CD19 CAR T-Cell Therapy Is Feasible for Patients With Pemphigus Vulgaris Treated Without Lymphodepletion in the RESET-PV Trial
Findings from the RESET-PV substudy of the phase 1/2 DesCAARTes trial suggest that CD19 CAR T-cell therapy can be given without lymphodepleting preconditioning in pemphigus vulgaris. Reported by researchers from the University of Texas Southwestern, Northwestern University, and the University of California, Davis, and sponsor Cabaletta Bio, RESET-PV showed clinical improvement, B-cell depletion, and CAR T-cell expansion comparable to that in lymphodepleted recipients across the first four patients treated. The findings suggest lymphodepletion may be dispensable for humanized CAR T-cell activity in autoimmune disease.
Pemphigus vulgaris is driven by autoantibodies against desmoglein 3 and desmoglein 1, and relapse after rituximab is common. Lymphodepletion is standard before CAR T-cell infusion in hematologic malignancy, but its contribution in autoimmune disease, where there is no tumor burden, is unclear. Four patients with disease refractory to standard care received a single infusion of resecabtagene autoleucel, a fully human autologous 4-1BBζ CD19 CAR T-cell product, at 1 × 106 cells per kg. Results were compared with 38 rese-cel-treated patients with autoimmune disease who received fludarabine and cyclophosphamide across four RESET studies.
Patients had a mean age of 59 years and baseline pemphigus disease area index (PDAI) total activity scores of 22 to 83, with at least 24 weeks of follow-up. Clinically meaningful PDAI reductions were observed in all four patients by week 4; two maintained low scores through week 24 without immunomodulatory medication, while two relapsed. One grade 1 cytokine release syndrome episode occurred at day 14, and no neurotoxicity or dose-limiting toxicity was reported. Peak CAR T-cell expansion occurred at a median of 14 days without lymphodepletion compared with 13 days with it, and leukocyte counts and serum IL-15 remained stable without preconditioning. Three of four patients achieved B-cell aplasia within 12 to 19 days. Serum BAFF was lower in the non-lymphodepleted group at baseline (P = .0005) and at maximum postinfusion concentration (median, 10,597 vs 36,391 pg/mL; P = .0002), though maximum fold change was comparable (P = .567). Anti-desmoglein autoantibodies decreased in two of four patients while vaccine-associated antibodies remained stable. The authors conclude that these hypothesis-generating data warrant exploration of higher CAR T-cell doses.
Reference:
Nunez D, Stadanlick J, Furmanak T, et al. CD19 CAR T-cell therapy is feasible for patients with pemphigus vulgaris treated without lymphodepletion in the RESET-PV trial. Blood. 2026;148(5):574-580. http:/doi.org/10.1182/blood.2025032093