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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Trial registration <p>ClinicalTrials.gov identifier: ChiCTR2000039638.</p>

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Neoadjuvant camrelizumab combined with metronomic chemotherapy in patients with advanced esophageal squamous cell carcinoma: a pilot randomized phase 2 trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月3日

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  • Zhiming Chen,
  • Wenshuai Li,
  • Yumeng Guo,
  • Yongjun Zhu,
  • Yang Song,
  • Jiayan Wu,
  • Wanwei Zheng,
  • Yujen Tseng,
  • Lishuang Lin,
  • Feng Tang,
  • Beibei Mao,
  • Peng Zhao,
  • Xiangyu Guo,
  • Shiman Fu,
  • Gang Chen,
  • Ning Wu,
  • Bin Lv,
  • Yao Liu,
  • Shenyang Zhao,
  • Shaocong Mo,
  • Kewei Ma,
  • Kaiyi Fu,
  • Hongyang Zhang,
  • Jun Zhang,
  • Feifei Luo,
  • Zhongguang Luo,
  • Jie Liu

摘要

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.