CAR-NK Therapy for Cardiac Amyloidosis

Official title

Clinical Study of CAR-NK Cells Targeting BCMA/CD19 in the Treatment of Refractory/Relapsed Light-Chain Cardiac Amyloidosis

Overview

Relapsed/refractory (R/R) light chain cardiac amyloidosis is associated with a poor prognosis, and cellular immunotherapy constitutes a crucial therapeutic modality for these patients. The efficacy and safety of CAR-T therapy have been reported in relevant studies; however, CAR-T manufacturing requires a lengthy timeline, and the leukapheresis procedure places an additional cardiac burden on patients. CAR-NK therapy boasts superior safety profiles compared with CAR-T therapy, and natural killer (NK) cells feature a wide range of sources. Investigators have accumulated prior experience in the clinical application of CAR-NK therapy, and has also achieved the successful development and preclinical application of CD19/BCMA dual-target CAR-T products. Furthermore, in the institution of the Investigator, there are dozens of newly diagnosed and more than 100 follow-up patients with AL cardiac amyloidosis each year. Investigators propose to initiate a phase I/II prospective clinical study to assess the safety and efficacy of umbilical cord blood-derived BCMA/CD19-targeted CAR-NK cell therapy for participants with relapsed/refractory light chain cardiac amyloidosis.

Interventions

• Procedure CAR-NK
  R/R AL cardiac amyloidosis patients in the CD19/BCMA dual-target CAR-NK therapy arm

Primary outcome measures

• safty and efficacy [Time frame: Starting on Day 0 (CB CAR-NK-BCMA/CD19 infusion), participants will return to the outpatient clinic at the following intervals:• Days 1, 4, 7, 10, 14, 21, 28• Month 2 (±1 week)• Month 3 (±1 week)]
• the safety and efficacy of umbilical cord blood-derived CAR-NK cells targeting BCMA/CD19 (CB CAR-NK-BCMA/CD19) in the treatment of patients with light chain cardiac amyloidosis [Time frame: 1.Follow-up visits will be conducted on Days 1, 4, 7, 10, 14, 21, and 28 post-infusion (treatment phase). 2. Within the first year: Assessments will be performed once monthly From Year 1 to Year 2: Assessments will be performed once every 3 months]

Eligibility criteria

Inclusion Criteria：

• 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.

5\. 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.

6\. 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.

9\. 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.

11\. 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.

12\. 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07504289 · 2026-0335

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