A Study of Metabolically Armed Autologous CD19 CAR T-Cell Therapy (META 10-19) in Patients with Relapsed/Refractory Autoimmune Hemolytic Anemia

This is a Phase I clinical study evaluating metabolically armed autologous CD19 CAR T-cell therapy (META 10-19) in patients with relapsed/refractory autoimmune hemolytic anemia (AIHA). The main purpose of this study is to assess the safety and tolerability of this therapy in patients with relapsed/refractory AIHA.

-Primary Objective: To evaluate the safety and tolerability of metabolically armed autologous CD19 CAR T-cell therapy (META 10-19) in patients with relapsed/refractory autoimmune hemolytic anemia (AIHA).

-Secondary Objectives:

1. To evaluate the preliminary efficacy of metabolically armed autologous CD19 CAR T-cell therapy (META 10-19) in study participants with relapsed/refractory AIHA.
2. To assess the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the metabolically armed autologous CD19 CAR T-cell therapy (META 10-19).

Inclusion Criteria:

• Aged 18 to 75 years, regardless of genders.

• Diagnosis of AIHA (including warm antibody type, mixed warm and cold antibody type, cold agglutinin disease) or Evans syndrome, consistent with the Chinese Expert Consensus on the Diagnosis and Treatment of Autoimmune Hemolytic Anemia (2023), or the Diagnosis and Treatment of Autoimmune Hemolytic Anemia in Adults: Recommendations from the First International Consensus Meeting (Blood Rev, 2020), or the Chinese Expert Consensus on the Diagnosis and Treatment of Evans Syndrome (2024 Edition).

• Definition of relapsed/refractory disease, meeting all of the following criteria:

  1. Hemoglobin < 10 g/dL with clinical manifestations of hemolytic anemia;
  2. After treatment with at least two immunosuppressive agents (which must include an anti-CD20 monoclonal antibody, with a cumulative dose of the anti-CD20 antibody reaching at least 375 mg/m² × 4, or a total dose of 2.0 g, or at least 6 cumulative administrations with an interval of ≥1 week between each);
  3. Glucocorticoid therapy for no less than 3 months (except for those with comorbidities that contraindicate corticosteroid use, severe infection, severe osteoporosis, previous fractures, or intolerance to glucocorticoids).

• Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2;

• Estimated life expectancy ≥12 weeks;

• Adequate organ function as assessed by laboratory tests: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN); and minimal pulmonary reserve, defined as dyspnea ≤ grade 1 and oxygen saturation ≥ 93% while breathing room air; creatinine clearance (estimated by Cockcroft-Gault) ≥ 45 mL/min; cardiac ejection fraction ≥ 50%, with no signs of pericardial effusion on echocardiography (ECHO) and no clinically significant electrocardiogram (ECG) abnormalities.

• During the study period (from the signing of this informed consent form until at least 12 months after META 10-19 infusion, and until two consecutive PCR tests show no detectable CAR-T cells in the body), the study participant and their spouse/partner must use appropriate and effective contraceptive measures (excluding rhythm method/calendar-based contraception).

• Study participants must sign a written informed consent form approved by the Ethics Committee prior to the initiation of any screening procedures.

Exclusion Criteria:

• Previously diagnosed definite lymphoproliferative neoplasms; other malignant tumors within the past 5 years (excluding cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, breast carcinoma in situ, and cervical carcinoma in situ).

• Secondary AIHA caused by drugs or infection.

• Presence of active hepatitis or a history of severe liver disease or condition during the screening period:

  1. Hepatitis B: HBsAg or HBeAg positive; or hepatitis B e antibody (HBe-Ab) and/or hepatitis B core antibody (HBc-Ab) positive with HBV-DNA copy number above the lower limit of detection.
  2. Hepatitis C: Anti-HCV positive and HCV RNA ≥ lower limit of quantification (LLoQ).
  3. Human immunodeficiency virus (HIV) antibody positive.
  4. Active syphilis infection (excluding those with only positive syphilis-specific antibodies).

• Previous history of organ transplantation or hematopoietic stem cell transplantation.

• Severe cardiovascular diseases:

  1. Cardiovascular disease with New York Heart Association (NYHA) class > 2 within 6 months prior to the first study drug administration.
  2. Unstable angina or severe arrhythmia requiring medication, including QTcF > 480 ms (calculated by Fridericia's formula).
  3. Other significant electrocardiogram (ECG) abnormalities, including second-degree type II atrioventricular block, third-degree atrioventricular block, bradycardia (ventricular rate < 50 bpm with clinical symptoms), etc.
  4. Myocardial infarction within the past 6 months.
  5. Other cardiac diseases considered unsuitable for enrollment by the investigator.

• Undergone major surgery within the past 4 weeks that is deemed by the investigator as unsuitable for enrollment.

• Presence of active infection (e.g., sepsis, bacteremia, fungemia, uncontrolled pulmonary infection, active tuberculosis, etc.); active infection requiring intravenous anti-infective therapy within 7 days prior to screening.

• Receipt of CAR T-cell therapy within 6 months prior to screening, or positivity for ADA, or positivity for HAMA, or receipt of in vivo CAR T-cell therapy within the previous 6 months; or a history of severe immediate hypersensitivity reaction to any cellular product, excipients, or related drugs used in this study.

• Individuals with a history of epilepsy or other active central nervous system diseases (including but not limited to cerebrovascular accident, cerebral hemorrhage, cerebral infarction, severe traumatic brain injury, dementia, organic brain syndrome, etc.).

• Women with a positive pregnancy test or who are breastfeeding; women of childbearing potential and all male study participants who are unwilling or unable to use effective contraceptive methods during the study period and for at least 12 months after study drug infusion.

• Any other condition or circumstance that, in the investigator's opinion, would make the participant unsuitable for participation in this study.