TROP2 CAR工程化IL-15转导脐带血来源NK细胞治疗晚期实体瘤的I期研究（TROPIKANA）

Background: Adoptive cell therapy (ACT) has revolutionized outcomes in hematologic malignancies; however, its application in solid tumors remains limited by antigen heterogeneity, manufacturing complexity, and toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Natural killer (NK) cells mediate cytotoxicity without prior antigen exposure. Chimeric antigen receptor (CAR)-NK has emerged as a promising alternative for CAR-T, offering innate cytotoxicity that could mitigate antigen escape, improved “off-the-shelf” feasibility and reduced toxicity. TROP2, a transmembrane glycoprotein overexpressed in multiple epithelial malignancies, including breast cancer and non-small cell lung cancer (NSCLC), is associated with poor prognosis. Its therapeutic relevance is supported by the success of TROP2-directed antibody-drug conjugates.TROP2 CAR-NK is a cord blood-derived NK-cell product transduced with IL-15 to enhance persistence and an inducible caspase-9 (iC9) safety switch. Preclinical studies demonstrated potent and antigen-specific cytotoxicity against TROP2-positive tumors including breast and NSCLC models, without off-tumor toxicity in normal human cell lines. We hypothesize that this approach will be safe and demonstrate preliminary antitumor activity in patients with advanced high TROP2-expressing solid tumors. Methods: TROPIKANA (NCT06066424) is a single-center, open-label, first-in-human phase 1 dose-escalation and expansion study of TROP2 CAR-NK cells in adult patients with advanced TROP2-positive solid tumors. Primary objectives are to evaluate the safety/tolerability, optimal cell dose, maximum tolerated dose, and recommended Phase 2 dose of TROP2-CAR-NK. Secondary objectives are to assess the preliminary efficacy, CAR-NK persistence, and pharmacodynamic immune effects. Approximately 54 patients with advanced or metastatic solid tumors with high TROP2 expression (IHC 2+ or 3+) will be enrolled using a Bayesian Optimal Interval Phase I/II (BOIN12) design. Dose expansion cohorts include patients with NSCLC and HER2-low/negative breast cancer with high TROP2 expression.Patients receive lymphodepleting chemotherapy (cyclophosphamide/fludarabine, days −5 to −3, followed by TROP2 CAR-NK infusion on day 0, up to 4 doses every 8 weeks. Primary endpoints are incidence and severity of adverse events as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Key secondary endpoints include overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, progression-free and overall survival. Exploratory analyses will evaluate longitudinal blood-based biomarkers, ctDNA dynamics, and immune profiling. The first patient on this trial was treated in January 2024 and is actively enrolling patients.