Pre- and On-treatment Multi-omics Profiling of Locally Advanced Rectal Cancer
A Prospective Observational Study of Tumour Microenvironment Remodelling During Neoadjuvant Therapy in Locally Advanced Rectal Cancer Using Single-Cell and Spatial Multi-omics
This prospective observational study characterises the tumour immune microenvironment and microbial ecology of locally advanced rectal cancer before and during neoadjuvant therapy. Tumour tissue and peripheral blood are profiled by whole-genome sequencing, single-cell RNA sequencing with paired T-cell and B-cell receptor repertoire sequencing, spatial transcriptomics of formalin-fixed paraffin-embedded sections, multiplex immunofluorescence, and blood-based proteomic, cytokine and bulk T-cell receptor analyses. The study examines how immune and stromal states change during treatment and how they relate to major pathological response.
Studienübersicht
Status
Bedingungen
Detaillierte Beschreibung
Locally advanced rectal cancer is increasingly treated with total neoadjuvant therapy combining short-course radiotherapy, chemotherapy and programmed cell death protein 1 (PD-1) blockade, but the effect of treatment sequence on the tumour microenvironment is unresolved, and few patients have been profiled with matched pre- and on-treatment single-cell data. In this observational study, we collect tumour tissue and peripheral blood from patients with locally advanced rectal cancer at baseline, before any neoadjuvant treatment, and again after completion of short-course hypofractionated radiotherapy (5 Gy in 5 fractions) followed by one cycle of chemo-immunotherapy, together with archival formalin-fixed paraffin-embedded tissue where available. Additional formalin-fixed paraffin-embedded specimens from treatment-naive patients undergoing primary surgery, and from end-of-treatment biopsies, are used as controls for the spatial analyses. Fresh tumour tissue is analysed by whole-genome sequencing and by single-cell RNA sequencing with paired T-cell and B-cell receptor repertoire sequencing. Formalin-fixed paraffin-embedded tissue is analysed by spatial transcriptomics and multiplex immunofluorescence. Peripheral blood mononuclear cells are analysed by bulk T-cell receptor repertoire sequencing, and plasma or serum by proteomic and cytokine profiling where material permits. The principal clinical endpoint is major pathological response (mPR) at resection. We examine changes in immune and stromal populations between baseline and the on-treatment time point, features of the immune microenvironment associated with mPR, and, as exploratory analyses, the tumour microbial ecology associated with response together with differences between neoadjuvant treatment sequences. Analyses are descriptive and hypothesis-generating; no intervention, treatment assignment or change in clinical care is involved. The study was approved by the Ethics Committee of Fujian Medical University Union Hospital (2024KY297, approved 30 December 2024; and 2024KJCX060, approved 18 September 2024); archival specimens are used under a waiver of additional informed consent, and fresh biopsy or surgical tissue and blood are collected with written informed consent.
Studientyp
Einschreibung (Geschätzt)
Kontakte und Standorte
Studienkontakt
- Name: Wan-cai Que
- Telefonnummer: 0086-0591-86218304
- E-Mail: xhyyjgb@163.com
Studienorte
-
-
Fujian
-
Fuzhou, Fujian, China, 350001
- Rekrutierung
- Fujian Medical University Union Hospital
-
-
Teilnahmekriterien
Zulassungskriterien
Studienberechtigtes Alter
- Kind
- Erwachsene
- Älterer Erwachsener
Akzeptiert gesunde Freiwillige
Studienberechtigte Geschlechter
Probenahmeverfahren
Studienpopulation
Patients with locally advanced rectal adenocarcinoma treated at Fujian Medical University Union Hospital, China, from whom tumour tissue and peripheral blood were collected before and during neoadjuvant therapy.
Beschreibung
Inclusion Criteria:
- Age 18 to 75 years
- Eastern Cooperative Oncology Group performance status 0-1
- Histologically confirmed rectal adenocarcinoma
- Locally advanced disease staged as cT3-T4N0 or cT2-T4N+ without distant metastasis (AJCC 8th edition)
- Lower border of the tumour within 10 cm of the anal verge
- Scheduled to receive neoadjuvant therapy followed by surgery, with tumour tissue and peripheral blood available before and during neoadjuvant therapy
- Written informed consent for fresh biopsy or surgical tissue, or a waiver granted by the institutional ethics committee for archival specimens
Exclusion Criteria:
- Insufficient tissue or nucleic acid quality for the planned profiling assays
- Incomplete clinical records precluding assessment of pathological or clinical response
- A history of other malignancy within 5 years other than adequately treated carcinoma in situ or basal cell carcinoma
Studienplan
Wie ist die Studie aufgebaut?
Designdetails
- Beobachtungsmodelle: COHORT
- Zeitperspektiven: PROSPECTIVE
Kohorten und Interventionen
Gruppe / Kohorte |
|---|
|
Achieved pathological or clinical complete response
Patients whose resection specimen showed a pathological complete response (ypT0N0) or who achieved a sustained clinical complete response, from whom pre-treatment and on-treatment tissue and blood were profiled. |
|
Did not achieve pathological or clinical complete response
Patients with residual viable tumour at resection or without a sustained clinical complete response, from whom pre-treatment and on-treatment tissue and blood were profiled. |
Was misst die Studie?
