Safety and Efficacy of BAFF-R CART for Refractory Neuroimmune Diseases

Overview

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.

Detailed description

* Phase I: Frequency, type, and severity of adverse events (according to the National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE V5.0) occurring within 4 weeks after BAFF-R CART infusion; * Phase II: Number of recurrences at 52 weeks after BAFF-R CART infusion; * Characterization of BAFF-R CART cell expansion levels over time in subjects (peripheral blood, cerebrospinal fluid, bone marrow, etc.); * Characteristics of BAFF-R+ B cell and antibody secreting cell (ASC) lymphocyte ablation in subjects; * Changes in disease-related clinical scores at baseline, 24 and 52 weeks after BAFF-R CART infusion; * Changes in the cumulative total number of MRI active lesions in MS and NMOSD patients at 24 and 52 weeks after BAFF-R CART infusion; * Frequency, type, and severity of treatment-related laboratory index abnormalities (according to the National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE V5.0); * Characterization of changes in disease-associated antibody titers in the subject; * Changes in vital signs (blood pressure, pulse rate, weight, ECG).

Interventions

• Drug BAFF-R CART
  Biological: 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

Primary outcome measures

• Types and incidence of dose-limiting toxicity (DLT) after BAFF-R CART cells infusion [Time frame: Up to 3 months post BAFF-R CART cells infusion]
• Incidence and severity of AEs, including changes in vital signs, physical examination, laboratory parameters, Electrocardiograms and Echocardiograms. [Time frame: Up to 2 years post BAFF-R CART cells infusion]

Secondary outcome measures (5)

• PD-Soluble BAFF [Time frame: Up to 2 years post BAFF-R CART cells infusion]
• PD-Pathogenic antibody [Time frame: Up to 2 years post BAFF-R CART cells infusion]
• PD-Nfl（MS） [Time frame: Up to 2 years post BAFF-R CART cells infusion]
• PK-VCN [Time frame: Up to 15 years post BAFF-R CART cells infusion]
• PK-BAFF-R CAR-T cells [Time frame: Up to 2 years post BAFF-R CART cells infusion]

Eligibility criteria

Inclusion criteria

1\. Assessed by the investigator as having a refractory neuroimmune disease;

Refractory neuroimmune diseases were defined as:

• 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.

2\. Male study participants must agree to use contraception during the treatment period for 1 year after receiving study treatment, and sperm donation is prohibited throughout the study period;

3\. In the case of females with childbearing potential, need to agree to use contraception during the treatment period and for at least 1 year after receiving study treatment. Participants must have a negative serum pregnancy test result at screening and a confirmed negative urine pregnancy test result prior to first CART treatment.

Exclusion criteria

• 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;
• The study participant has received a live attenuated vaccination within 8 weeks prior to baseline; or is scheduled to receive a live vaccination (including COVID-19 vaccine) within 8 weeks after treatment;
• Study participants who have received prior treatment with rituximab within 6 months prior to baseline;
• Study participants had received tolizumab, eculizumab within 3 months prior to baseline;
• Study participants who have received intravenous human immunoglobulin, plasma exchange, undergone immunotherapy within 4 weeks prior to baseline;
• Known concomitant serious underlying diseases, such as hepatic and renal impairment, hematologic disorders, previous severe cardiovascular disease, severe hypertension, diabetes mellitus, poor control of blood pressure and blood glucose;
• Comorbid mental illness, suicidal ideation (affirmative answer (yes) to question 4 or question 5 of the Colombian Suicide Severity Rating Scale (C-SSRS) indicating a suicide attempt within the last 6 months);
• Any of the following laboratory abnormalities during the screening period (a repeat measurement may be taken during the screening period prior to randomization to confirm results); (1) Elevated liver enzymes: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN); (2) Total bilirubin > 1.5 times the ULN; (3) Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2; (4) CD19 + B cell count <40 cells/µL;
• Presence of a history of tuberculosis infection, high risk of acquired tuberculosis infection;
• known immunodeficiency diseases, including human immunodeficiency virus (HIV) infection;
• Viral hepatitis B surface antigen (HBsAg) positivity during the screening period;
• Receiving blood transfusion therapy 4 weeks prior to baseline or during the screening period;
• Any other condition that the investigator deems inappropriate for participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

China · 1 center

• Tianjin Medical University General Hospital — Tianjin

Identifiers

NCT: NCT07022197 · IRB2024-YX-274-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