YTS109 in Pediatric Relapsed/Refractory Autoimmune Diseases

Background: Autoimmune diseases (AIDs) comprise a heterogeneous group of disorders in which dysregulated immune responses target self-antigens, resulting in chronic inflammation and tissue damage. Although therapeutic options for AIDs have advanced in recent years, a subset of pediatric patients with relapsed or refractory disease continues to experience inadequate disease control, cumulative organ damage, and substantial treatment-related toxicity. B cells play a central role in the pathogenesis of many AIDs through autoantibody production, antigen presentation, and cytokine secretion. CD19-directed cellular immunotherapies, including CAR-T/related platforms, have emerged as promising approaches for severe autoimmune disease by enabling deep and potentially durable B-cell depletion, and therefore warrant further clinical evaluation in pediatric populations. YTS109 is a universal allogeneic CD19-targeting STAR-T cell therapy designed to efficiently eliminate CD19+ B cells and attenuate pathogenic autoimmune responses.

Design: This is a single-center, single-arm, prospective exploratory clinical trial designed to evaluate the safety profile, preliminary therapeutic efficacy, and pharmacokinetic/pharmacodynamic (PK/PD) characteristics of YTS109 cell therapy in children with relapsed/refractory autoimmune diseases. Eligible indications include systemic lupus erythematosus, diffuse systemic sclerosis, idiopathic inflammatory myopathies, Sjögren's syndrome, ANCA-associated vasculitis, and antiphospholipid syndrome, as defined by the protocol eligibility criteria. Approximately 12 patients aged 5 to <18 years will receive a single intravenous infusion of YTS109 cells, with dose escalation conducted using a standard 3+3 design starting at 1.5 × 10^6 cells/kg. The primary endpoint includes the type, severity, and frequency of adverse events (AEs), together with protocol-defined efficacy assessments. Secondary endpoints include PK/PD measures of YTS109 cell kinetics and immune reconstitution biomarkers. The study was approved by the Ethics Committee of Children's Hospital of Fudan University (Approval No. 2025-207). Written informed consent will be obtained from all participants and/or their legal guardians prior to study procedures.

Inclusion criteria

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• Age 5 to <18 years at screening; sex not restricted.
• CD19 positivity: Presence of CD19-positive B cells in peripheral blood, confirmed by flow cytometry.
• Adequate major organ function, meeting all of the following criteria:

1）Bone marrow function:

• Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L (no colony-stimulating factor use within 2 weeks prior to testing; neutropenia attributable to the underlying disease may be allowed);
• Hemoglobin ≥ 60 g/L. 2）Hepatic function: ALT ≤ 3 × ULN (exceptions allowed for elevations attributable to the underlying disease); AST ≤ 3 × ULN (exceptions allowed for elevations attributable to the underlying disease); Total bilirubin (TBIL) ≤ 1.5 × ULN (exceptions allowed for elevations attributable to the underlying disease).

3）Renal function: Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m², calculated using the Schwartz formula (exceptions allowed for reduced renal function attributable to the underlying disease).

4）Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN and prothrombin time (PT) ≤ 1.5 × ULN.

5）Cardiac status: Hemodynamically stable. 4. Females of childbearing potential must be not pregnant and not breastfeeding during screening and throughout the study period.

• The participant and the legal guardian are willing to participate, provide written informed consent, and can comply with study procedures and follow-up.

Specific inclusion criteria:

Recurrent refractory systemic lupus erythematosus

• Meets the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE).

• Active disease, defined as either: SELENA-SLEDAI ≥ 6 and at least one BILAG-2004 organ domain score of A (severe activity) or two domains scored B (moderate activity), or a combination thereof; or SELENA-SLEDAI ≥ 8.

• Relapsed/refractory or intolerant to conventional therapy, defined as one of the following: Inadequate response after >3 months of conventional therapy; or intolerance to treatment-related adverse effects; or Disease flare/recurrence after achieving remission based on the LLDAS criteria. Conventional therapy is defined as treatment with glucocorticoids and cyclophosphamide, and one or more of the following immunomodulatory agents: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, or any biologic agent, including rituximab, belimumab, and telitacicept.

• If renal involvement is present, a kidney biopsy must have been performed within 12 months prior to treatment, demonstrating active lesions or predominantly active lesions on pathology.

Relapsing refractory/progressive diffuse systemic sclerosis

• Meets the 2013 ACR classification criteria for systemic sclerosis and is consistent with the diffuse cutaneous subtype (dcSSc).
• Positive for any antinuclear antibody (ANA) or systemic sclerosis-associated autoantibody.
• Evidence of diffuse cutaneous skin sclerosis and/or active interstitial lung disease (ILD), defined as ground-glass opacities on high-resolution computed tomography (HRCT).
• Inadequate response to conventional therapy for >3 months or disease relapse/recurrence after achieving remission. Conventional therapy is defined as treatment with glucocorticoids and cyclophosphamide, and one or more of the following immunomodulatory agents: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, JAK inhibitors, or any biologic agent, including rituximab, tocilizumab, TNF-α inhibitors (etanercept, adalimumab, infliximab), and telitacicept.
• Progressive disease, defined as either:

1） Rapid skin progression: mRSS increase >25%; or 2） Progressive lung disease: FVC decline ≥10%, or FVC decline ≥5% accompanied by DLCO decline ≥15%.

Note: Criterion 4 or 5 must be met (either one is sufficient).

