CAR-NK Therapy for Cardiac Amyloidosis

Inclusion criteria

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• Voluntarily participate in this study and sign the informed consent form.
• Aged 18 to 75 years, of either sex.
• Pathologically confirmed amyloidosis, with positive Congo red staining of tissue specimens, green birefringent material observed under polarizing microscope, or characteristic electron microscopic findings.
• Presence of measurable light chain amyloidosis lesions meeting at least one of the following criteria:

1）Serum M-protein ≥ 0.5 g/dL (detected by routine serum protein electrophoresis and immunofixation electrophoresis).

2）Abnormal κ/λ ratio, with the difference between involved and uninvolved free light chains (dFLC) ≥ 50 mg/L.

• Confirmed cardiac involvement by amyloidosis, meeting at least one of the following criteria; extramyocardial organ involvement is permitted:

• Echocardiography: Mean ventricular wall thickness > 12 mm with no other identifiable cardiac etiologies.
• Elevated NT-ProBNP level (> 332 ng/L) without concomitant renal failure or atrial fibrillation.

• Having received at least one course of first-line therapy based on bortezomib or CD38 monoclonal antibody with suboptimal hematological response, meeting at least one of the following criteria:

• Failure to achieve partial response (PR) after 1 treatment cycle.
• Failure to achieve very good partial response (VGPR) after 2 treatment cycles. 7. Estimated overall survival ≥ 12 weeks. 8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 3.

• Sufficient organ function reserve excluding the heart, meeting all the following criteria:

• Peripheral blood neutrophil count ≥ 1000/μL, hemoglobin ≥ 7 g/dL, platelet count ≥ 50,000/μL; red blood cell or platelet transfusion is permitted within 1 week prior to screening.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper normal limit (UNL).
• Serum total bilirubin ≤ 1.5 × UNL.
• Estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m², calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
• Baseline oxygen saturation > 92% in a natural indoor air environment. 10. A prior history of one hematopoietic stem cell transplantation is permitted.

• At least 3 weeks have elapsed since the completion of approved therapeutic interventions for AL cardiac amyloidosis (e.g., systemic chemotherapy, immunotherapy) prior to the administration of the study drug.

• Female subjects of childbearing potential must have a negative pregnancy test and agree to adopt effective contraceptive measures during the trial period.

Exclusion criteria

• NT-ProBNP ≥ 8500 ng/L;
• Heart failure of New York Heart Association (NYHA) functional class IIIB or IV ;
• Heart failure judged by the investigator to be caused by ischemic heart disease (e.g., a previous myocardial infarction with documented elevated cardiac enzymes and electrocardiographic changes) or uncorrected valvular heart disease, rather than primarily by AL amyloidosis;
• Hospitalization for unstable angina or myocardial infarction within 6 months prior to the first dose, or percutaneous coronary intervention with recent stent implantation within 6 months, or coronary artery bypass grafting within 6 months;
• For subjects with congestive heart failure, hospitalization for cardiovascular-related diseases within 4 weeks prior to screening;
• Baseline corrected QT interval by Fridericia's formula (QTcF) > 500 milliseconds on a 12-lead electrocardiogram at screening. Subjects with a permanent pacemaker implanted may be enrolled regardless of their calculated QTc interval;
• Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic hypotension (defined as a decrease in systolic blood pressure > 20 mmHg upon standing despite pharmacotherapy (e.g., midodrine, fludrocortisone) and no hypovolemia);
• A history of hypersensitivity to any component of the cellular product;
• A history of other malignant neoplasms;
• Receipt of BCMA-targeted therapy, including antibody-drug conjugates (ADCs), bispecific antibodies, and cellular therapy, within 3 months prior to screening;
• Receipt of gene therapy within 3 months prior to screening;
• Active infections requiring treatment (excluding uncomplicated urinary tract infections and bacterial pharyngitis); prophylactic antibiotic, antiviral, and antifungal therapy is permitted, however;
• Subjects infected with hepatitis B (HBsAg-positive with HBV-DNA < 10³ copies/mL is not an exclusion criterion) or hepatitis C virus (including virus carriers), syphilis, and other acquired or congenital immunodeficiency diseases, including but not limited to human immunodeficiency virus (HIV) infection;
• Unresolved toxicities from prior antineoplastic therapy (toxicities per CTCAE Version 5.0 not recovered to ≤ Grade 1, except for fatigue, anorexia, and alopecia);
• Subjects with a history of epilepsy or other central nervous system diseases;
• Lactating women who are unwilling to discontinue breastfeeding;
• Any other condition that the investigator deems may increase the risk to the subject or interfere with the trial results.