medwireNews: Chimeric antigen receptor (CAR) T-cell therapy has been linked to a potentially new toxicity syndrome in people with autoimmune disease by German researchers.
Termed local immune effector cell-associated toxicity syndrome (LICATS), the syndrome is characterized by a variety of different new-onset or worsening changes in kidney, skin, joint, heart, lung, muscle, or gastrointestinal (GI) parameters in the organs affected by the autoimmune condition before CAR T-cell therapy that cannot be explained by other causes.
These changes include but are not limited to creatinine values 50% higher than baseline levels or a raised urine protein-creatinine ratio; inflammatory skin rashes or mucosal lesions; arthritis or enthesitis, persistent arthralgia or enthesial pain; increased troponin I concentrations; dyspnea not explained by pneumonia or pulmonary embolism; and diarrhea or abdominal pain.
“LICATS represents an immune reset-mediated toxicity, which is organ-specific, starts days to weeks after CAR T-cell therapy and, most importantly, is self-limited, as an important discriminator from an actual disease recurrence,” report Georg Schett (FAU Erlangen-Nürnberg and Universitätsklinikum Erlangen) and co-authors in The Lancet Rheumatology.
Additionally, it is distinct from cytokine release syndrome (CRS) and “most likely based on immune-mediated cleansing processes in tissues affected by autoimmune disease before CAR T-cell therapy,” they say.
For their observational study, the researchers systematically searched for organ-specific reactions in all patients with autoimmune disease who received CD19-targeted CAR T-cell therapy between March 2021 and October 2024 at two German centers and had at least 1 month of follow-up data.
A total of 39 patients were included, of whom 20 (51%) had systemic lupus erythematosus (SLE), 13 (33%) had systemic sclerosis, and six (15%) had idiopathic inflammatory myopathy (IIM).
Overall, there were more women (64%) than men (36%) in the study. Although, when broken down by the type of autoimmune disease, there were more men than women in the systemic sclerosis group (62 vs 38%). The median age of the study participants was 36 years.
Prior to CAR T-cell therapy, the median duration of disease was 3 years and participants had received a median of five prior immunosuppressive treatments. Thirty-eight (97%) participants received CAR T-cell therapy with MB-CART 19.1, and one (3%) with KYV-101.
The overall number of LICATS events recorded was 54, occurring in 30 (77%) participants. These occurred a median of 10 days after CAR T-cell therapy infusion and lasted for a median of 11 days.
“LICATS exclusively occurred during the B-cell aplasia phase and only involved organs previously affected by the respective autoimmune disease,” say Schett et al.
Most of the LICATS events affected the skin (35%) or kidneys (22%), with LICATS events seen in the muscle, lung, GI system, or heart in a respective 9%, 6%, 6%, and 4% of cases.
LICATS events were graded according to their severity, with 64.8% graded as 1 meaning there was spontaneous resolution without the need for any other treatment. A further 29.6% were graded as 2. This meant that glucocorticoid treatment had to be given as the symptom(s) lasted for 1 week or more, or there was the presence of inner organ involvement.
Three (5.6%) LICATS events were graded as 3, meaning there had been a prolonged or new hospitalization. But there were no grade 4 events, which were defined as those that would have needed intensive care treatment.
“All events of LICATS resolved without sequelae,” the researchers report.
Discussing the work in a related commentary, Samuel Good and Elizabeth Volkmann, both from the University of California in Los Angeles, USA, note that CAR T-cell therapy “represents an exciting new therapeutic modality for patients with autoimmune disease.”
They add that known adverse events of this approach particularly in malignancies include CRS and immune effector cell-associated neurotoxicity syndrome, neither of which occurred to any significant degree in the study.
The study suggests that “less severe, tissue-specific adverse effects, such as LICATS might occur more commonly” in autoimmune disease, and “[a]s such the safety profile of CAR T-cell therapy is potentially more favorable in autoimmune disease as compared with hematological malignancies,” the commentators point out.
They say that a “limitation of this study and previous studies investigating CAR T-cell therapy in autoimmune disease is the absence of a control group,”
The commentators explain: “While the likelihood of LICATS in a placebo group is low, it is difficult to assess the true prevalence of LICATS in patients treated with CAR T-cell therapy without a comparator group.”
Good and Volkmann also suggest that “larger, confirmatory studies are needed to ensure that LICATS is truly a self-limited clinical phenomenon and not a harbinger of a future autoimmune disease flare.”
And, considering LICATS can occur in vital organs perhaps already compromised by the autoimmune disease, “close monitoring is essential for all patients receiving CAR-T therapies,” they conclude.
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Lancet Rheumatol 2025; doi:10.1016/S2665-9913(25)00091-8
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