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

Официальное название

An Open-Label, Multicenter, Phase 1/2 Study of Allogeneic Dual-target CD70/CAIX (CA9) Chimeric Antigen Receptor Natural Killer Cells in Adults With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Обзор

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.

Подробное описание

Advanced clear cell RCC remains difficult to treat after immune checkpoint blockade and VEGF-pathway therapy. Both CD70 and CAIX are attractive RCC targets: CAIX is broadly expressed in clear cell RCC, while CD70 is frequently overexpressed and has already generated encouraging clinical cell-therapy signals in RCC \[3-11\]. The investigational product in this example is an allogeneic, cord blood-derived NK cell product engineered to express a dual CAR recognizing CD70 and CAIX/CA9, membrane-bound IL-15 to enhance persistence, and an inducible caspase-9 safety switch to improve controllability. The allogeneic CAR-NK strategy is intended to provide an off-the-shelf platform with lower theoretical risk of graft-versus-host disease than allogeneic T-cell products and with innate NK killing as a complementary antitumor mechanism \[1, 2, 11\]. The study uses a standard dose-escalation phase followed by a biomarker-guided expansion phase. All participants receive lymphodepletion with fludarabine and cyclophosphamide and then one infusion of dual-target CAR-NK cells on Day 0; an optional second infusion on Day 15 is allowed for participants without doselimiting toxicity, uncontrolled cytokine-mediated toxicity, or rapid progression.

During expansion, participants remain in a single treatment arm but are prospectively analyzed in CD70-high, CAIX-high, and dual-high subgroups. Because earlier CAIX CAR-T studies in metastatic RCC reported on-target hepatobiliary toxicity related to low-level CAIX expression in biliary epithelium, this example protocol incorporates enhanced liver screening, exclusion of significant biliary disease, staggered first-patient dosing at each dose level, frequent liver function monitoring, and an explicit early stopping rule for recurrent protocoldefined hepatobiliary toxicity \[5, 6\].

The translational objective is not only to identify a recommended phase 2 dose but also to learn which antigen context appears most actionable in patients. If activity clusters in CD70-high tumors with cleaner safety, later development may pivot toward a CD70-led construct. If CAIX-high tumors uniquely benefit without meaningful hepatobiliary toxicity, CAIX/CA9 may remain central. If dual-high tumors clearly outperform single-high tumors without added risk, the dual-target program should continue.

Вмешательства

• Биопрепарат EB-701/CA9-NK
  dual-target allogeneic CAR-NK cells (single infusion on Day 0; optional second infusion on Day 15 if safety criteria are met)
• Препарат Fludarabine
  lymphodepletion

Первичные конечные точки

• Incidence of dose-limiting toxicities (DLTs) [Срок оценки: 28 Days]
• Determination of recommended phase 2 dose [Срок оценки: 8 weeks]

Вторичные конечные точки (2)

• Objective response rate (ORR) per RECIST 1.1 by independent radiologic review [Срок оценки: 6 months]
• Overall Survival (OS) [Срок оценки: 12 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking University Shenzhen Hospital — Шэньчжэнь

Идентификаторы

NCT: NCT07551349 · EBNK-RCC-70CA9-120

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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