Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results

Abstract

Chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) have great potentials in autoimmune diseases and could be novel therapeutics for relapsed/refractory neuromyelitis optica spectrum disorder (NMOSD). To evaluate the safety and efficacy of the CT103A, a self-developed BCMA-targeting CAR construct against BCMA, in patients with AQP4-IgG seropositive NMOSD, an ongoing, investigator-initiated, open-label, single-arm, phase 1 clinical trial is conducted at our center. In total, 12 patients were administered with a CAR-BCMA infusion. Ten of the 12 patients dosed were women (83.3%), with a median age of 49.5 years (range, 30-67). were The most common events of grade 3 or higher were hematologic toxic effects. Seven patients (58%) developed infections, but no grade 4 infections occurred. Cytokine release syndrome was reported in all patients with only events of grade 1 or 2 observed. During the follow-up of a median 5.5 months, 11 patients had no relapse; all patients generally reported improvement in disabilities and quality-of-life outcomes; 11 patients' AQP-4 antibodies in serum showed a downward trend by the cutoff date. CAR T-cell expansion was associated with responses, and persisted more than 6 months post-infusion in 17% of the patients. In summary, CAR T-cell therapy shows a manageable safety profile and therapeutic potentials for patients with relapsed/refractory AQP4-IgG seropositive NMOSD. Another expansion phase is currently underway to determine the safety and efficacy of CAR T-BCMA infusion in patients with other neuro-inflammatory diseases.

Fig. 1

CONSORT diagram. *One patient suffered a severe NMOSD attack while her manufacturing failed. She refused another apheresis and discontinued before lymphodepletion. ^†One patient underwent leukapheresis but discontinued before initial CT103A infusion for personal reason

Fig. 2

Attack frequency before, during, and after CAR T therapy

Fig. 3

CT103A expansion and persistence, kinetic changes of serum AQP4-IgG and BCMA post-infusion. a Kinetic changes of CAR transgene detected by ddPCR and CAR T-cell percentage in CD3⁺ T lymphocytes detected by flowcytometry post infusion. LLOQ denotes lower limit of quantification (32 copies/μg DNA). b, c Kinetic changes of serum AQP4-IgG detected by cell-based assay (CBA) and BCMA post-infusion. LLOQ denotes lower limit of quantification (3.2 ng/mL). Levels of sBCMA lower than LLOQ were shown as 1/2 LLOQ

Fig. 4

Functional improvement after CT103A infusion. a Distribution of EDSS score at baseline and post infusion. EDSS were shown individually at baseline and last visit. b Individual values of corrected visual acuity by Snellen E chart, functional system score from the Expanded Disability Status Scale in ambulation (scored from 0 [Unrestricted] to 12 [essentially restricted to bed or chair or perambulated in wheelchair]), and bowel and bladder functions (scored from 0 [no symptoms] to 6 [loss of bowel and bladder function]) at baseline and last visit. Solid and dotted lines represent changes of corrected visual acuity in oculus dexter (OD) and oculus sinister (OS), respectively. c Individual values of disability and quality-of-life outcomes. Secondary endpoints for disability and quality-of-life outcomes were evaluated, including the modified Rankin scale (scored from 0 [no symptoms] to 6 [death]); the Expanded Disability Status Scale (EDSS, range from 0 [normal neurologic examination] to 10 [death]), visual analog scale (VAS) score for pain (on a scale from 0 to 100, with higher scores indicating more pain); the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) score (on a scale from 0 to 52, with higher scores indicating less fatigue); the EuroQol-5 Dimensions (EQ-5D) instrument (scored on a scale from −0.109 to 1, with higher scores indicating a better health state); EQ-5D-VAS (on a scale from 0 to 100, with higher scores indicating better condition); the 36-item Short Form Health Survey (SF-36; eight sections with scores transformed to 0 to 1, with lower scores indicating greater disability). Data were shown individually at baseline and last visit. Data with same values were displayed overlapped. Comparison was performed by Wilcoxon-matched-pair-signed rank test

Fig. 5

Post‑infusion levels of cytokines. a Kinetic changes of post-infusion values of various cytokines in median according to dose group. Bars indicate 95% confidence intervals. b Post-infusion fold-changes of cytokine release. IL denotes interleukin. TNF denotes tumor necrosis factor. CRP denotes C-reactive protein