An Early Clinical Study Evaluating the Safety and Efficacy of AcNK-Sup003 Cell Injection in the Treatment of Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

The AcNK technology has successfully achieved the direct, covalent, and directional conjugation of intact antibodies which includes the Fc domain to the surface of NK cells via a one-step enzymatic reaction. This novel approach yields a non-genetically modified NK cell that is conjugated with dual-targeting antibodies, referred to as AcNK. Specifically, AcNK-Sup003 cells are cryopreserved NK cells that have been conjugated with bispecific antibodies target both CD20 and CD19. This clinical trial is an open-label, nonrandomized, investigator-initiated clinical trial to evaluate the safety, tolerability, pharmacokinetics, and efficacy of AcNK-Sup003 cell injection in patients with elapsed or refractory B-cell non-Hodgkin's lymphoma. The treatment cycle in this study is 28 days. A modified "3+3" design principle combined with accelerated titration is used, with three dose cohorts and one alternative dose cohort, each including 1 to 6 subjects (adjustments may be made based on the safety and efficacy results of enrolled subjects). The dose levels are: Dose Level 1: 3×10^8 AcNK-Sup003 cells, Dose Level 2: 1×10^9 AcNK-Sup003 cells, Dose Level 3: 3×10^9 AcNK-Sup003 cells, Dose Level 4 (alternative dose): 9×10^9 AcNK-Sup003 cells (with a flexibility range of ±20%). Treatments are administered up to three times from Day 0 to Day 14 of each cycle (recommended D0/D7/D14, the frequency of infusion per cycle may be adjusted by the investigator based on obtained PK data and the subject's actual situation).

Inclusion criteria

• Signed an informed consent form in writing and is able to comply with the visits and related procedures specified in the protocol.
• Age ≥18 years old, with an expected survival of more than 3 months.
• Confirmed by pathology to have CD20+ relapsed or refractory B-cell non-Hodgkin's lymphoma (according to the WHO 2016 lymphoma classification standards), including but not limited to diffuse large B-cell lymphoma, high-grade B-cell lymphoma, and grade 3b follicular lymphoma.
• Relapsed or refractory disease, defined by one or more of the following:

• Relapse, non-response, or progression after hematopoietic stem cell transplantation.
• Disease stabilization but with a duration of ≤6 months after at least two cycles of second-line therapy (must have received CD20-targeted drugs [excluding CD20-negative tumors] and anthracycline drugs).
• Disease progression or relapse after second-line therapy (must have received CD20-targeted drugs [excluding CD20-negative tumors] and anthracycline drugs).
• ECOG performance status of 0-2.
• Males with fertility potential and women of childbearing age must agree to use effective contraception from the time of signing the informed consent form until 6 months after the last administration of the study drug; women of childbearing age must have a negative pregnancy test at screening.
• Lymphoma must have at least one measurable lesion according to the Lugano 2014 criteria, that is, lymph node lesions with a long diameter >15 mm or extranodal lesions with a long diameter >10 mm, and positive FDG-PET scan (5PS score of 4 or 5); lesions that have previously received radiotherapy are only considered measurable if there is clear evidence of radiographic disease progression after completion of radiotherapy.
• Hematological parameters (within 7 days before testing without transfusion or hematopoietic growth factor treatment): Hemoglobin (Hb) ≥80 g/L, Absolute Neutrophil Count (ANC) ≥1×10^9/L, Platelet Count (PLT) ≥50×10^9/L.
• Coagulation function: International Normalized Ratio (INR) ≤1.5×ULN, and Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN (subjects on prophylactic anticoagulant therapy must have an INR between 2.0-3.0).
• Hepatic, renal, and pulmonary function must meet the following requirements:

• Serum creatinine ≤1.5×ULN, or creatinine clearance ≥50 mL/min (estimated by the Cockcroft-Gault formula).
• Total bilirubin ≤1.5×ULN (≤3×ULN for subjects with liver lesions or Gilbert's syndrome).
• ALT and AST ≤3×ULN (≤5×ULN for subjects with liver lesions).
• Under indoor ventilation conditions and without oxygen supplementation, blood oxygen saturation is ≥92%.

Exclusion criteria

• Primary central nervous system lymphoma, or active central nervous system involvement or symptoms of central involvement.
• Accompanying active autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's syndrome, immune thrombocytopenia, etc.), uncontrolled multi-cavity effusions; presence of grade 2-4 acute graft-versus-host disease (GVHD) or moderate to severe chronic GVHD within 4 weeks before screening.
• Severe cardiovascular and cerebrovascular history, including but not limited to:

• Serious cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, second- or third-degree atrioventricular block, etc.
• Prolonged QT interval corrected by the Fridericia formula (QTcF), >450 ms for males; >470 ms for females.
• Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurring within 6 months before screening.
• Heart failure with a New York Heart Association (NYHA) functional classification of ≥II or left ventricular ejection fraction (LVEF) <50%.
• Clinically uncontrollable hypertension, with systolic blood pressure still ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg after standardized drug treatment.
• Received autologous hematopoietic stem cell transplantation or other autologous cell therapy products within 3 months before lymphodepletion; received allogeneic hematopoietic stem cell transplantation or other allogeneic cell therapy products within 6 months before lymphodepletion; subjects who have undergone other organ transplants.
• Received anti-tumor drug treatment or participated in other interventional clinical studies within 4 weeks before lymphodepletion or within 5 half-lives (whichever is shorter), including but not limited to chemotherapy drugs, small molecule targeted drugs, monoclonal antibodies, antibody-drug conjugates, etc.
• Received live attenuated vaccine immunization or major surgery within 4 weeks before lymphodepletion, or subjects who require live attenuated vaccine immunization or major surgery during the study period.
• Requires long-term (≥3 days) systemic corticosteroid treatment during the study period (dose ≥10 mg/day prednisone or equivalent corticosteroids), excluding inhaled or topical use; as determined by the investigator.
• History of other malignant tumors (except for cervical carcinoma in situ, non-invasive basal cell or squamous cell skin cancer, or localized prostate cancer treated with radical therapy, and ductal carcinoma in situ after radical surgery) in the past or concurrently; suffering from severe diabetes or other severe underlying diseases.
• Subjects with fungal, bacterial, viral, tuberculosis, or other infections requiring systemic anti-infective treatment within 14 days before lymphodepletion.
• Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with HBV DNA copies above the lower limit of detection; positive for hepatitis C virus (HCV) antibody with HCV RNA copies above the lower limit of detection; positive for human immunodeficiency virus (HIV) antibody; positive for syphilis spirochete antibody.
• Has life-threatening hypersensitivity reactions or other intolerable conditions to the drugs used in the study, or severe allergic constitution.
• Pregnant or breastfeeding women.
• The investigator deems that the subject has other conditions that may affect compliance or is not suitable for participating in this study.