Dual-Target Nectin-4/HER2 CAR-NK Cells in Advanced Urothelial Carcinoma

Prior treatment

• Active or untreated central nervous system metastases or leptomeningeal disease. Previously treated CNS disease is allowed if clinically stable and off escalating corticosteroids.
• Prior allogeneic hematopoietic stem cell transplant, prior solid-organ transplant, or active graft-versus-host disease.
• Clinically significant autoimmune disease requiring systemic immunosuppression within the defined washout window.
• Use of systemic corticosteroids or other immunosuppressive medications above protocol-allowed limits within the washout window.

Other illness

• Uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV, sepsis, or active tuberculosis.
• Clinically significant pulmonary disease (for example, uncontrolled interstitial lung disease or oxygen-dependent respiratory compromise).
• History of severe hypersensitivity to fludarabine, cyclophosphamide, or cell-product excipients.
• Another active malignancy requiring systemic therapy or likely to interfere with protocol assessments, except for protocol-allowed low-risk cancers.

Lab values

• Clinically significant cardiac disease, active myocarditis, unstable angina, recent myocardial infarction, uncontrolled arrhythmia, or clinically meaningful decline in left ventricular ejection fraction that would increase risk from HER2-directed cell therapy.

Other

• Pregnancy or breastfeeding.

• Age 18-75 years at consent.
• Histologically confirmed urothelial carcinoma of the bladder, ureter, renal pelvis, or urethra that is unresectable locally advanced or metastatic.
• Disease progression after, intolerance to, or ineligibility for standard therapy, including platinum-based chemotherapy and PD-1/PD-L1 blockade when appropriate for the patient and region. Prior enfortumab vedotin and prior HER2-directed therapy are allowed, but a fresh biopsy is strongly preferred after the latest systemic regimen.
• At least one measurable lesion per RECIST v1.1.
• Tumor tissue available for central review demonstrating Nectin-4 positivity (for example, IHC ≥1+ in ≥10% tumor cells) and HER2 status assessed by IHC/ISH. At least one of the selected therapeutic targets must be present; dose expansion preferentially enrolls Nectin-4-positive disease.
• ECOG performance status 0-1.
• Adequate bone marrow, hepatic, renal, and coagulation function.
• Life expectancy of at least 12 weeks.
• Negative pregnancy test for women of childbearing potential and agreement to use highly effective contraception during study treatment and follow-up as defined in the protocol.
• Ability to understand and sign informed consent.