Clinical Validation of the Microbial-Sensory Coupling (MSC) Index as a Predictive Biomarker for Anti-PD-1 Immunotherapy Responsiveness in Esophageal Squamous Cell Carcinoma Patients
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 270
- 试验地点
- 1
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
The intratumoral microbiota is a key modulator of the tumor immune microenvironment. This study aims to clinically validate a novel, AI-driven digital pathology biomarker-the Microbial-Sensory Coupling (MSC) index-which measures the spatial proximity between the intratumoral bacterium Campylobacter gracilis(C. gracilis) and host Trace Amine-Associated Receptor 1 (TAAR1)+ tumor cells. The study will evaluate whether the MSC index, measured in pre-treatment tumor biopsy tissues, can accurately predict clinical responsiveness and survival outcomes in ESCC patients undergoing anti-PD-1-based immunotherapy.
详细描述
Emerging evidence indicates that C. gracilis secretes a unique xenometabolite, cadaverine, which binds to and activates the host TAAR1 receptor on ESCC cells, thereby promoting tyrosine kinase FAK-dependent secretion of the chemokine and cytokine. This pathway orchestrates immune cells, leading to resistance to anti-PD-1 therapy.
This retrospective observational study employs multiplexed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) / multiplex immunofluorescence (mIF), combined with deep-learning-based image segmentation, to quantify the spatial relationship between C. gracilis and TAAR1+ tumor cells.
The study consists of two phases:
- Discovery Phase (Cohort A, n=120): To establish the mathematical model of the MSC index and determine the optimal cut-off value using ROC analysis.
- Validation Phase (Cohort B, n=150): An independent retrospective cohort to validate the predictive specificity, sensitivity, and clinical utility (PFS, OS, and ORR) of the pre-determined MSC index cut-off.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed esophageal squamous cell carcinoma (ESCC).
- •Received standard anti-PD-1 antibody therapy (e.g., pembrolizumab, camrelizumab, sintilimab, toripalimab) combined with chemotherapy or as monotherapy, with at least one post-treatment response evaluation available.
- •Availability of adequate, high-quality archived pre-treatment tumor tissue biopsies (FFPE blocks or unstained slides) containing sufficient tumor and stromal areas.
- •At least one measurable target lesion according to RECIST 1.1 criteria at baseline.
- •ECOG performance status of 0 or 1 at the initiation of anti-PD-1 therapy.
- •Complete clinicopathological and follow-up data retrievable from medical records.
排除标准
- •Histology other than squamous cell carcinoma (e.g., adenocarcinoma, small cell carcinoma).
- •Prior systemic exposure to anti-PD-1, anti-PD-L1, anti-CTLA-4, or other immunotherapy agents.
- •Concomitant systemic antibiotic, antifungal, or antiviral treatment within 14 days prior to tissue biopsy collection.
- •Active autoimmune diseases or psychiatric disorders that prevent compliance.
- •Insufficient tumor tissue specimen for dual ISH-IF spatial analysis.
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Up to 12 months from the first dose of anti-PD-1 therapy
Percentage of patients achieving Complete Response (CR) or Partial Response (PR) based on RECIST 1.1 criteria, compared between MSC-high and MSC-low groups.
次要结局
- Diagnostic Accuracy (AUC)(Up to 12 months from the first dose of anti-PD-1 therapy (best overall response assessment))
- Progression-Free Survival (PFS)(Up to 24 months)
- Overall Survival (OS)(Up to 36 months)