Phase I trial of personalized AI-identified TCR-transduced T cell therapy in advanced solid tumors.

Abstract

2535 Background: TCR-T cell therapy shows promise in treating solid tumors but is limited by the need for personalized TCR identification. We developed TCR-XFinder, a deep learning model using a 3-stage transfer-learning strategy, to rapidly identify personalized tumor-reactive TCRs within 10 days after tumor tissue acquisition. This study reports the first-in-human phase I trial of KSX01, a TCR-transduced T cell therapy identified by TCR-XFinder. Methods: We conducted a phase I, dose-escalation study (NCT06150365) to evaluate the safety and efficacy of KSX01 in patients with advanced solid tumors. Tumor tissues were subjected to single-cell RNA sequencing and TCR sequencing to identify tumor-reactive TCRs using TCR-XFinder. These TCRs were validated and transduced into autologous T cells, which were expanded and infused back into patients. Patients received preconditioning with cyclophosphamide (500 mg/m²/day) and fludarabine (30 mg/m²/day) for 3 days, followed by intravenous infusion of KSX01 TCR-T cells at two dose levels (5×10⁹ ± 30% and 1×10¹⁰ ± 30% cells). Safety was assessed by monitoring adverse events and cytokine release syndrome (CRS). Efficacy was evaluated by RECIST v1.1 criteria. Results: Four patients with advanced solid tumors (alveolar soft part sarcoma, epithelioid sarcoma, colon cancer, and clear cell renal cell carcinoma) were enrolled. KSX01 TCR-T cells were well-tolerated at both dose levels, with no dose-limiting toxicities (DLTs) observed. All patients experienced Grade 3–4 pancytopenia, which was expected following lymphodepletion. One patient developed Grade 2 CRS, resolved with tocilizumab. No Grade 3 or higher AEs related to KSX01 were noted. At the first tumor assessment (Day 28), all patients showed disease control, with one patient achieving a partial response (PR) and a 46% reduction in target lesion size. Another patient achieved PR with second infusion at higher dose. qPCR analyses confirmed the infiltration and long-term anti-tumor effect of infused TCR-T cells. A transient post-infusion increase in interferon-γ (IFN-γ), interleukin-6(IL-6), IL-10, IL-4, tumor necrosis factor-α (TNF-α), and CRP levels was observed in all patients. While the C max and T max values varied among cytokines, the first T max for 80% of cytokines and CRP occurred within the first week post-infusion. Re-biopsy of tumor lesions showed infiltration of infused TCR-T with persistent cytotoxic function and ameliorate the microenvironment for the endogenous tumor-reactive T cells. Conclusions: The first-in-human phase I trial of KSX01 TCR-T cell therapy demonstrated promising safety and efficacy in patients with advanced solid tumors. TCR-XFinder enabled rapid identification of personalized tumor-reactive TCRs, supporting the clinical feasibility of this approach. Further studies are warranted to explore optimal dosing and combination strategies to maximize clinical benefit. Clinical trial information: NCT06150365 .