ANCA Associated Vasculitis (AAV), Antiphospholipid Syndrome (APS), Diffuse Systemic Sclerosis, Idiopathic Inflammatory Myopathies (IIMs), Sjogren's Syndrome (SS), Systemic Lupus Erythematosus (SLE)
Conditions
Brief summary
This exploratory, single-arm, open-label study will evaluate the safety and preliminary efficacy of YTS109 cell therapy in pediatric patients with relapsed/refractory autoimmune diseases, including systemic lupus erythematosus, diffuse systemic sclerosis, idiopathic inflammatory myopathies, and Sjögren's syndrome, as well as other eligible autoimmune diseases defined by the protocol eligibility criteria. Approximately 12 patients aged 5 to \<18 years will be enrolled at Children's Hospital of Fudan University and will receive a single intravenous infusion of YTS109 cells. Dose escalation will follow a standard 3+3 design starting at 1.5 × 10\^6 cells/kg. The primary objective is to assess the safety and preliminary efficacy of YTS109 cell therapy in this population. Secondary objectives include characterizing the pharmacokinetic and pharmacodynamic profiles of YTS109 cells. Primary endpoints include the type, severity, and frequency of adverse events, along with efficacy assessments.
Detailed description
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.
Interventions
BIOLOGICALYTS109 cell
Single intravenous infusion of YTS109 cells; dose escalation per 3+3 design starting at 0.75×10\^6 cells/kg.
Sponsors
Children's Hospital of Fudan University
China Immunotech (Beijing) Biotechnology Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
\- 1. Age 5 to \<18 years at screening; sex not restricted. 2. CD19 positivity: Presence of CD19-positive B cells in peripheral blood, confirmed by flow cytometry. 3. Adequate major organ function, meeting all of the following criteria: 1）Bone marrow function: 1. 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); 2. 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. 5\. 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 1\. Meets the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE). 2\. 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. 3\. 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. 4\. 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 1. Meets the 2013 ACR classification criteria for systemic sclerosis and is consistent with the diffuse cutaneous subtype (dcSSc). 2. Positive for any antinuclear antibody (ANA) or systemic sclerosis-associated autoantibody. 3. Evidence of diffuse cutaneous skin sclerosis and/or active interstitial lung disease (ILD), defined as ground-glass opacities on high-resolution computed tomography (HRCT). 4. 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. 5. 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: 1\. Meets the 2017 EULAR/ACR classification criteria for idiopathic inflammatory myopathies (including dermatomyositis \[DM\], polymyositis \[PM\], antisynthetase syndrome \[ASS\], and necrotizing myopathy \[NM\]). 2\. Positive for myositis-specific and/or myositis-associated autoantibodies. 3. Evidence of active disease meeting either of the following: 1\) 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). 4\. 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. 5\. 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 1. Meets the 2002 American-European Consensus Group (AECG) classification criteria for primary Sjögren's syndrome or the 2018 Japanese classification criteria. 2. Active disease, defined as ESSDAI ≥ 6. 3. Positive for anti-SSA/Ro antibodies. 4. 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: 1. 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). 2. Positive for ANCA, defined as MPO-ANCA and/or PR3-ANCA positivity. 3. Active vasculitis, defined as Paediatric Vasculitis Activity Score (PVAS) ≥ 15 (maximum score 65). 4. 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: 1\. Meets the 2006 revised Sydney classification criteria for primary antiphospholipid syndrome (APS). 2\. 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. 3\. Relapsed/refractory APS, defined as recurrent thrombosis despite standard-of-care therapy, including: 1. 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 2. Prior treatment with glucocorticoids and cyclophosphamide, with subsequent recurrent thrombosis. 4\. 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
1. History of severe drug allergy or a known allergic predisposition. 2. Presence of, or suspected uncontrolled infection requiring treatment, including fungal, bacterial, viral, or other infections. 3. 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. 4. Cardiac dysfunction deemed unable to tolerate study treatment (i.e., inadequate cardiac function at the investigator's discretion). 5. Known congenital immunoglobulin deficiency. 6. 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. 7. History of malignancy within the past 5 years. 8. End-stage renal disease. 9. 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. 10. Psychiatric illness or severe cognitive impairment. 11. Participation in another clinical trial within 3 months prior to enrollment. 12. 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. 13. Pregnant or planning pregnancy (females). 14. Any other condition that, in the investigator's opinion, makes the participant unsuitable for enrollment in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | 12weeks for safety measurements during the treatment assessment period | Safety assessments are conducted using the NCI-CTCAE version 5.0 standards. |
