RD06-05 Universal CD19/BCMA CAR-T for Refractory Pediatric Autoimmune Diseases

Study Duration:

Approximately 4 years (2026-2030), with individual participant participation lasting up to 24 months post-infusion.

Follow-up:

Patients are followed for safety, efficacy, PK/PD, and quality of life assessments at predefined time points through 24 months post-infusion.

Key Endpoints:

Primary: Incidence of TEAEs, SAEs, and AESIs (including cytokine release syndrome, ICANS, GvHD, infections, and secondary malignancies).

Secondary: Disease-specific response rates (e.g., LLDAS/DORIS for SLE/LN, mRSS for SSc, MMT-8 for IIM, UPCR for IgAN, remission for MDR-NS), changes in eGFR, autoantibody levels, quality of life (PedsQL 4.0), CAR-T expansion (Cmax, AUC0-28), persistence, and anti-drug antibody incidence.

Exploratory: B-cell aplasia duration and B-cell subset reconstitution.

Inclusion criteria

• Voluntary participation with signed informed consent from patient or legal guardian.
• Age >=5 to <20 years, male or female.
• Important organ function meeting the following requirements (excluding abnormalities related to autoimmune disease activity): a) Bone marrow: ANC >=1.0x10^9/L, hemoglobin >=60 g/L, platelets >=30x10^9/L; b) Liver: ALT <=3xULN (except IIM-related elevation), AST <=3xULN, total bilirubin <=2xULN (<=3xULN for Gilbert syndrome); c) Kidney: eGFR >=30 mL/min/1.73m^2 (lower eGFR or on renal replacement may be allowed if benefit > risk by investigator judgment); d) Cardiac: LVEF >=55% by echocardiogram; e) Pulmonary: No severe lung disease, SpO2 >=92%.
• Negative serum or urine pregnancy test for females of childbearing potential at screening.
• Females of childbearing potential must use highly effective contraception from at least 28 days before lymphodepletion through 12 months post-infusion. Males must use effective barrier contraception and not donate sperm from start of lymphodepletion through 12 months post-infusion.

Disease-Specific Inclusion Criteria for SLE/LN:

• Diagnosis of SLE by 2019 EULAR/ACR or 2012 SLICC criteria.
• If renal involvement: kidney biopsy within 2 years showing active nephritis (class III, IV, V, or combination). Renal involvement defined as proteinuria >0.15g/24h, or hematuria, or eGFR <90.Inadequate response to standard therapy: high-dose glucocorticoid (>=1 mg/kg/d prednisone equivalent) + hydroxychloroquine + at least 2 DMARDs for 3 months, or intolerance, or unable to taper steroid to <=5 mg/day at 6 months.
• Positive ANA, anti-dsDNA, or anti-Smith antibody.
• SLEDAI-2K >=8 and clinical SLEDAI-2K >=4 (renal proteinuria >0.5g/24h or UPCR >500 mg/g or active urinary sediment may waive the clinical SLEDAI-2K requirement).
• Physician Global Assessment (PGA) >=1.0 (0-3 VAS).

Disease-Specific Inclusion Criteria for SSc:

• Diagnosis of SSc by 2013 ACR/EULAR criteria.
• Diffuse cutaneous SSc.
• Evidence of active disease (e.g., new SSc within 2 years, new skin involvement or worsening mRSS within 6 months, tendon friction rubs, lung function decline, ILD progression).
• FVC >=50% and DLCO >=45% predicted.
• Failed or relapsed on conventional therapy (glucocorticoid >0.5 mg/kg/d prednisone equivalent + at least two immunomodulators for >6 months).

Disease-Specific Inclusion Criteria for IIM:

• Diagnosis of IIM (dermatomyositis, antisynthetase syndrome, IMNM) by 2017 ACR/EULAR criteria (probability >=55%).
• Active disease: at least 2 of 6 core set abnormalities (MMT-8<142, PhGA >=2 cm, PtGA >=2 cm, extra-muscular MDAAT >=2 cm, PedsQL >=60, CK >=1.5xULN).
• Positive myositis-specific autoantibody.
• Failed or relapsed on conventional therapy (glucocorticoid >1 mg/kg/d prednisone equivalent + at least 2 immunomodulators for >=6 months).

Disease-Specific Inclusion Criteria for IgAN:

• Biopsy-confirmed IgA nephropathy.
• On ACEi/ARB for >=3 months, and at least one of: a) proteinuria >=500 mg/24h or UPCR >=0.5 mg/mg after >=3 months of steroid + at least one immunosuppressant/biologic; b) eGFR decline >50% within 3 months; c) 22.intolerance to conventional therapy with benefit > risk.

Disease-Specific Inclusion Criteria for MDR-NS:

23.Meets 2025 KDIGO definition of steroid-resistant nephrotic syndrome. 24.At least one of: a) failed to achieve remission after 12 months of two different mechanism steroid-sparing agents (at least one calcineurin inhibitor); b) no remission after 3-6 months of one CNI with benefit > risk; c) intolerance to conventional therapy; d) coexisting systemic disease requiring long-term immunosuppression.

