Safety and Efficacy Study of hAESCs Therapy for aGVHD

Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a process in which hematopoietic stem cells from a donor are injected into the recipient's body, are the treatment of choice for many hematologic malignancies. Graft-versus-host disease (GVHD) is a common and important complication after allogeneic HSCT. GVHD is a major obstacle to the success of HSCT treatment and a leading cause of death after HSCT treatment. Hormone therapy is currently the standard treatment for aGVHD, i.e., the first-line treatment. However, 40%\~50% of aGVHD cannot be controlled by hormone therapy, and additional therapeutic intervention is required. According to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for hematopoietic stem cell transplantation - pre-transplant recipient evaluation and management of GVHD (2021.V3), the recommended drugs for second-line treatment of grade II\~IV aGVHD include: alemtuzumab, α-1 antitrypsin, antithymocyte globulin, basiliximab, calcineurin inhibitors, etanercept, extracorporeal photopheresis replacement therapy, infliximab, mammalian rapamycin target protein inhibitors, mycophenolate mofetil, Pentostatin, ruxolitinib, tocilizumab. Second-line treatment is based on retrospective data and there is no standard salvage therapy, which is reflected in the inconsistent treatment strategy for aGVHD across transplant centers. One of the biological functions of hAESCs in amniotic membranes in vivo is to exert reproductive immunomodulatory effects and protect the fetus from rejection by the maternal immune system, so hAESCs have natural immunomodulatory functions. hAESCs have significant inhibitory effects on T cells, antigen-presenting cells (APCs), natural killer (NK) cells, macrophages, neutrophils, B cells and other immune cells associated with organ damage during the pathogenesis of aGVHD, and hAESCs have great potential in the treatment of aGVHD. Therefore, the sponsor developed hAESCs injections intended for the treatment of aGVHD. The experimental drug in this study is hAESCs injection, which is intended to be used for the treatment of adult patients with grade III.\~IV. refractory aGVHD after hematopoietic stem cell transplantation, and to explore the safety and preliminary efficacy of its treatment.

Inclusion Criteria A subject will be eligible for inclusion in this study only if ALL of the following criteria are met: 1. The subject or his/her legal guardian has agreed to participate in this clinical trial and has signed the Informed Consent Form (ICF), indicating that the subject understands the purpose and procedures of this clinical trial and is willing to participate in the study. 2. Aged ≥ 18 years; male or female. 3. First-episode refractory acute graft-versus-host disease (aGVHD) with an overall clinical grade of III to IV as determined by the Mount Sinai Acute GVHD International Consortium (MAGIC) grading criteria. If other etiologies can be excluded by clinical diagnosis, biopsy confirmation is not required. Subjects must also meet ALL of the following conditions: 1. Patients with hematologic malignancies who have received hematopoietic stem cell transplantation from any donor type and any stem cell source (bone marrow, peripheral blood, or umbilical cord blood), with myeloablative conditioning prior to transplantation (patients with acute lymphoblastic leukemia or chronic myeloid leukemia will be given priority for enrollment); 2. aGVHD refractory to second-line therapy: subjects with steroid-resistant aGVHD who have subsequently received at least one second-line agent (e.g., anti-CD25 monoclonal antibody, ruxolitinib), with progression or no improvement of aGVHD symptoms. Note: Steroid-resistant aGVHD is defined as disease progression (PD) assessed within 3-5 days of treatment with intravenous methylprednisolone at a starting dose of 1-2 mg/kg/day or an equivalent corticosteroid dose (worsening of aGVHD in at least one target organ by at least one grade, with or without improvement of aGVHD in other organs), or no response (NR) assessed within 5-7 days of treatment (no improvement and no worsening of aGVHD severity in any target organ), or failure to achieve complete response (CR) by Day 14 (all involved organs achieving grade 0). 4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 5. Adequate function of major organs, as defined by the following criteria: 1. Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%; 2. Hepatic function: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); if the elevation of AST or ALT is related to aGVHD, AST or ALT ≤ 5 × ULN; 3. Renal function: serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance (Ccr) ≥ 30 mL/min (calculated by the Cockcroft-Gault formula); 4. Peripheral oxygen saturation (SpO₂) ≥ 92%. 6. If the subject or the subject's spouse is a woman of childbearing potential, the subject agrees to use effective contraception during the trial period (non-pharmacological contraceptive measures will be used by the subject). Exclusion Criteria A subject will be excluded from this study if he/she meets ANY of the following criteria: 1. Receiving treatment in another therapeutic clinical trial within 4 weeks prior to infusion of the investigational treatment. 2. Subjects with a history of other solid organ transplantation. 3. Subjects who have received mesenchymal stem cell (MSC) or human amniotic epithelial stem cell (hAESC) therapy, or any other stem cell therapy (other than hematopoietic stem cells), within 6 months prior to infusion of the investigational treatment. 4. Receipt of a live or attenuated virus vaccine within 4 weeks prior to infusion of the investigational treatment. 5. Positive for hepatitis B surface antigen (HBsAg) and/or positive for hepatitis B core antibody (HBcAb) with HBV DNA above the upper limit of normal (if HBsAg, HBeAg, and HBcAb are all positive, HBV DNA testing is not required and the subject will be directly excluded); positive for hepatitis C virus (HCV) antibody; positive for human immunodeficiency virus (HIV) antibody; positive for syphilis antibody. Note: Laboratory results obtained within 1 month prior to enrollment are acceptable for the above virologic examinations. 6. Known hypersensitivity to any component of the treatment used in this study (including DMSO and BAT). 7. Known uncontrolled pulmonary diseases, including but not limited to pulmonary fibrosis, interstitial lung disease, acute exacerbation of chronic obstructive pulmonary disease (COPD), and active pulmonary infection. 8. Severe hepatic veno-occlusive disease (VOD). 9. Pregnant or lactating women. 10. The investigator determines that the subject is unlikely to complete all protocol-required visits or procedures (including the follow-up period), or has insufficient compliance for participation in this study. 11. Any underlying or current medical or psychiatric condition that, in the investigator's opinion, would interfere with the treatment and evaluation of the subject, including but not limited to: poorly controlled hypertension (systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 100 mmHg), uncontrolled infection, pulmonary hypertension, clinically significant (e.g., active) cardiovascular or cerebrovascular disease, such as cerebrovascular accident (within 6 months prior to signing the ICF), myocardial infarction (within 6 months prior to signing the ICF), unstable angina, congestive heart failure of New York Heart Association (NYHA) class III or IV, or severe arrhythmia that cannot be controlled by medication or that may potentially affect the investigational treatment; clinically significant abnormalities on electrocardiogram (ECG), or QTcF ≥ 480 ms.