Lancet Rheumatol. 2025 Jun;7(6):e424–e433.
- Lu TY, Ng KP, Cambridge G, et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: The first fifty patients. Arthritis Rheum. 2009 Apr 15;61(4):482–487.
- Garantziotis P, Beretta L, Lindblom J, et al. Differential molecular signatures in response to CD19-CAR T cell therapy compared with conventional pharmacotherapy in systemic lupus erythematosus. Ann Rheum Dis. 2025 Jul 22:S0003–S4967(25)04187-1.
