CD19/BCMA UCAR-T for B Cell-Related Autoimmune Disease

• Background and Rationale • This study investigates a novel cell therapy for patients with relapsed or refractory B-cell-mediated autoimmune diseases (AID). QT-219CX Cell Injection is a universal allogeneic CAR-T cell product derived from healthy donors, designed to target both CD19 and BCMA.

Dual-Targeting Design: By targeting both CD19+ B cells and BCMA+ plasma cells, the therapy aims to achieve deep and extensive depletion of pathogenic immune cells, potentially leading to immune "resetting".

• Study Objectives

• Primary Objective: To evaluate the safety, tolerability, and preliminary efficacy of QT-219CX in subjects with B-cell-related autoimmune diseases, and to determine the Dose-Limiting Toxicities (DLTs).
• Secondary Objective: To characterize the pharmacokinetics (PK, e.g., transgene copy numbers) and pharmacodynamics (PD, e.g., cytokine levels and B-cell depletion) of QT-219CX.
• Exploratory Objective: To explore correlations between baseline status (e.g., NK cell phenotype), PK/PD, safety, and efficacy, as well as the impact on growth and development (Tanner stage) in pediatric subjects.
• Study Design and Dose Escalation ：This is an open-label, single-arm, dose-escalation, and expansion study. Dose Escalation: A standard "3+3" design is employed, with an estimated 6-15 subjects in this phase.

• Enrollment Priority: Enrollment will prioritize older pediatric subjects.
• Clinical Procedures

• Screening (Day -28 to -5): Subjects provide informed consent and undergo baseline laboratory and imaging assessments.

• Conditioning : Subjects receive a lymphodepletion regimen.

• Infusion (Day 0): Upon confirming adequate organ function and absence of active infection, a single intravenous dose of QT-219CX is administered.

• DLT Observation (Day 0 to 28): Subjects are closely monitored for 28 days post-infusion to assess hematologic and non-hematologic toxicities.
• Follow-up and Efficacy Evaluation • Safety Management: Intensive monitoring for Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), GvHD, infections, and viral reactivation .

Efficacy Assessment: Evaluations are conducted at Days 28, 60, 90, and 180, with Day 90 and Day 180 serving as key clinical efficacy time points.

• Long-term Follow-up: Starting six months post-infusion, subjects enter a long-term follow-up phase with visits every 3 months for up to 2 years or as clinically indicated.

Inclusion criteria

• Common Inclusion Criteria:
• 1.Major organ function must meet the following criteria (exceptions allowed for abnormalities related to autoimmune disease activity):

• Bone Marrow Function: a. Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L; b. Hemoglobin ≥ 60 g/L; c. Platelet count ≥ 30 × 10⁹/L.
• Hepatic Function: ALT ≤ 3 × ULN (except when elevation is attributable to inflammatory myopathy); AST ≤ 3 × ULN (except when elevation is attributable to inflammatory myopathy); Total bilirubin ≤ 2.0 × ULN (≤ 3.0 × ULN allowed for Gilbert syndrome).
• Renal Function: eGFR ≥ 30 mL/min/1.73 m².(Participants with eGFR < 30 mL/min/1.73 m² and/or those receiving renal replacement therapy may be considered eligible if, in the investigator's judgment, the potential benefit outweighs the risk and the participant or guardian provides fully informed consent.)
• Cardiac Function: Echocardiography shows no significant structural abnormalities and left ventricular ejection fraction (LVEF) ≥ 55%.
• Pulmonary Function: No severe pulmonary disease, and SpO₂ ≥ 92%.
• 2.Women of childbearing potential must use medically acceptable contraception or practice abstinence during the study treatment period and for at least 12 months after the end of study treatment.
• 3.Informed consent: The participant (and guardian if the participant is a minor) must provide written informed consent, indicating understanding of the study purpose and procedures and willingness to participate.
• Disease-Specific Inclusion Criteria
• SLE:
• 1.Age ≥ 5 years.
• 2.Meets the 2012 SLICC or 2019 EULAR/ACR classification criteria for SLE.
• 3.Must meet at least one of the following adequate treatment conditions:

