The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. We designed a phase 1 clinical trial of TAC01-HER2, an autologous T cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and a dose-expansion at the recommended phase 2 dose (RP2D). A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events were cytokine release syndrome (n=14, 60.9%), anemia (n=5, 21.7%), and increased alanine aminotransferase (n=5, 21.7%). The RP2D was 6-8 × 10[6] per kg. No treatment-related deaths or adverse events leading to study discontinuation were reported. Two of 9 patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses, and the disease control rate (stable disease or partial response) was 61.1% in the 18 patients with evaluable assessments. The median progression-free survival was 2.6 months (range 0.8-12.4 months), and the overall survival rate at 6 months was 57.9% (95% CI, 36.3%-76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. In summary, we demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T cell activity through cellular therapy.

Brain metastases (BM) occur in nearly half of patients with lung cancer and significantly impair survival and quality of life. Historically, limited blood-brain barrier penetration and low intracranial efficacy of systemic therapies restricted treatment options. However, advances in immune checkpoint inhibitors and next-generation CNS-penetrant targeted therapies have reshaped the therapeutic landscape, improving intracranial control and patient outcomes. In parallel, stereotactic radiotherapy has emerged as a precise and effective local treatment with a more favorable safety profile compared with whole-brain radiotherapy. The integration of systemic and local approaches, guided by personalized medicine, offers new opportunities to optimize central nervous system disease control. Nevertheless, these advances raise key challenges regarding treatment sequencing, patient selection, and risk-adapted strategies. This review summarizes the evolving management of lung cancer BM and highlights future directions for clinical trial design, emphasizing the integration of clinical, biological, and radiological tools to guide individualized treatment strategies.