Spatial MSC Index for Predicting Anti-PD-1 Efficacy in Esophageal Cancer

N/AActive Not RecruitingNCT07745322

Peking University Cancer Hospital & Institute270 enrolled

Overview

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.

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: 1. 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. 2. 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.

Study Type

OBSERVATIONAL

Enrollment

270

Conditions

Esophageal Squamous Cell Carcinoma Esophageal Neoplasms

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Histologically confirmed esophageal squamous cell carcinoma (ESCC). 2. 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. 3. Availability of adequate, high-quality archived pre-treatment tumor tissue biopsies (FFPE blocks or unstained slides) containing sufficient tumor and stromal areas. 4. At least one measurable target lesion according to RECIST 1.1 criteria at baseline. 5. ECOG performance status of 0 or 1 at the initiation of anti-PD-1 therapy. 6. Complete clinicopathological and follow-up data retrievable from medical records. Exclusion Criteria: 1. Histology other than squamous cell carcinoma (e.g., adenocarcinoma, small cell carcinoma). 2. Prior systemic exposure to anti-PD-1, anti-PD-L1, anti-CTLA-4, or other immunotherapy agents. 3. Concomitant systemic antibiotic, antifungal, or antiviral treatment within 14 days prior to tissue biopsy collection. 4. Active autoimmune diseases or psychiatric disorders that prevent compliance. 5. Insufficient tumor tissue specimen for dual ISH-IF spatial analysis.

Outcomes

Primary Outcomes

Objective Response Rate (ORR)

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.

Time frame: Up to 12 months from the first dose of anti-PD-1 therapy

Secondary Outcomes

Diagnostic Accuracy (AUC)

Calculated using ROC analysis to evaluate the capability of the MSC index to discriminate between immunotherapy responders (CR/PR) and non-responders (SD/PD).

Time frame: Up to 12 months from the first dose of anti-PD-1 therapy (best overall response assessment)

Progression-Free Survival (PFS)

Time from the first dose of anti-PD-1 therapy to the date of objective disease progression or death from any cause, whichever occurs first.

Time frame: Up to 24 months

Overall Survival (OS)

Time from the first dose of anti-PD-1 therapy to the date of death from any cause.

Time frame: Up to 36 months