Abstract
BACKGROUND: Compared to conventional chemotherapy, metronomic chemotherapy (MCT), with lower drug dosage which may cause less damage to the immune system, has shown potential for synergy in combination with PD-1-based immunotherapy. However, this synergistic immunotherapy efficacy in neoadjuvant setting for advanced esophageal squamous cell carcinoma (ESCC) requires further clinical validation. METHODS: This pilot phase 2, single-center, randomized clinical trial enrolled 30 untreated patients with resectable stage II or III ESCC. Participants were randomly assigned to either the MCT group (paclitaxel, cisplatin, and 5-fluorouracil) or the IO + MCT group (same regimen plus camrelizumab). Primary outcomes included the pCR rate after neoadjuvant therapy, and the safety of each regimen assessed by adverse events. Digital spatial profiling (DSP-WTA), multiplex immunofluorescent staining (mIF), and bulk RNA sequencing were performed to explore the possible therapeutic mechanisms. RESULTS: Twenty-four patients (13 in MCT, 11 in IO + MCT) underwent R0 resection. The pCR rates were 15.4% in the MCT group and 54.5% in the IO + MCT group. Both treatments were well tolerated, with manageable side effects. DSP-WTA and mIF revealed that IO + MCT effectively decreased the number of tumor-infiltrating T cells with the positive expression of terminal exhaustion marker CD39 and increased the number of primary and secondary follicle-like tertiary lymphoid structures (TLSs), particularly in pCR patients. CONCLUSIONS: Neoadjuvant MCT combined with camrelizumab led to an increased pCR rate (54.5 vs. 16.7%) in ESCC patients compared to MCT alone. This combination therapy may offer a promising approach for enhancing cancer treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ChiCTR2000039638.