Clinical Study of BCT301 Cell Injection Therapy for Refractory Autoimmune Diseases

A Study of BCT301 (Anti-CD19 Chemically Induced Pluripotent Stem Cell (CiPSC)-Derived CAR-iT Cells) Therapy for Refractory Autoimmune Diseases

This study primarily involves the use of BCT301, an anti-CD19 Chemically induced pluripotent stem cell (CiPSC)-derived CAR-iT cells, for the treatment of patients with refractory autoimmune diseases, aiming to evaluate its safety, tolerability, and dose-limiting toxicities(DLT), and to determine the recommended therapeutic dose for further investigation. Additionally, the study assesses the efficacy of BCT301 cell injection in refractory autoimmune diseases, as well as the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics in study participants.

Autoimmune diseases are a class of disorders caused by abnormal immune responses against the body's own tissues or organs. Although significant therapeutic advances have been made, such as the use of biologics (e.g., rituximab), most available drugs can only alleviate symptoms or slow disease progression, rather than achieve a complete cure.BCT301 cell injection is a CD19-targeted CAR-iT (chemically induced T-cell) therapy derived from human chemically induced pluripotent stem cells (CiPSCs) through chemical reprogramming technology. Starting from healthy donor cells, human CiPSCs are generated via small molecule-based reprogramming, followed by induced hematopoietic differentiation, iT-cell differentiation and expansion, and finally CAR lentiviral transduction to produce the off-the-shelf, CD19-targeted CAR-iT cell product (BCT301 cell injection). This approach holds promise as a potentially effective treatment strategy.

Inclusion Criteria:

General Inclusion Criteria

1. Voluntarily sign the informed consent form.

2. Male or female, aged 18-80 years (inclusive), with a body weight ≥40 kg.

3. Female participants of childbearing potential and male participants with female partners of childbearing potential must use medically approved contraceptive methods or practice abstinence during the treatment period and for at least 6 months after the end of the treatment. Female participants of childbearing potential must have a negative serum human chorionic gonadotropin (HCG) test within 7 days prior to enrollment and must not be breastfeeding.

4. Participants currently receiving one or more of the following treatments at stable doses: glucocorticoids, antimalarials, immunosuppressants:

   1. If the participant is receiving glucocorticoid therapy, the following conditions must be met: the maximum dose at screening and during the screening period is 30 mg/day of prednisone (or equivalent). The dose must have been stable for ≥7 days prior to screening, and adjustments during the screening period must not exceed 5 mg/day of prednisone (or equivalent);
   2. If the participant is receiving antimalarials and/or conventional immunosuppressants: the treatment must have been initiated ≥12 weeks prior to screening. The dose must have been stable for ≥8 weeks prior to screening and remain stable during the screening period;
   3. If biological agents (belimumab, telitacicept, rituximab, etc.) were used prior to the screening period, a washout period of at least 5 half-lives must be completed before screening.

5. Peripheral blood B cells must show positive CD19 expression as detected by flow cytometry.

Disease-Specific Inclusion Criteria

1. Systemic Lupus Erythematosus (SLE)

1. Meet the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE.
2. Have moderate to severe disease activity at screening, with a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) score >6.
3. Have inadequate response to conventional therapy or experience disease relapse after remission. Conventional therapy includes glucocorticoids (at full or pulse doses), two or more immunosuppressants, or biologic agents for at least 6 months, including cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, leflunomide, methotrexate, belimumab, telitacicept, and rituximab.
4. Have positive serological autoantibody tests: positive antinuclear antibodies (ANAs) and/or anti-ds-DNA antibodies and/or anti-Sm antibodies.

2. Systemic Sclerosis (SSc)

1. Meet the 2013 EULAR/ACR classification criteria for SSc.

2. Fulfill either (a) or (b) below:

   1. Inadequate response to conventional therapy or disease relapse after remission. Conventional therapy includes glucocorticoids (at full or pulse doses), two or more immunosuppressants, or biologic agents for at least 6 months, including cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, leflunomide, methotrexate, belimumab, telitacicept, and rituximab.
   2. Disease progression: skin progression with a modified Rodnan Skin Score (mRSS) ≥10; and/or interstitial lung disease evidenced by ground-glass opacities on high-resolution computed tomography (HRCT); a decline in forced vital capacity (FVC) ≥10%, or a decline in FVC ≥5% accompanied by a decline in diffusing capacity for carbon monoxide (DLCO) ≥15%.

