Universal STAR-T Cell Injection in R/R Autoimmune Diseases.

An Exploratory Clinical Study of Universal STAR-T Cell Injection in Subjects With Relapsed/Refractory Autoimmune Diseases

This is a Phase I, single-arm, open-label, dose-escalation and dose-expansion study.

This study evaluates the safety and efficacy of universal STAR-T cells in patients with R/R CTD-associated Immune Thrombocytopenia (CTD-ITP). Approximately 9 patients aged 18-65 will receive infusion of universal STAR-T cells at the starting dose of 3E6 STAR+T cells/kg. The main purpose of exploratory clinical research is to explore the efficacy and safety of universal STAR-T cell and the lymphodepletion regimen. The primary endpoint is observations of types, severity, and frequency of adverse events (AEs) and efficacy assessment. This single-arm, open-label trial will enroll patients across Chinese People's Liberation Army (PLA) General Hospital.

Background: Connective Tissue Disease-associated Immune Thrombocytopenia (CTD-ITP) is a severe complication of autoimmune disorders, including Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome (pSS), and Antiphospholipid Syndrome (APS). Thrombocytopenia occurs in 20%-40% of SLE patients and up to 50% of APS patients. While often mild, severe cases lead to significant bleeding risk, poor quality of life, and increased mortality.

Current standard therapies-glucocorticoids, intravenous immunoglobulin (IVIG), and immunosuppressants (e.g., cyclophosphamide, mycophenolate mofetil)-often fail in refractory or relapsing cases. Long-term dependence on high-dose steroids results in severe adverse events (infections, osteoporosis) and poor prognosis.

B cells play a central role in autoantibody production and immune dysregulation in CTD-ITP. Novel strategies focusing on deep B-cell depletion or immune reconstitution offer a promising new approach for patients who have exhausted conventional treatments.

This study aims to evaluate the safety and preliminary efficacy of universal STAR-T cell in patients with relapsed/refractory CTD-ITP. Approximately 3~6 patients aged 18-65 will be enrolled in the dose-escalation phase to receive infusion of universal STAR-T cells at the starting dose of 3E6 STAR+T cells/kg.

In patients with relapsed/refractory connective tissue disease-associated immune thrombocytopenia, the primary efficacy endpoint is the complete response rate at week 12, while the secondary efficacy endpoints include the complete response rate at week 24; the partial response rate, overall response rate, and change in platelet count from baseline at both weeks 12 and 24; as well as time to response, drug-free remission duration, and response duration.

Study endpoints include primary endpoints such as dose - limiting toxicity (DLT), the type, severity, and frequency of adverse events (AE), and efficacy endpoints; secondary endpoints encompass the in - vivo expansion and persistence of universal STAR - T cells, main pharmacokinetic (PK) parameters (including peak expansion (Cₘₐₓ), time to peak (Tₘₐₓ), area under the blood concentration - time curve (AUC), and studies on cell subtypes and dominant clones), main pharmacodynamic (PD) parameters (such as changes in cytokines and the level and characteristics of immune cell reconstitution like CD19 - positive B cells), and immunogenicity - related studies (including the production of anti - drug antibodies (ADA) against universal STAR - T cells and replication - competent associated virus (RCA) in peripheral blood).

Inclusion Criteria:

1. Age ranges from 18 to 65 years old (including threshold), regardless of gender.

2. Confirmed diagnosis of a connective tissue disease (CTD) according to the latest international classification criteria, including but not limited to Systemic Lupus Erythematosus (SLE), Primary Sjögren's Syndrome (pSS), Antiphospholipid Syndrome (APS), and Undifferentiated Connective Tissue Disease (UCTD).

3. Confirmed diagnosis of CTD-associated immune thrombocytopenia meeting one of the following:

   Platelet count < 30 × 10⁹/L; Platelet count < 50 × 10⁹/L accompanied by bleeding tendency.

4. Bone marrow morphology consistent with the characteristics of immune thrombocytopenia (ITP).

5. Prior Treatment History: Failure to achieve partial remission (PR) after receiving at least one of the following regimens continuously for ≥ 3 months, or inability to maintain efficacy during glucocorticoid tapering:

At least one course of glucocorticoid pulse therapy; Or high-dose glucocorticoids combined with one or more immunosuppressants (including biologics).

6. Essential Organ Function Criteria:

1. Bone marrow: Neutrophils ≥1×10^9/L (within 2 weeks, excluding granulocyte colony-stimulating factor use).

   Hemoglobin ≥60 g/L.

2. Liver: ALT/AST ≤3×ULN (disease-related elevations permitted). TBIL

   ≤1.5×ULN (disease-related elevations permitted).

3. Renal: CrCl≥30mL/min (Cockcroft-Gault formula, excluding acute declines).

4. Coagulation: INR/PT ≤1.5×ULN.

5. Cardiovascular: Hemodynamic stability. 7. Fertile females or males with partners of childbearing age must use medically approved contraception or abstain during and ≥12 months post- treatment. Negative serum HCG test (within 7 days pre-enrollment) for fertile females; non-lactating.

8. Voluntary participation with signed informed consent and compliance.

Exclusion Criteria:

• Subjects who meet any of the following exclusion criteria will not be admitted to the study:

  1. Individuals with a severe history of drug allergies or those with an allergic constitution;
  2. Individuals with existing or suspected uncontrolled or treatable fungal, bacterial, viral, or other infections;
  3. Subjects with central nervous system diseases (excluding those with a history of epilepsy, psychiatric disorders, organic brain disease syndromes, cerebrovascular accidents, encephalitis, or central nervous system vasculitis resulting from the underlying disease);
  4. Subjects whose cardiac function cannot tolerate the study interventions;
  5. Subjects with congenital immunoglobulin deficiencies;
  6. Subjects with a history of malignant tumors within the past five years;
  7. Subjects with end-stage renal failure;
  8. Subjects who are positive for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA titers exceeding the upper limit of detection; subjects who are positive for hepatitis C virus (HCV) antibody and peripheral blood HCV RNA; subjects who are positive for human immunodeficiency virus (HIV) antibody; and subjects who are positive for syphilis testing;
  9. Subjects with psychiatric disorders or severe cognitive dysfunction;
  10. Subjects who have participated in other clinical trials within the past three months prior to enrollment;
  11. Subjects who have received immunosuppressive agents with therapeutic effects on the disease within five half-lives prior to enrollment or biological agents within four weeks prior to enrollment;
  12. Pregnant women or women planning to become pregnant;
  13. Subjects whom the investigator believes have other reasons that preclude their inclusion in this study.