25.Prior kidney biopsy showing minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS).

Exclusion criteria

• Co-existing autoimmune disease that may interfere with disease activity attribution or add safety risk (unless stable >=3 months and approved).
• Prior B-cell/ASC depletion therapy: a) Anti-CD20 or T-cell engager within 3 months (allowed if >3-6 months and CD19+ B-cells > LLN); b) Prior CD19 and BCMA dual-targeted therapy, or CD19 or BCMA targeted therapy within 6 months (allowed if >6 months and B-cells > LLN); c) Other B-cell/ASC targeted therapies require approval.
• Rapidly progressive glomerulonephritis (RPGN): >=50% crescents on biopsy, or doubling of serum creatinine within 2 months, or investigator judgment.
• Cardiac disease: NYHA class III/IV heart failure, MI, angioplasty/stent, unstable angina, or other severe cardiac disease within 12 months.
• Severe CNS disease (traumatic brain injury, impaired consciousness, epilepsy, cerebrovascular ischemia/hemorrhage) that may affect compliance or assessment.
• Malignancy history except cured non-melanoma skin cancer or carcinoma in situ, unless disease-free for >=3 years.
• Primary immunodeficiency.
• Uncontrolled infection (simple UTI or upper respiratory infection allowed).
• Known history of HIV, hepatitis C, or syphilis infection.
• Active or latent hepatitis B infection.
• Positive EBV or CMV DNA or IgM at screening.
• History of recurrent tuberculosis.
• Prior CAR-T or other transgenic immune cell therapy.
• Live attenuated vaccine within 4 weeks before enrollment.
• Allergy to any component of the cell therapy product.
• Hypersensitivity to tacrolimus or prior grade >=3 tacrolimus-related toxicity requiring hospitalization (exceptions may be approved).
• Participation in another clinical trial within 30 days before screening.
• Pregnancy, breastfeeding, or unwillingness to use effective contraception.
• Any other condition judged by investigator as unsuitable for study.

Disease-Specific Exclusion Criteria for SLE:

• Active/unstable neuropsychiatric lupus (seizures, psychosis, organic brain syndrome, CVA, encephalitis, CNS vasculitis) within 90 days requiring intervention.
• Prior treatments: belimumab/telitacicept within 4 weeks; ianalumab within 8 weeks unless B-cells > LLN; >1 systemic NSAID within 14 days; inability to wash out NSAID before disease activity assessment; intra-articular/IM glucocorticoid within 6 weeks; immunosuppressant doses above specified limits; initiation or dose change of hydroxychloroquine within 8 weeks; ACEi/ARB/SGLT2 inhibitor dose change within 4 weeks.
• Disease flare requiring increased corticosteroids (>20 mg/day prednisone equivalent) or new immunosuppression during screening.

Disease-Specific Exclusion Criteria for IIM:

• Severe rhabdomyolysis or CK >=20xULN.
• FVC <=60% predicted, or DLCO <=70% predicted, or worsening lung function compared to prior 3-12 months.

Disease-Specific Exclusion Criteria for SSc:

• Anti-centromere antibody positive without ATA or anti-RNAP3.
• Clinically significant respiratory disease other than ILD (severe COPD, severe asthma, recent severe respiratory infection, smoking).
• FVC <50% or DLCO <40% predicted.
• On lung transplant list or expected within 12 months.
• History of scleroderma renal crisis within 6 months.
• SSc-like disorders (morphea, eosinophilic fasciitis, etc.).
• Antifibrotic drugs within 4 weeks (colchicine, D-penicillamine, pirfenidone, tyrosine kinase inhibitors).
• Prior chlorambucil, bone marrow transplant, or total lymphoid irradiation.

Disease-Specific Exclusion Criteria for IgAN:

• Secondary IgAN (cirrhosis, celiac disease, HIV, malignancy).
• Other cause of chronic kidney disease (diabetic nephropathy, other primary glomerulopathy) that may interfere.
• Uncontrolled blood pressure.
• Prior treatments: hydroxychloroquine dose change within 8 weeks; biologics (infliximab, eculizumab, canakinumab) within 4 weeks; prednisone >30 mg/day or unstable dose; endothelin receptor antagonist within 4 weeks before lymphodepletion.

Disease-Specific Exclusion Criteria for MDR-NS:

• Secondary nephrotic syndrome/proteinuria (infection-related, drug-related, systemic disease) that may interfere.
• On maintenance dialysis, need for immediate renal replacement, or expected dialysis/transplant within 12 months.
• Prior treatments: ACEi/ARB dose change within 4 weeks; glucocorticoid dose adjustment within 2 weeks or need for >10 mg/day prednisone equivalent; 40.disease flare requiring increased steroids (>10 mg/day) or new immunosuppression during screening.