• Active disease persists despite adequate treatment with glucocorticoids (≥1 mg/kg/day prednisone or equivalent dose of other corticosteroids) in combination with at least two immunosuppressants or biologic agents for at least 3 months, or affected organ function has failed to improve; or inability to taper glucocorticoid dosage to ≤5 mg/day after 6 months of conventional treatment;
• Patients who have developed intolerable drug toxicity during conventional therapy, or have contraindications precluding standard treatment, or have experienced multiple treatment failures-may be considered for enrollment following full informed consent by the investigator and the patient or legal guardian;
• SLEDAI-2K Criteria: SLEDAI-2K score ≥8; or SLEDAI-2K score ≥6 combined with at least one BILAG-2004 Category A or two Category B organ system involvements (or both)；Patients with severe refractory SLE-ITP, characterized by a platelet count of <30×10⁹/L or <50×10⁹/L accompanied by bleeding tendency, regardless of the SLEDAI-2K score.
• 4.No occurrence of macrophage activation syndrome within 1 month prior to screening.
• 5.Occurrence of CNS lupus symptoms requiring intervention within 60 days prior to screening, including seizures, psychosis, cerebrovascular events, etc.
• MDR-SRNS
• 1.Age ≥3 years old, gender unlimited.
• 2.Diagnosed with SRNS according to the 2021 Kidney Disease: Improving Global Outcomes #KDIGO# Guidelines;
• 3. Must meet at least one of the following adequate treatment conditions:

• have not achieved a complete response after 12 months of treatment with two standard doses of hormone replacement drugs with different mechanisms of action or relapse of disease activity after remission(at least one of the two drugs is a calcineurin inhibitor such as cyclosporine or tacrolimus, Other replacement drugs include Mycophenolate Mofetil, cyclophosphamide, Telitacicept or rituximab).
• if no remission has been achieved after 3 to 6 months of adequate treatment with one calcineurin- inhibitor. The researcher judges that the benefits outweigh the risks and the patient or guardian has fully informed consent, the patient can be considered for inclusion.
• Patients unable to tolerate conventional therapy may be eligible if, in the investigator's judgment, the potential benefit outweighs the risk and the participant (or guardian if minor) provides fully informed consent.
• Patients with other diseases, such as systemic lupus erythematosus, requiring long-term systemic treatment with glucocorticoids or immunosuppressants, may be considered for inclusion after the investigator determines that the benefits outweigh the risks, and the patient or guardian has fully informed consent.
• 4.Renal biopsy was performed and the pathological type was determined to be minimal lesion nephropathy(MCD) or focal segmental glomerulosclerosis (FSGS);
• IgA nephropathy
• 1. Age: ≥ 5 years old, gender unlimited;
• 2. IgA nephropathy pathologically confirmed by renal biopsy;
• 3. Angiotensin-Converting Enzyme Inhibitors (ACEI) or angiotensin receptor blocker (ARB) treated for at least 3 months and meet at least one of the following requirements:

• Combination or sequential treatment with steroids and at least one immunosuppressant or biologic for ≥ 3 months; and 24-hour urine protein quantification ≥500mg or UPCR≥0.5mg/mg;
• >50% decline in eGFR within 3 months;
• Patients who are unable to tolerate conventional treatment and for whom the investigator determines the benefits outweigh the risks and who have obtained fully informed consent from the patient or guardian may be considered for inclusion;
• 4. Exclude subjects with other secondary causes; exclude patients with uncontrolled blood pressure.
• Systemic Sclerosis:
• 1. Age: ≥ 5 years old, gender unlimited;
• 2. Scleroderma fulfilling the 2013 ACR classification criteria
• 3. Positive scleroderma-related antibodies.
• 4. Modified Rodnan Skin Score (mRSS) ≥ 15 (total score 51).
• 5. Must meet at least one of the following adequate treatment conditions:

