New Syndrome Found to Be Associated With CAR T-Cell Therapy for Autoimmune Diseases

May 15, 2025

Researchers have identified a group of local toxic side effects specifically related to the treatment of autoimmune disorders with CD19-targeting chimeric antigen receptor (CAR) T cells. The findings, published in The Lancet Rheumatology, describe a syndrome that the researchers named “local immune effector cell-associated toxicity syndrome” (LICATS).

LICATS differs from cytokine release syndrome (CRS), a toxicity typically associated with CAR T-cell therapy for malignancies. Unlike CRS, LICATS is limited to the organs affected by the autoimmune condition, is associated with B-cell depletion, is subacute, and generally resolves on its own or with a short course of glucocorticoid steroids.

“Knowledge about LICATS is crucial to prevent misinterpretation and unnecessary immunosuppression,” the researchers wrote, “prospective assessment of LICATS in CAR T cell trials will help assess the prevalence of this toxicity among different cellular interventions in autoimmune disease and better characterize its management and outcome.”

The study included 39 patients with autoimmune disorders — 20 with systemic lupus erythematosus (SLE), 13 with systemic sclerosis and six with idiopathic inflammatory myopathy. All but one patient was treated with MB-CART 19.1 infusion (Miltenyi Biomedicine). The remaining patient was treated with KYV-101 infusion (Kyverna Therapeutics). Patients had a follow up at least 30 days following CAR T-cell infusion.

The researchers found that 54 LICATS events occurred in more than three-quarters of patients (77%), with half of patients having more than one event. Most patients experiencing more than one LICATS manifestation (67%) had SLE. The median time to onset was a median of 10 days post-infusion, with a median duration of 11 days.

In addition to noting toxicities such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hemotoxicity, researchers monitored patients changes in kidney function, new inflammatory skin rash or mucosal lesions, and active muscle inflammation associated with muscle destruction. New or worsening measures of any of these that could not be associated with any other cause were attributed to LICATS.

Researchers also assessed patients for new signs of arthralgia, enthesitis and arthritis. Serum troponin 1 was measured, with any increase that could not be otherwise explained attributed to LICATS, as was new or worsening dyspnea. Lastly, new onset diarrhea and/or abdominal pain without any other cause was attributed to LICATS.

All organ-specific changes following infusion were noted, along with time of onset after infusion, length of duration and severity. Severity was graded from 1 to 4:

Grade 1: Spontaneous resolution without treatment.
Grade 2: Glucocorticoid treatment due to symptoms lasting more than one week or presence of relevant inner organ involvement.
Grade 3: Prolonged or new hospitalization.
Grade 4: Intensive care treatment.

Half of LICATS events occurred in the first two weeks following infusion, 30% occurred between two weeks and one month, and 11% occurred more than one month post infusion. Most events were mild and resolved on their own or with a short course of steroids (grade 1, 65%); 30% were classified as grade 2; and three patients had events rated grade 3.

The most common LICATS manifestation was transient worsening of renal function or proteinuria, accounting for 22% of events, followed by transient skin rashes (35%) and musculoskeletal manifestations (19%).

Importantly, all LICATS events occurred only in organs affected by the autoimmune disease of each patient and were not attributed to the disease itself. In addition, the later onset and self-resolving (or resolving with a short course of steroids) nature of the events set the observed LICATS toxicities apart from CRS and ICANS seen following CAR T-cell infusion for malignancies.

“All events of LICATS occurred during B-cell aplasia with CAR T cells still present in the circulation,” the researchers noted. This led the researchers to hypothesize that the events could be based on “the action of the CAR T cell itself, following the local release of cytokines or target killing cells; triggered by autoreactive T cells, which are re-infused as non-transduced T cells and expand next to the CAR T cells in the patient; or by the re-emerging immune cells following lymphodepletion, including, but not limited to, effects of fludarabine on myeloid cells and regulatory T cells.”

They added, “given the local nature of LICATS, inflammatory reactions in the affected tissues associated with the cleansing of dead B cells and debris is, however, an attractive explanation.”

The removal of dead cells by phagocytes is known to be impaired in autoimmune disorders.