| Efficacy outcomes for SLE | 12 weeks for efficacy measurements during the treatment assessment period | SLE Response index 4(SR-4) response: Min/Max Value: Not specife: a decrease in score indicates improvement: hicher scores indicate worse outcome |
| Efficacy outcomes for Systemic Sclerosis | 12 weeks for efficacy measurements during the treatment assessment period | ACR-CRISS score (CRISS score ≥0.6 improvement, \< 0.6 no improvement) and modified CRISS score (rCRISS score) (percentage of patients with at least 3 of the 5 core items of ACR-CRISS improved by a certain percentage (e.g. 25%, except FVC (5%)) |
| Efficacy outcomes for Inflammatory Myopathy | 12 weeks for efficacy measurements during the treatment assessment period | Total Improvement Score (TlS): Min/Max Value: Not specified; an increase in score indicates improvement, higher scores indicate better outcomes. |
| Efficacy outcomes for Sjogren's Syndrome | 12 weeks for efficacy measurements during the treatment assessment period | Sjogren's tool for assessing response (STAR): Min/Max Value: Not specified: a decrease n score indicates improvement: higher scores indicate worse outcome |
| Efficacy outcomes for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis | 12 weeks for efficacy measurements during the treatment assessment period | Pediatric Vasculitis Activity Score Min/Max Value: 0 to 63: an increase in score indicates worsening condition. Higher cores indicate: Worse Outcome |
| Efficacy outcomes for antiphospholipid syndrome | 12 weeks for efficacy measurements during the treatment assessment period | Incidence of newly confirmed thrombotic events. New thrombotic events will be confirmed by objective imaging studies (e.g., Doppler ultrasonography, CT angiography, magnetic resonance imaging, or venography) and adjudicated according to the revised Sydney classification criteria for antiphospholipid syndrome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration (Cmax) of YTS109 | 12 and 24 weeks | Cmax will be determined using validated quantitative PCR assay in peripheral blood samples. |
| Time to Peak (Tmax) of YTS109 | 12 and 24 weeks | Time from infusion to observed Cmax (Days) . To evaluate the metabolic characteristics of YTS109 |
| Area under the plasma concentration versus time curve (AUC) of YTS109 | 12 and 24 weeks | Calculated using non-compartmental analysis. To evaluate the metabolic characteristics of YTS109 |
| Efficacy outcomes for SLE | 24 weeks for efficacy measurements during the treatment assessment period | SLE Response index 4 (SR-4) response: Min/Max Value: Not specific: a decrease in score indicates improvement. Higher scores indicate worse outcomes. |
| Efficacy outcomes for Systemic Sclerosis | 24 weeks for efficacy measurements during the treatment assessment period | ACR-CRISS score (CRISS score ≥0.6 improvement, \<0.6 no improvement) and modified CRISS score (rCRISS score) (percentage of patients with at least 3 of the 5 core items of ACR-CRISS improved by a certain percentage (e.g., 25%, except FVC (5%)). |
| Efficacy outcomes for Inflammatory Myopathy | 24 weeks for efficacy measurements during the treatment assessment period | Total Improvement Score (TlS): Min/Max Value: Not specified; an increase in score indicates improvement, higher scores indicate better outcomes. |
| Efficacy outcomes for Sjogren's Syndrome | 24 weeks for efficacy measurements during the treatment assessment period | Sjogren's tool for assessing response (STAR): Min/Max Value: Not specified: A decrease in score indicates improvement; higher scores indicate worse outcome |
| Efficacy outcomes for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis | 24 weeks for efficacy measurements during the treatment assessment period | Pediatric Vasculitis Activity Score Min/Max Value: 0 to 63: an increase in score indicates worsening condition. Higher cores indicate: Worse Outcome |
| Efficacy outcomes for Antiphospholipid Syndrome | 24 weeks for efficacy measurements during the treatment assessment period | Evaluation of new thrombosis as an indicator of relapsed/refractory/catastrophic Antiphospholipid syndrome. |
| Change from baseline in serum IL-6 concentration (pg/ml) | 12 weeks and 24 weeks | Detect the IL-6 concentration by Enzyme-linked immunosorbent assay (ELISA) |
| Change from baseline in serum TNF-α concentration (pg/ml) | 12 weeks and 24 weeks | Detect the TNF-α concentration by Enzyme-linked immunosorbent assay (ELISA) |
| Change from baseline in peripheral CD19+ B cell count (cells/µL) | 12weeks and 24 weeks | Peripheral CD19+ B cell counts will be quantified using flow cytometry in peripheral blood samples. Absolute B cell counts will be calculated based on total lymphocyte counts obtained from automated hematology analysis. Change from baseline will be calculated as the difference between post-infusion values and pre-infusion baseline levels. |
Countries
China
Contacts
CONTACTProfessor Hong Xu
Outcome results
None listed