• Treated with glucocorticoids (≥0.5 mg/kg/day) plus at least one immunomodulatory agent (including antimalarials, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, or biologics such as rituximab, belimumab, thalidomide) for more than 3 months without significant improvement.
• Meets criteria for rapidly progressive disease and is unresponsive to standard therapy; participant may be enrolled if the investigator determines that potential benefit outweighs risk and informed consent is obtained.
• Patients unable to tolerate conventional therapy may be eligible if the investigator determines that potential benefit outweighs risk and informed consent is obtained.
• 6. Presence of severe pulmonary arterial hypertension (PAH), defined as a mean pulmonary arterial pressure >45 mmHg, or other severe involvement of major organs will be exclude.
• Refractory/Relapsed ANCA-Associated Vasculitis:
• 1. Age: ≥ 5 years old, gender unlimited;
• 2. Meets the diagnostic criteria for ANCA-associated vasculitis according to the 2007 European Medicines Agency (EMA) algorithm or the 2022 ACR/EULAR classification criteria, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA).
• 3. Refractory AAV is defined as: a reduction in the Birmingham Vasculitis Activity Score (BVAS) of less than 50%, a persistent score of ≥ 3, or the occurrence of new organ involvement following ≥3 months of standard induction therapy (including glucocorticoids in combination with Rituximab [RTX] or Cyclophosphamide [CYC]) ;or a worsening of the disease during maintenance therapy or after treatment discontinuation following the achievement of remission (BVAS = 0), which necessitates the re-initiation of induction therapy;
• 4. Or meets the criteria for severe vasculitis, with inadequate response to standard-of-care therapy, and may be considered for enrollment if the investigator determines that the potential benefits outweigh the risks and the patient or legal guardian provides fully informed consent.
• 5. Evidence of active vasculitis meeting the following criteria: For participants <18 years of age: Pediatric Vasculitis Activity Score (PVAS) ≥10 (total score 63); For participants ≥18 years of age: Birmingham Vasculitis Activity Score (BVAS) ≥10 (total score 63); indicating active vasculitis.
• 6. Exclusion Criterion: Presence of alveolar hemorrhage requiring ventilatory support for more than one week.

Exclusion criteria

• 1. Subjects with known severe allergic reactions, hypersensitivity, contraindication to any medications during the trial (cyclophosphamide, tocilizumab), or subjects with a history of severe allergic reactions.
• 2.Subjects with grade III or IV heart failure (NYHA classification).
• 3.Have a history of congenital heart disease or acute myocardial infarction within 6 months prior to screening; Or severe arrhythmias (including multisource frequent supraventricular tachycardia, ventricular tachycardia, etc.); Or combined with moderate to massive pericardial effusion, serious myocarditis, etc; Or patients with unstable vital signs who need hypertensive drugs.
• 4. Uncontrollable infection, or active infection that requires systemic treatment at screening.
• 5. Had active pulmonary tuberculosis at screening.
• 6. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer greater than the normal reference value range; Or hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA titer greater than the normal reference value range; Or positive for human immunodeficiency virus (HIV) antibodies; Or syphilis test positive; Or cytomegalovirus (CMV) DNA test positive.
• 7. History of severe herpes infection prior to screening, such as herpetic encephalitis, ocular herpes, or disseminated herpes; Signs of herpes or varicella-zoster virus infection (especially chickenpox, shingles) within 12 weeks prior to screening.
• 8. Patients had active central nervous system disease.
• 9. Patients with malignant diseases such as tumors before screening.
• 10. Secondary or congenital immunodeficiency.
• 11. History of any cardiac, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, and renal disease or other major medical condition that would prevent the administration of QT-019B, except for lupus.
• 12. Received solid organ transplantation or hematopoietic stem cell transplantation within 3 months prior to screening; Acute graft-versus host disease (GVHD) of grade 2 or above was present within 2 weeks prior to screening.
• 13. Received live vaccine within 4 weeks before screening.
• 14. Tested positive in Blood pregnancy test.
• 15. Patients who had participated in other clinical trials and received any intervention within 3 months before enrollment.
• 16. Any abnormal laboratory test results judged by the investigator to be clinically significant and prevent the subject from participating in the study. Laboratory test values that are out of range and not of clinical significance will not be considered as exclusion criteria.
• 17. Any situation judged by the investigators that may increase the risk of the subjects or interfere with the clinical trial outcome.