Clinical Study on the Safety, Efficacy and Pharmacokinetics of Universal CLL1 Chimeric Antigen Receptor T-Cell in Relapsed/Refractory Acute Myeloid Leukemia

Clinical Study on the Safety, Efficacy and Pharmacokinetics of Universal CLL1 Chimeric Antigen Receptor T-Cell in Relapsed/Refractory Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a common type of acute leukemia in adults. Although the treatment of AML has improved in recent decades, the 5-year survival rate remains below 50% due to the chemoresistance or toxicity of these treatments. Most patients eventually die from relapse and/or progressive disease, and these patients urgently need new treatment strategies. Chimeric antigen receptor T-cell (CAR-T cell) therapy is an adoptive immunotherapy that expresses one or more specific chimeric antigen receptors (CARs) on T cells through genetic engineering, enabling them to target tumor cells. CAR-T cell immunotherapy has been a milestone in tumor immunotherapy in recent years and has achieved remarkable efficacy in the treatment of hematological malignancies. Human C-type lectin-like molecule 1 (CLL-1) is specifically expressed on the tumor cells of more than 90% of AML patients. CLL1 is selectively expressed on the surface of leukemia stem cells but not on normal hematopoietic stem cells, making it an ideal target for AML. Autologous CLL1 CAR-T cells have shown strong therapeutic effects in previous studies. However, autologous CAR-T cells have disadvantages such as long preparation time and high cost. Universal CAR-T cells have effectively solved this problem. In this study, universal CAR-T cells targeting the CLL1 target were prepared based on the non-gene editing intracellular membrane protein retention technology, further expanding the application of CAR-T in the treatment of acute myeloid leukemia.

Inclusion Criteria:

• The patient meets the diagnostic criteria for AML as per the 2022 WHO Fifth Edition Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO-HAEM5) and the definitions of relapse and refractory AML in the "Chinese Guidelines for the Diagnosis and Treatment of Relapsed and Refractory Acute Myeloid Leukemia (2023 Edition)":Relapsed AML is defined as the reappearance of leukemia cells in the peripheral blood after achieving complete remission (CR), or the presence of more than 5% blasts in the bone marrow (excluding other causes such as bone marrow regeneration after consolidation chemotherapy), or the presence of leukemia cell infiltration in extramedullary sites.Refractory AML is defined as cases that do not respond to two standard treatment courses as initial therapy; cases that relapse within 12 months after achieving CR and consolidation therapy; cases that relapse after 12 months and do not respond to conventional chemotherapy; cases with two or more relapses; and cases with persistent extramedullary leukemia.
• Diagnosis based on bone marrow and/or peripheral blood morphology within 28 days before enrollment.
• Leukemia cells express CLL1 at a level greater than 50%.
• Previous use of approved targeted drugs for relevant mutations.
• After treatment with CLL1 CAR-T, the subject must have a confirmed stem cell donor.Available for potential allo-SCT at any time.
• ECOG performance score of 0 or 1.
• Adequate bone marrow reserve function: a) Absolute neutrophil count (ANC) ≥ 1000/μL, unless the investigator believes that the neutropenia is due to the underlying leukemia; b) Platelet count ≥ 50,000/μL, unless the investigator believes that the thrombocytopenia is due to the underlying leukemia; c) Absolute lymphocyte count (ALC) ≥ 100/μL.
• Adequate renal, hepatic, pulmonary and cardiac function:a) Creatinine clearance (estimated by the Cockcroft-Gault formula) ≥ 60 mL/min; b) Serum alanine aminotransferase/aspartate aminotransferase ≤ 2.5 times the upper limit of normal; c) Total bilirubin ≤ 1.5 mg/dL, except for patients with Gilbert's syndrome; d) Ejection fraction ≥ 50%, with no clinical significance in pericardial effusion as determined by echocardiogram (ECHO) and no clinical significance in electrocardiogram (ECG); e) Baseline oxygen saturation > 92%, with no clinically significant pleural effusion as determined by chest imaging.
• Contraception: Male and female patients of reproductive potential must agree to use effective contraceptive methods.
• Pregnancy test: Female patients of reproductive potential must have a negative serum or urine pregnancy test.

Exclusion Criteria:

• Patients diagnosed with acute promyelocytic leukemia.
• Patients who underwent autologous hematopoietic stem cell transplantation (SCT) within 6 weeks before enrollment.
• Patients who received donor lymphocyte infusion (DLI) within 28 days before enrollment.
• Patients with grade II-IV acute graft-versus-host disease (GVHD).
• Patients with active disease involving the central nervous system.
• Patients with a history of other malignancies except non-melanoma skin cancer or carcinoma in situ (such as cervical cancer, bladder cancer or breast cancer), who have been disease-free for at least 3 years since the last curative treatment, can be enrolled.
• Patients with a history of severe hypersensitivity reactions to aminoglycoside drugs.
• Patients with genetic syndromes related to bone marrow failure.
• Patients with hereditary syndromes increase the risk of allo-SCT, such as Down syndrome (trisomy 21), which should be excluded.
• Those with a history of myocardial infarction, coronary angioplasty or stent placement, unstable angina, New York Heart Association class II or higher congestive heart failure, atrial fibrillation or other clinically significant heart diseases within 12 months prior to enrollment.
• Patients with leukemia involving the atria or ventricles.
• Those with a history of symptomatic deep vein thrombosis (DVT) or pulmonary embolism within 6 months prior to enrollment, or a history of distal upper extremity DVT within 3 months prior to conditioning.
• Patients with primary immunodeficiency diseases.
• Those with a history of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection.
• Patients with mental disorders.
• Those with existing or suspected fungal, bacterial, viral or other uncontrolled infections.
• Those who have received live vaccines within 4 weeks prior to enrollment or are expected to receive live vaccines during the study.
• Those who cannot tolerate prophylactic antifungal and antibacterial treatments.
• Those with persistent grade 2 or higher toxicity from previous treatments, excluding hematological toxicity.
• Pregnant or lactating women of childbearing age.