3. Have positive SSc-related autoantibodies. 3. Antiphospholipid Syndrome (APS)

1) Meet the 2006 Sydney criteria for primary antiphospholipid syndrome. 2) Have medium to high titers of antiphospholipid antibodies (lupus anticoagulant [LA], anti-β2-glycoprotein 1 [β2GP1] IgG/IgM, or anti-cardiolipin [aCL] IgG/IgM); 3) Fulfill either (a) or (b) below:

1. Receiving standard treatment with warfarin or alternative vitamin K antagonists (maintaining target international normalized ratio [INR]), or standard therapeutic doses of low molecular weight heparin (LMWH), and/or glucocorticoids and immunosuppressants/biologics (e.g., cyclophosphamide, cyclosporine, tacrolimus, rituximab, etc.).
2. Meet all four criteria for catastrophic APS:

i) Involvement of three or more organs, systems, and/or tissues; ii) Development of manifestations within one week; iii) Histopathological confirmation of small vessel occlusion in at least one organ or tissue; iv) Positive antiphospholipid antibodies (aPL).

4. Inflammatory Myopathy (IM)

1. Meet the 2017 EULAR/ACR classification criteria for inflammatory myopathy (including dermatomyositis, polymyositis, anti-synthetase syndrome, and immune-mediated necrotizing myopathy).
2. Have positive myositis-specific autoantibodies.
3. For participants with muscle involvement: a Manual Muscle Test-8 (MMT-8) score <142, and at least two of the following five core abnormalities: Physician Global Assessment ≥2, Patient Global Assessment ≥2, or extramuscular disease activity score ≥2; Health Assessment Questionnaire (HAQ) total score ≥0.25; muscle enzyme levels ≥1.5 times the upper limit of normal; or MMT-8 ≥142 but with active interstitial lung disease (ground-glass opacities on HRCT).

5. Sjögren's Syndrome (SS)

1. Meet the 2016 ACR/EULAR classification criteria for Sjögren's syndrome.
2. Have a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ≥5.
3. Have positive anti-SSA/Ro antibodies.
4. Have inadequate response to conventional therapy or disease relapse after remission. Conventional therapy includes glucocorticoids (at full or pulse doses), two or more immunosuppressants, or biologic agents for at least 6 months, including cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, leflunomide, methotrexate, belimumab, telitacicept, and rituximab.

6. Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV)

1. Meet the 2022 ACR/EULAR classification criteria for ANCA-associated vasculitis (AAV), including microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis.
2. Have a history of or currently positive ANCA.
3. Have a Birmingham Vasculitis Activity Score (BVAS) ≥15 (total score 63).
4. Have inadequate response to conventional therapy or disease relapse after remission. Conventional therapy includes glucocorticoids (at full or pulse doses), two or more immunosuppressants, or biologic agents for at least 6 months, including cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, leflunomide, methotrexate, belimumab, telitacicept, and rituximab.

Exclusion Criteria:

Study participants who meet any of the following criteria will be excluded from the study:

1. Any medical condition that, in the opinion of the investigator, would contraindicate participation in the study, such as a life-threatening illness.

2. Decreased organ function reserve not attributable to the primary disease:

   a) Neutrophil count <1×10⁹/L; lymphocyte count <0.3×10⁹/L; hemoglobin <70 g/L; platelet count <50×10⁹/L; b) Alanine aminotransferase (ALT) >3 × upper limit of normal (ULN); aspartate aminotransferase (AST) >3 × ULN; total bilirubin >2 × ULN; c) Creatinine clearance <40 mL/min; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²; or serum creatinine >2.5 mg/dL; d) Left ventricular ejection fraction (LVEF) <45% as measured by echocardiography; e) Oxygen saturation <92% on room air.

3. History of alcohol or substance abuse within the past 24 weeks.

4. History of malignancy other than B-cell lymphoma.

5. Presence of infections including human immunodeficiency virus (HIV), hypogammaglobulinemia, T-cell deficiency, syphilis, chronic hepatitis B or C, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

6. Known active tuberculosis (TB) infection or active bacterial infection.

7. History of myocardial infarction, coronary angioplasty or stenting, unstable angina, clinically significant arrhythmia, or other clinically significant cardiac disease within 6 months prior to screening.

8. Symptomatic deep vein thrombosis or pulmonary embolism within 6 months prior to screening, except in cases of antiphospholipid syndrome (APS).

9. History of severe allergic reaction to any component of cellular therapy or other immunotherapeutic agents.

10. Prior organ transplant requiring ongoing immunosuppressive therapy.

11. Concurrent participation in another clinical trial that may interfere with disease assessment or study treatment.

12. Prior treatment with CD19- and/or BCMA-targeted therapy or any CAR-T cell product; except in cases where prior therapy is deemed to have clearly failed (e.g., no response, short duration of response, or disease progression) as assessed by the investigator, the current disease state warrants the study treatment, and there is no clear evidence that toxicity from prior therapy would compromise the safety of the current study.

13. Severe psychiatric disorder or significant cognitive impairment.

14. Pregnancy, lactation, or planned pregnancy.

15. Any other condition that, in the judgment of the investigator, would make the participant unsuitable for enrollment in this clinical trial.