Neoadjuvant immunochemotherapy plus thymalfasin in locally advanced gastric cancer: a prospective clinical trial.
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BACKGROUND: Neoadjuvant immunochemotherapy has emerged as a promising strategy for locally advanced gastric and gastroesophageal junction (G/EGJ) adenocarcinoma, but a substantial proportion of patients derive limited benefit. Thymalfasin is an immunomodulatory peptide that may amplify antitumor immunity while attenuating toxicity. We conducted a phase II trial to evaluate anti-PD-1 plus SOX (S-1 and oxaliplatin) immunochemotherapy combined with thymalfasin as neoadjuvant treatment for G/EGJ adenocarcinoma. METHODS: The prospective trial enrolled patients aged 18-75 with cStage III G/EGJ adenocarcinoma, ECOG 0-1, and adequate organ function. Treatment included three 21-day cycles of serplulimab (anti-PD-1) plus SOX (S-1 and oxaliplatin) and 9 weeks of thymalfasin, followed by curative gastrectomy. The primary endpoint was pathological complete response (pCR). Secondary endpoints included major pathological response (MPR), safety, survival, and other efficacy measures. Peripheral immune remodeling was assessed by flow cytometry, and bulk RNA sequencing of peripheral blood mononuclear cells (PBMCs) interrogated thymalfasin-associated transcriptional programs. RESULTS: Thirty patients were enrolled and all underwent curative-intent minimally invasive gastrectomy. pCR was achieved in 30.0% (9/30), and MPR in 56.7% (17/30). ypN0 status was observed in 63.3% (19/30), with N-stage downstaging in 80.0% (24/30). At a median follow-up of 14.0 months (range 10.0-17.2), only one retroperitoneal nodal relapse had occurred at 14.4 months after diagnosis; no deaths were documented. Any-grade adverse events (AEs) occurred in 93.3% of patients, grade ≥ 3 AEs in 26.7%, and immune-related AEs in 23.3%. Flow cytometry showed expansion of CD8⁺ T cells with increased CD69 expression and a concurrent reduction in HLA-DR-positive T cells, suggesting dynamic remodeling from broad systemic activation toward a more focused effector or memory response. RNA-seq revealed thymalfasin-associated upregulation of genes involved in antigen processing and presentation, type I interferon signaling, and identified immune co-expression modules linked to treatment and response. CONCLUSIONS: Neoadjuvant serplulimab, SOX, and thymalfasin produced encouraging pathological response, substantial nodal clearance, and an acceptable safety profile in stage III G/EGJ adenocarcinoma. Peripheral immune and transcriptomic profiling are consistent with a hypothesis in which thymalfasin may help preserve and coordinate systemic antitumor immunity without excessive toxicity. These findings warrant further larger randomized trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06461910, 2024-06-14.