Dual-target CD70/CAIX CAR-NK Cells for Advanced Clear Cell Renal Cell Carcinoma

Summary

Phase 1/2 study evaluates the safety, feasibility, and preliminary antitumor activity of allogeneic dual-target CD70/CAIX CAR-NK cells after fludarabine/cyclophosphamide lymphodepletion in adults with advanced or metastatic clear cell RCC that has progressed after standard therapy. The study is designed to determine a recommended dose and schedule, characterize hepatobiliary safety, and explore whether CD70-high, CAIX-high, or dual-high tumors derive the greatest benefit. Biomarker-defined activity signals will be used to guide whether later development should prioritize CD70, CAIX/CA9, or continued dual-targeting.

Eligibility

Inclusion Criteria:

* Written informed consent and willingness to comply with protocol procedures.
* Age \>= 18 years at the time of consent.
* Histologically confirmed unresectable or metastatic clear cell RCC, or RCC with a clear-cell component, with radiographic progression after standard therapy.
* Prior exposure to at least one PD-1 / PD-L1-based regimen and at least one VEGF-pathway targeted regimen, or documented intolerance / unsuitability for available standard systemic options.
* At least one measurable lesion by RECIST 1.1.
* Available archival tumor tissue or willingness to undergo fresh biopsy for central biomarker testing; protocoldefined tumor positivity for CD70 and/or CAIX is required. Dual-positive cases are preferred for the biomarkerexpansion portion.
* ECOG performance status 0-1.
* Adequate marrow, liver, cardiac, pulmonary, and renal function as defined by the protocol (for example, ANC, platelets, bilirubin, AST/ALT, creatinine clearance, oxygen saturation, and left ventricular function within protocoldefined limits).
* Life expectancy of at least 12 weeks.
* Negative pregnancy test for participants of childbearing potential and agreement to highly effective contraception during protocol-defined risk windows.
* Previously treated brain metastases are allowed if clinically stable and off escalating corticosteroids for at least 14 days before lymphodepletion.

Exclusion Criteria:

* Active, untreated, or symptomatic central nervous system metastases, leptomeningeal disease, or uncontrolled seizure disorder.
* Prior gene-modified cellular therapy (including prior CAR-T, CAR-NK, CAR-NKT, or TCR-engineered therapy) within the protocol-defined washout window.
* Prior allogeneic stem cell transplant or solid organ transplant with ongoing clinically significant immunosuppression.
* Active autoimmune disease requiring systemic immunosuppressive treatment; physiologic replacement doses are permitted.
* Active uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV, tuberculosis, or sepsis.
* Clinically significant hepatobiliary disease that could increase risk from CAIX-directed therapy, such as active cholangitis, primary sclerosing cholangitis, biliary obstruction, Child-Pugh B/C cirrhosis, or prior hepatic venoocclusive disease.
* Clinically significant cardiovascular disease (for example, unstable angina, recent myocardial infarction, uncontrolled arrhythmia, or clinically meaningful heart failure).
* Systemic corticosteroid use greater than 10 mg prednisone equivalent daily within 7 days before lymphodepletion, unless required as physiologic replacement.
* Pregnancy or breastfeeding.
* Another active invasive malignancy requiring systemic treatment, except for protocol-defined low-risk exceptions.
* Known hypersensitivity to fludarabine, cyclophosphamide, or a critical study-product excipient.

Conditions2

Interventions2

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