This study is a phase Ib/IIa dose-escalation study designed to evaluate the safety, tolerability, and preliminary efficacy of autologous T cells expressing chimeric antigen receptor (CAR)-targeted B-cell activating factor receptor (BAFFR) in refractory neuroimmune diseases. The study design is divided into two parts, the first of which will be given to each patient at 3 incremental dose levels to establish the maximum tolerated dose (MTD). Each disease is expected to enroll 12 patients who meet the inclusion criteria. In the second part, 15 patients per disease will be recruited to further characterize the efficacy of the MTD.
Poor symptom control on at least three immunosuppressive agents for more than one year;
Clinical evidence of at least two relapses within 12 months or three relapses within 24 months and one relapse within 12 months prior to screening.
Any medical or psychiatric condition that, in the opinion of the investigator, may jeopardize the study participant or affect the study participant's ability to participate in this study;
A history of drug or alcohol abuse within the 12 months prior to baseline, or any condition that in the opinion of the investigator is associated with poor adherence;
Women who are breastfeeding or pregnant, or who plan to become pregnant at any time during the 12-month time period following treatment with CART, or a history of spontaneous or induced abortion within 4 weeks prior to screening;
Study participants with a clinically relevant active infection (e.g., sepsis, pneumonia, or abscess) or serious infection (resulting in hospitalization or requiring antibiotic therapy) within 4 weeks prior to baseline;
Single group
BAFF-R CART
DrugBiological: BAFF-R CART cells Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture BAFF-R CART cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with BAFF-R CART cells by intravenous (IV) infusion. The initial dose of 0.5×10\^6 CART cells/kg will be infused on day 0. Drug: Cyclophosphamide and fludarabine Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to BAFF-R CART cells infusion on Day 0. Subjects will be given IV infusion of cyclophosphamide 250 mg/m2/day on day -5, -4 and -3, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.
Types and incidence of dose-limiting toxicity (DLT) after BAFF-R CART cells infusion
To evaluate the DLT occurred within 3 months after BAFF-R CART cells infusion.
Incidence and severity of AEs, including changes in vital signs, physical examination, laboratory parameters, Electrocardiograms and Echocardiograms.
To evaluate the AEs occurred within 2 years after BAFF-R CART cells infusion.
PD-Soluble BAFF
The changes of concentration of soluble BAFF in the peripheral blood after BAFF-R CART cells infusion.
PD-Pathogenic antibody
The changes of pathogenic antibody titers in peripheral blood or cerebrospinal fluid.
PD-Nfl（MS）
The changes of peripheral blood Neurofilament Light chain (NfL) concentration in patients with MS.
PK-VCN
The number of BAFF-R CAR gene copies (VCN, copies/μg DNA) in peripheral blood and cerebrospinal fluid after administration.
NMOSD: the number of attacks
The number of attacks divided by observed year after BAFF-R CART cells infusion.
NMOSD: Accumulated total active MRI lesions
the number of accumulate total active MRI lesions after BAFF-R CART cells infusion.
NMOSD: Expanded Disability Status Scale (EDSS) score
EDSS and its associated functional system (FS) score provide a system for quantifying disability and monitoring changes in the level of disability over time. EDSS is a scale for assessing neurologic impairment in multiple sclerosis (MS). It consists of 7 FS (visual FS, brainstem FS, pyramidal FS, cerebellar FS, sensory FS, bowel and bladder FS, and cerebral FS) which are used to derive EDSS score ranging from 0 (normal neurological exam) to 10 (death from MS). A negative change from baseline indicates improvement. A participant was considered to have a worsening in overall EDSS score of at least 2 if baseline EDSS score was 0, or at least 1 point if baseline EDSS score is 1 to 5, or at least 0.5 point if baseline EDSS score is 5.5 or more.
NMOSD: Modified Rankin Scale
Modified Rankin Scale (mRS) is a profoundly valid and reliable measure of disability and is broadly utilized for assessing stroke outcomes and degree of disability. We characterized a favorable outcome as mRS ranging from zero up to two, while unfavorable outcome ranging for 3 up to 6.
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