First-in-human phase I study of UCL70802, a LACO-Stim armored Anti-CD70 CART cell therapy, in patients with metastatic clear cell renal cell carcinoma (mccRCC)

Background: UCL70802 is a novel autologous CART product engineered to co-express an anti-CD70 CAR and a Lymphocyte-APC-Co-stimulator (LACO-Stim) molecule, designed to target CD70-positive tumors through dual mechanisms: direct tumor lysis via CAR engagement and systemic immune activation via LACO-Stim. LACO-Stim provides co-stimulation through CD40 and CD28, enhancing T cell and APC function, remodeling the tumor microenvironment, and promoting anti-tumor immunity. Methods: Eligible patients with CD70 positive mccRCC who failed standard therapies were enrolled. Primary endpoints included safety, dose-limiting toxicities, and maximum tolerated dose. Secondary endpoints covered pharmacokinetics and antitumor response per RECIST v1.1. Results: As of December 30, 2025, 6 patients were treated. Safety analysis showed manageable Grade 1-2 cytokine release syndrome (CRS) in 4 patients and Grade 3 CRS in 2 patients (recover to Grade 2 in 1 day). Treatment-related adverse events (TRAEs) included lymphopenia (100%), erythema (100%), and edema (83.3%). All Grade 3 or higher TRAEs were hematological toxicities associated with the lymphodepletion. NO DLTs were observed. Anti-tumor activity was observed across all dose levels except one patient with the dose of 0.6×10⁶/kg (DL1). At the dose level of 2×10⁶/kg (DL3), 2 out of 3 patients achieved a partial response (PR). One patient achieved a conformed PR (-68.9%). The other patient experienced a tumor shrinkage at M1(-17.3%) and achieved PR at M2 (-32.3%). There is a correlation between dose and CAR-T exposure. In DL3, the median peak CAR copy number (Cmax) reached 37750 copies/μg, which is much higher than in DL2. Notably, one patient at DL2 demonstrated mild exposure with C max of 1,368 copies/μg DNA yet achieved sustained tumor shrinkage. Although CAR copies were undetectable at M1, tumor shrinkage persisted for over six months, with tumor reduction increasing from -17.4% at M1 to -26.5% at M6. This indicates that after the initial antitumor response induced by anti-CD70 CAR-T cells, sustained activity was maintained by the innate immune system activated via the LACO-Stim molecule. Conclusions: UCL70802 demonstrated a manageable safety profile and promising preliminary antitumor activity in mccRCC patients. Its dual mechanism -combining direct CAR-mediated targeting with systemic immune activation via LACO-Stim-may help overcome resistance seen with conventional CAR-T therapies. Dose escalation continues to further assess efficacy and safety.