Overview

This is a Phase I, single-arm, open-label, dose-escalation and dose-expansion study. The primary objective is to evaluate the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of YTS109 STAR-T cell therapy in patients with autoimmune hemolytic anemia who have failed ≥3 lines of therapy. The objective is to evaluate the safety, preliminary efficacy, pharmacokinetics/pharmacodynamics (PK/PD), and immune cell reconstitution characteristics of YTS109 cell therapy in Multi-rAIHA subjects who have failed third-line or higher-line treatments.

This study will also conduct an exploratory investigation into the impact of non-lymphodepleting conditioning prior to the infusion of STAR-T cells. For the non-lymphodepleting exploratory cell infusion, it can be administered as a single infusion or divided into 1 to 3 infusions (with the fractionated infusions to be completed within 7 days (and in any case no later than 15 days)). Dose escalation will commence at 5E6 cells/kg or the starting dose may be adjusted based on accumulated data.

Eligibility

Inclusion Criteria:

• Age ≥12 years, regardless of gender.
• Diagnosis of AIHA or Evans syndrome [including warm antibody, mixed AIHA and cold antibody AIHA (Cold agglutinin disease)].
• Failure or intolerance to at least 3 lines of therapy: glucocorticoids and/or rituximab, and any one of the following treatments (splenectomy, cyclosporine, cyclophosphamide, azathioprine, mycophenolate mofetil, bendamustine, fludarabine, bortezomib, etc.Biologics, including anti-CD38 monoclonal antibody, BTK inhibitor, Syk inhibitor and complement inhibitor) (HGB < 100g/L).
• Adequate organ function: a. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN. b. Creatinine clearance (CrCl) (Cockcroft-Gault formula) ≥60ml/min. c.Blood oxygen saturation (SpO2) ≥92%.
• ECOG performance status≤2
• Subjects of childbearing potential will be required to follow contraception requirements from the time of enrollment until the end of the 12-month safety follow-up period.
• The subjects voluntarily participate in the study, sign the informed consent, demonstrate good compliance, and cooperate with follow-up.

Exclusion Criteria:

• Diagnosis of lymphoproliferative tumor
• Other hereditary or acquired hemolytic diseases (Secondary AIHA caused by drugs or infection)
• The platelet count in peripheral blood<30×10^9/L
• Pregnant or breast-feeding subjects
• Receive any of the following treatments within the specified time before cell infusion: a.anti-CD20 monoclonal antibodies <12 weeks, b.sutimlimab or other marketed biologics <5 half-lives,c.plasma exchange <4 weeks, d.post-splenectomy <12 weeks, e. BTK inhibitors, anti-CD38 monoclonal antibody, Syk inhibitors, BAFF inhibitors < 5 half-lives.
• Previously received organ or stem cell transplantation
• History of new thrombosis or organ infarction in the past 6 months
• Diagnosis of the active stage of the connective tissue disease.
• Have active infections, such as sepsis, bacteremia, fungemia, uncontrolled pulmonary infection and active tuberculosis, etc.
• Positive hepatitis B surface antigen (HBsAg) or hepatitis B e antigen (HBeAg); positive hepatitis B e antibody (HBe-Ab) or hepatitis B core antibody (HBc-Ab), and the HBV-DNA copy number is above the lower limit of the measurable capacity; positive hepatitis C (HCV) antibody; positive human immunodeficiency virus (HIV) antibody; positive syphilis test.
• Underwent major surgery within 4 weeks before screening, as determined by the investigator to be unsuitable for enrollment.
• Have malignant tumors within 5 years before enrollment, except tumors with negligible risk of metastasis or death and curable tumors, such as adequately treated cervical carcinoma in situ, cutaneous basal cell carcinoma, etc.
• Have any of the following cardiovascular diseases: a.Left ventricular ejection fraction (LVEF) ≤45%, b. presence of active heart disease or congestive heart failure (New York Heart Association [NYHA] Class III or IV)), c.severe arrhythmias requiring treatment, d.have myocardial infarction, bypass surgery, or stent placement within the 6 months before the study, e.other heart diseases judged by the researcher to be unsuitable for enrollment.
• Have a history of live attenuated vaccines within 6 weeks before enrollment.
• Have a history of epilepsy or other active central nervous system diseases.
• Have an allergy to the ingredients of the medicine used in this study.
• Previously received CAR-T cell therapy.
• Patients considered to be ineligible for the study by the investigator for reasons other than the above.