Mivocabtagene Autoleucel CD19 Chimeric Antigen Receptor T-Cell Therapy in Stiff Person Syndrome

Importance Stiff person syndrome (SPS) is a progressive, autoimmune neurologic disease characterized by muscle stiffness and painful spasms, leading to substantial disability. Mivocabtagene autoleucel, a fully human, autologous CD19 chimeric antigen receptor (CAR) T-cell therapy with CD28 costimulation, showed durable clinical benefit on a named-patient basis in SPS. Objective To evaluate the efficacy and safety of mivocabtagene autoleucel in adult SPS. Design, Setting, and Participants This pivotal, single-arm, open-label, nonrandomized phase 2 study enrolled participants from September 2024 to May 2025 at 3 US sites. Individuals aged 18 to 75 years with antibody-positive SPS and inadequate response to immunomodulatory/immunosuppressive therapies as determined by investigators were included. Intervention Patients received low-dose lymphodepletion (fludarabine, 30 mg/m 2 /d, and cyclophosphamide, 300 mg/m 2 /d, for 3 days), followed by a single mivocabtagene autoleucel infusion (1 × 10 8 CAR T cells). Main Outcomes and Measures Primary end points were the change from baseline to week 16 in the timed 25-ft walk (T25FW) and safety. Secondary end points were modified Rankin Scale score, Distribution of Stiffness Index score, Heightened Sensitivity Scale score, and Hauser Ambulation Index score. Exploratory end points included pharmacokinetic and pharmacodynamic assessments and biomarkers. Results Of 27 patients enrolled, 26 (median [range] age, 56.0 [32.0-73.0] years; 16 [61.5%] female) were treated. Median (range) follow-up was 6.5 (4.4-12.2) months. The primary efficacy end point was met, with significant week 16 improvement from baseline in T25FW of a mean of −7.69 seconds (SD, 10.03; 95% CI, −11.74 to −3.64; P < .001) and a median (IQR) of −4.8 (−11.9 to −2.5) seconds (45.6% median improvement); improvement was sustained (median, 44.4%) among 16 of 26 patients who reached the 24-week time point. All secondary efficacy end points showed significant week 16 improvements from baseline (modified Rankin Scale score: mean, −0.8 points [SD, 0.86; 95% CI, −1.1 to −0.4; P < .001], Distribution of Stiffness Index score: mean, −1.5 points [SD, 1.75; 95% CI, −2.2 to −0.8; P < .001]; Heightened Sensitivity Scale score: mean, −3.2 points [SD, 2.01; 95% CI, −4.0 to −2.3; P < .001]; Hauser Ambulation Index score: mean, −1.6 points [SD, 1.13; 95% CI, −2.1 to −1.2; P < .001]). The most common grade 3/4 treatment-related adverse event was neutropenia (5/26 patients [19.2%]). Low-grade cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome occurred in 24 of 26 patients (92.3%; 10/26 [38.5%] grade 1; 14/26 [53.8%] grade 2) and 3 of 26 patients (11.5%; all grade 1), respectively; all resolved without sequelae. B-cell depletion and clear changes suggestive of immune reset were observed. At last follow-up, all patients remained free of immunomodulatory therapies for SPS. Conclusions and Relevance In this nonrandomized clinical trial, a single dose of mivocabtagene autoleucel resulted in immunotherapy-free remissions with a consistent, well-tolerated safety profile, demonstrating a highly effective therapy in antibody-positive SPS with the potential for durable remissions. Long-term follow-up is ongoing. Trial Registration ClinicalTrials.gov Identifier: NCT06588491