In a letter to the editor published in The New England Journal of Medicine, Markus F. Neurath, MD, of Friedrich-Alexander-University Erlangen–Nuremberg, Erlangen, Germany, and colleagues described the course of treatment in a 21-year-old woman with severe multidrug-resistant ulcerative colitis who had declined colectomy and her response to autologous chimeric antigen receptor (CAR) T cells targeting CD19.1
“The data suggest the possibility that CD19 CAR T-cell therapy can induce rapid drug-free remission in refractory ulcerative colitis, a disease that was previously thought to be largely B-cell–independent, given that rituximab treatment showed no efficacy,” the investigators remarked.
Mucosal inflammation in ulcerative colitis is marked by infiltration of adaptive (T cells, B cells, plasmablasts) and innate (neutrophils, macrophages) immune cells. Current therapies inhibit T-cell trafficking and cytokine production, but, according to the investigators, they do not address the activated B-cell compartment. They furthermore noted that many patients do not respond to these targeted treatments and continue to experience abdominal pain, bloody diarrhea, poor quality of life, and disease-associated complications (eg, colorectal cancer).
Treatment Strategy
For this 21-year-old patient with severe multidrug-resistant ulcerative colitis who had declined colectomy, treatments with prednisolone, mesalamine, infliximab, ustekinumab, ozanimod, filgotinib, vedolizumab, upadacitinib, and cyclosporine combined with mirikizumab-mrkz did not induce clinical remission. Previous studies have shown dysregulated mucosal B-cell responses in ulcerative colitis,2 and thus the investigators opted to treat the patient with blinatumomab. They reported that three doses of this CD19-directed T-cell engager produced only transient amelioration of disease activity and did not result in sustained blood and colonic B-cell depletion or decreased anti–integrin αvβ6 antibodies.
To achieve deeper B-cell depletion, the investigators proceeded with autologous CD19 CAR T-cell therapy. Evidence from a case series indicated that this approach might induce deep tissue depletion of B cells and plasmablasts in B-cell–mediated autoimmune diseases.3
After undergoing standard lymphodepleting chemotherapy,3 the patient received autologous CD19 CAR T-cell infusion at 1 × 106 cells/kg. The CAR T cells were reported to rapidly expand, resulting in peripheral and mucosal B-cell depletion. Clinical and biochemical remissions were achieved and maintained over the 14-week follow-up period without concomitant therapy. Endoscopic, histologic, and ultrasonographic evaluations demonstrated evidence of mucosal healing over time. The patient experienced a 9-kg gain in body weight and was able to resume her professional activities.
Safety Observations
Apart from a spontaneously resolving grade 1 cytokine-release syndrome event on day 3, no acute toxicities related to CAR T-cell therapy were reported by the investigators. Documented findings included asymptomatic hypogammaglobulinemia and an isolated event of neutropenia, the latter managed with a single dose of granulocyte colony-stimulating factor. Therapeutic response was found to be associated with reduced levels of secretory IgA in the stool and loss of serum anti–integrin αvβ6 antibodies.
The investigators concluded: “Because these findings are based on a single case, more patients with ulcerative colitis will need to be treated with CD19 CAR T cells to interpret the safety and efficacy of this treatment and to evaluate whether certain subgroups of patients are particularly prone to treatment response.”
DISCLOSURE: For full disclosures of the study authors, visit nejm.org.
REFERENCES
1. Müller F, Atreya R, Völkl S, et al: CD19 CAR T-cell therapy in multidrug-resistant ulcerative colitis. N Engl J Med 393:1239-1241, 2025.
2. Uzzan M, Martin JC, Mesin L, et al: Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat Med 28:766-779, 2022.
3. 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 390:687-700, 2024.