Recurrent refractory/progressive inflammatory myopathy:

• Meets the 2017 EULAR/ACR classification criteria for idiopathic inflammatory myopathies (including dermatomyositis [DM], polymyositis [PM], antisynthetase syndrome [ASS], and necrotizing myopathy [NM]).

• Positive for myositis-specific and/or myositis-associated autoantibodies. 3. Evidence of active disease meeting either of the following:

• Muscle involvement: CMAS < 30 and at least two abnormal findings among the following core measures: Physician Global Assessment (PhGA) ≥ 2, Patient/Parent Global Assessment (PtGA) ≥ 2, extra-muscular disease activity score ≥ 2, and/or serum muscle enzymes ≥ 1.5 × ULN; or 2) Interstitial lung disease (ILD): CMAS ≥ 30 but with active ILD, defined as ground-glass opacities on high-resolution computed tomography (HRCT).

• Inadequate response to conventional therapy for >3 months, or intolerance to treatment-related adverse effects, or relapse/recurrence after achieving remission. Conventional therapy is defined as treatment with glucocorticoids and cyclophosphamide, and one or more of the following immunomodulatory agents: antimalarials, intravenous immunoglobulin (IVIG), azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, JAK inhibitors, or any biologic agent, including rituximab, tocilizumab, TNF-α inhibitors (etanercept, adalimumab, infliximab), and telitacicept.

• Progressive disease, defined as worsening myositis or rapidly progressive interstitial lung disease (RP-ILD).

Note: Criterion 4 or 5 must be met (either one is sufficient). Recurrent refractory sjogren's syndrome

• Meets the 2002 American-European Consensus Group (AECG) classification criteria for primary Sjögren's syndrome or the 2018 Japanese classification criteria.
• Active disease, defined as ESSDAI ≥ 6.
• Positive for anti-SSA/Ro antibodies.
• Inadequate response to conventional therapy for >3 months or relapse/recurrence after achieving remission. Conventional therapy is defined as treatment with glucocorticoids and cyclophosphamide, and one or more of the following immunomodulatory agents: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, or any biologic agent, including rituximab, belimumab, and telitacicept.

Recurrent/refractory ANCA-associated vasculitis:

• Meets the 2022 ACR/EULAR classification criteria for ANCA-associated vasculitis, including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA).
• Positive for ANCA, defined as MPO-ANCA and/or PR3-ANCA positivity.
• Active vasculitis, defined as Paediatric Vasculitis Activity Score (PVAS) ≥ 15 (maximum score 65).
• Inadequate response to conventional therapy for >3 months or relapse/recurrence after achieving remission. Conventional therapy is defined as treatment with glucocorticoids and cyclophosphamide, and one or more of the following immunomodulatory agents: azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, or any biologic agent, including rituximab, belimumab, and telitacicept.

Recurrent refractory/catastrophic antiphospholipid syndrome:

• Meets the 2006 revised Sydney classification criteria for primary antiphospholipid syndrome (APS).

• Positive for antiphospholipid antibodies (aPL) at medium to high titers, defined as lupus anticoagulant (LA), anti-β2-glycoprotein I (anti-β2GPI) IgG/IgM, and/or anticardiolipin (aCL) IgG/IgM, with ≥2 positive tests at least 12 weeks apart.

• Relapsed/refractory APS, defined as recurrent thrombosis despite standard-of-care therapy, including:
• Anticoagulation with warfarin or another vitamin K antagonist (VKA) with INR maintained within the target therapeutic range, or therapeutic-dose low-molecular-weight heparin (LMWH), and
• Prior treatment with glucocorticoids and cyclophosphamide, with subsequent recurrent thrombosis.

• Catastrophic antiphospholipid syndrome (CAPS), defined by fulfillment of all four criteria:1) Involvement of three or more organs, systems, and/or tissues; 2) Development of manifestations within one week; 3)Histopathologic confirmation of small-vessel thrombosis/occlusion in at least one organ or tissue; 4) aPL positivity.

Note: Criterion 3 or 4 must be met (either one is sufficient).

Exclusion criteria

• History of severe drug allergy or a known allergic predisposition.
• Presence of, or suspected uncontrolled infection requiring treatment, including fungal, bacterial, viral, or other infections.
• Central nervous system (CNS) disorders, except for prior seizures, psychosis, organic brain syndrome, cerebrovascular accident, encephalitis, or CNS vasculitis attributable to the underlying disease, as determined by the investigator.
• Cardiac dysfunction deemed unable to tolerate study treatment (i.e., inadequate cardiac function at the investigator's discretion).
• Known congenital immunoglobulin deficiency.
• Presence of severe congenital structural malformations or syndromic birth defects (e.g., severe cardiovascular malformations, severe CNS malformations), or a confirmed diagnosis of a severe inherited metabolic disorder that, in the investigator's judgment, may significantly increase trial-related risk or interfere with compliance and interpretation of results.
• History of malignancy within the past 5 years.
• End-stage renal disease.
• Evidence of certain chronic/active infections, including: HBsAg-positive, or HBcAb-positive with peripheral blood HBV DNA above the upper limit of detection; Anti-HCV antibody positive with detectable HCV RNA; HIV antibody positive; Positive syphilis test.
• Psychiatric illness or severe cognitive impairment.
• Participation in another clinical trial within 3 months prior to enrollment.
• Use of immunosuppressive agents with therapeutic effects on the underlying disease within five half-lives prior to enrollment, or use of biologic agents within 4 weeks prior to enrollment.
• Pregnant or planning pregnancy (females).
• Any other condition that, in the investigator's opinion, makes the participant unsuitable for enrollment in this study.