CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.
* Uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV, sepsis, or active tuberculosis.
* 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.
* Clinically significant pulmonary disease (for example, uncontrolled interstitial lung disease or oxygen-dependent respiratory compromise).
* Use of systemic corticosteroids or other immunosuppressive medications above protocol-allowed limits within the washout window.
* History of severe hypersensitivity to fludarabine, cyclophosphamide, or cell-product excipients.
* Pregnancy or breastfeeding.
* Another active malignancy requiring systemic therapy or likely to interfere with protocol assessments, except for protocol-allowed low-risk cancers.

主要终点：Incidence of dose-limiting toxicities (DLTs) · 28 Days；Incidence and severity of treatment-emergent adverse · Incidence and severity of treatment-emergent adverse events graded by CTCAE v5.0,including CRS, ICANS, infusion reactions, GvHD, and organ-specific toxicities · 12 months
次要终点：Objective response rate (ORR) by RECIST v1.1；Disease control rate；Duration of response；Progression-free survival；Overall survival

• Dose Escalation · EXPERIMENTAL · Participants receive lymphodepletion with cyclophosphamide and fludarabine followed by EB-DT-NK-UC101 IV infusions on Day 1 and Day 8 of a 21-day cycle. Planned dose levels: 1 × 10\^7, 3 × 10\^7, and 1 × 10\^8 CAR-NK cells/kg
• Dose Expansion · EXPERIMENTAL · Participants receive the RP2D identified in Arm A using the same lymphodepletion backbone and infusion schedule. Expansion enriches for Nectin-4-positive disease and captures HER2 co-expression prospectively.

This hypothetical first-in-human study is designed to evaluate the safety, feasibility, and preliminary anti-tumor activity of an allogeneic dual-target Nectin-4/HER2 CAR-NK cell product in adults with relapsed/refractory locally advanced or metastatic urothelial carcinoma. Based on public urothelial-cancer evidence, Nectin-4 was selected as the lead antigen because it has the strongest disease-specific clinical validation; HER2/ERBB2 was chosen as the secondary co-target to broaden tumor coverage and reduce antigen-escape risk. EpCAM is not selected as a therapeutic co-target in this example because of broader normal epithelial expression and weaker tumor specificity in urothelial carcinoma.