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
|
Change in immune and stromal cell composition in tumour tissue during neoadjuvant therapy
Zeitfenster: Baseline (before treatment) and week 4 after treatment initiation
|
Cell-type composition and transcriptional states of T, natural killer (NK), B and myeloid populations and of stromal subsets before treatment and during neoadjuvant therapy, determined by single-cell RNA sequencing. |
Baseline (before treatment) and week 4 after treatment initiation
|
|
Major pathological response (mPR) and its association with immune microenvironment features
Zeitfenster: Through study completion, an average of 4 years
|
Proportion of patients achieving major pathological response, defined as 10% or less residual viable tumour at resection, and the association of pre-treatment and on-treatment immune microenvironment features with mPR. |
Through study completion, an average of 4 years
|
Sekundäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
|
Transcriptional states of immune populations before and during treatment
Zeitfenster: Baseline (before treatment) and week 4 after treatment initiation
|
Exhaustion, activation and memory programmes of T and NK cells and B-cell states, determined by single-cell RNA sequencing with paired T-cell and B-cell receptor repertoire sequencing. |
Baseline (before treatment) and week 4 after treatment initiation
|
|
Spatial organisation of tumour and immune compartments before and during treatment
Zeitfenster: Baseline (before treatment) and week 4 after treatment initiation
|
Spatial distribution of tumour, immune and stromal compartments determined by spatial transcriptomics of formalin-fixed paraffin-embedded sections and multiplex immunofluorescence, compared with specimens from treatment-naive patients undergoing primary surgery and from end-of-treatment biopsies as controls. |
Baseline (before treatment) and week 4 after treatment initiation
|
|
Comparison of microenvironment remodelling between neoadjuvant treatment sequences
Zeitfenster: Through study completion, an average of 4 years
|
Between-group comparison of the change in tumour microenvironment composition between baseline and week 4, expressed as the percentage of cluster of differentiation 8 (CD8)-positive T cells, NK cells, B cells and plasma cells among all cells measured by single-cell RNA sequencing, in patients receiving radiotherapy before versus after chemo-immunotherapy. |
Through study completion, an average of 4 years
|
|
Somatic genomic alterations associated with response to neoadjuvant therapy
Zeitfenster: Baseline (before treatment) and week 4 after treatment initiation
|
Somatic mutations, copy-number alterations and mutational signatures determined by whole-genome sequencing of tumour tissue before and during neoadjuvant therapy. |
Baseline (before treatment) and week 4 after treatment initiation
|
|
Clonal diversity of the peripheral blood T-cell receptor repertoire
Zeitfenster: Baseline (before treatment) and week 4 after treatment initiation
|
Diversity and distribution of T-cell receptor clonotypes in peripheral blood mononuclear cells, expressed as the Shannon diversity index and the proportion of expanded clonotypes, measured by bulk T-cell receptor repertoire sequencing. |
Baseline (before treatment) and week 4 after treatment initiation
|
|
Correlation of tumour microbial composition with major pathological response
Zeitfenster: Baseline (before treatment) and week 4 after treatment initiation
|
Correlation between the relative abundance of tumour-associated bacterial taxa, expressed as the percentage of sequencing reads assigned to each taxon measured by small-subunit ribosomal RNA gene sequencing or shotgun metagenomic sequencing of tumour tissue, and major pathological response, expressed as the percentage of patients with 10% or less residual viable tumour at resection (exploratory). |
Baseline (before treatment) and week 4 after treatment initiation
|
|
Plasma protein and cytokine concentrations before and during neoadjuvant therapy
Zeitfenster: Baseline (before treatment) and week 4 after treatment initiation
|
Concentrations of plasma or serum proteins and cytokines, expressed in pg/mL, measured by multiplex proteomic and cytokine assays. |
Baseline (before treatment) and week 4 after treatment initiation
|
Mitarbeiter und Ermittler
Ermittler
- Studienleiter: Jian Liu (jianliu@nankai.edu.cn), PhD, Nankai University
Studienaufzeichnungsdaten
Haupttermine studieren
Studienbeginn (Tatsächlich)
Primärer Abschluss (Geschätzt)
Studienabschluss (Geschätzt)
Studienanmeldedaten
Zuerst eingereicht
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
Zuerst gepostet (Tatsächlich)
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Tatsächlich)
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
Zuletzt verifiziert
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Schlüsselwörter
Zusätzliche relevante MeSH-Bedingungen
Andere Studien-ID-Nummern
- FJMUUH-RECT-OMICS-2024-01
Plan für individuelle Teilnehmerdaten (IPD)
Planen Sie, individuelle Teilnehmerdaten (IPD) zu teilen?
Beschreibung des IPD-Plans
Individual participant data, including clinical records and sample-level identifiers, will not be shared. De-identified single-cell, bulk RNA sequencing and spatial transcriptomic data will be deposited in the Genome Sequence Archive for Human (GSA-Human), National Genomics Data Center, China, and will be made available for research use through the repository according to its access policy after publication.
Arzneimittel- und Geräteinformationen, Studienunterlagen
Studiert ein von der US-amerikanischen FDA reguliertes Arzneimittelprodukt
Studiert ein von der US-amerikanischen FDA reguliertes Geräteprodukt
Diese Informationen wurden ohne Änderungen direkt von der Website clinicaltrials.gov abgerufen. Wenn Sie Ihre Studiendaten ändern, entfernen oder aktualisieren möchten, wenden Sie sich bitte an register@clinicaltrials.gov. Sobald eine Änderung auf clinicaltrials.gov implementiert wird, wird diese automatisch auch auf unserer Website aktualisiert .