Molecular Characterization of Tumor-Microenvironment Interactions to Predict Drug Resistance in Gastric and GEJ Adenocarcinoma (GASTROIMMUNE)
Molecular Characterization of Tumor-Microenvironment Interactions to Predict Drug Resistance to Perioperative Treatment in Patients With Gastric and Gastroesophageal Junction Adenocarcinoma
Surgical resection remains the only curative option for resectable gastric cancer, but perioperative FLOT chemotherapy is associated with substantial rates of chemoresistance and recurrence, largely driven by marked tumor heterogeneity. Recent data from the MATTERHORN phase III trial have shown that adding durvalumab to perioperative FLOT improves pathological complete response and survival, supporting this combination as a new standard of care for resectable gastric and gastroesophageal junction adenocarcinoma.
This observational multicenter study aims to characterize angiogenic and immune profiles within the tumor microenvironment and peripheral blood, in order to identify cellular and molecular signatures associated with response or resistance to perioperative FLOT plus durvalumab. Longitudinal biospecimen collection (PBMCs, serum, plasma, endoscopic biopsies, surgical specimens) will be integrated with multiparametric flow cytometry, single-cell transcriptomics and TCR/BCR sequencing, immunohistochemistry, pathomics and multiplex immunoassays, to provide mechanistic insights and potential predictive biomarkers.
A tanulmány áttekintése
Állapot
Részletes leírás
This observational multicenter study will prospectively enroll approximately 250 patients with operable, locally advanced gastric or gastroesophageal junction adenocarcinoma who receive perioperative FLOT plus durvalumab according to current clinical practice. Patients typically present with locally advanced disease (T ≥2 and/or node-positive) as defined by the AJCC 8th edition, and are candidates for perioperative chemo-immunotherapy followed by surgery.
Peripheral blood samples for PBMC isolation and serum/plasma storage will be obtained at baseline before neoadjuvant treatment (N1), before surgery (N2), and approximately 2 months after completion of adjuvant therapy (N3). Tumor tissue will be collected through diagnostic endoscopic biopsies and surgical resections; fresh and FFPE specimens will be used for immunohistochemistry, pathomics and omics analyses, including organoid cultures.
The study will implement a multiparametric registry integrating clinical, imaging and omics data, ensuring harmonized data collection across the two IRCCS centers (IRCCS Saverio de Bellis and Humanitas Clinical and Research Center). Tumor-infiltrating lymphocytes and PBMCs will be profiled by spectral flow cytometry (up to 40 markers), single-cell RNA sequencing and TCR/BCR sequencing to define immune subsets, activation and exhaustion states, and clonal expansion patterns.
Whole-slide digital histology (HE-stained sections) will be analyzed to derive robust pathomic biomarkers related to vascular architecture and immune cell distribution, previously associated with response to anti-angiogenic therapies; these biomarkers will be validated in the perioperative gastric/GEJ cohort. Serum cytokine and chemokine panels will be assessed using Luminex xMAP technology, while CT imaging acquired for staging and follow-up will be annotated to calibrate mathematical models predicting treatment response.
Statistical analyses will treat this project as a pilot study, given the lack of previous evidence on predictors of complete response to perioperative therapy. Patients will be stratified by Tumor Regression Grade (TRG), with TRG 1-2 considered responders and TRG 3-4 non-responders, and effect-size measures, ensemble machine-learning algorithms and multilevel longitudinal models will be used to identify and evaluate angiogenic and immune markers associated with short-term outcomes.
Tanulmány típusa
Beiratkozás (Becsült)
Kapcsolatok és helyek
Tanulmányi kapcsolat
- Név: Gianluigi Giannelli, MD
- Telefonszám: +390804994721
- E-mail: gianluigi.giannelli@irccsdebellis.it
Tanulmányozza a kapcsolattartók biztonsági mentését
- Név: Rosalba D'Alessandro, Biologist
- Telefonszám: 0804994178
- E-mail: rosalba.dalessandro@irccsdebellis.it
Részvételi kritériumok
Jogosultsági kritériumok
Tanulmányozható életkorok
- Felnőtt
- Idősebb felnőtt
Egészséges önkénteseket fogad
Mintavételi módszer
Tanulmányi populáció
Leírás
Inclusion Criteria:
- Histologically confirmed adenocarcinoma of the stomach (gastric cancer, GC) or gastroesophageal junction (GEJ)
- Operable, locally advanced disease (T >= 2 and/or node-positive) according to AJCC 8th edition staging
- Candidate for perioperative chemotherapy with FLOT regimen combined with durvalumab, as per clinical practice
- Age >= 18 years
- Provision of written informed consent prior to any study-specific procedure
Exclusion Criteria:
- Presence of another active malignant disease
- Advanced or metastatic gastric/GEJ cancer not eligible for surgical treatment
- Inability or unwillingness to provide written informed consent
Tanulási terv
Hogyan készül a tanulmány?
Tervezési részletek
Kohorszok és beavatkozások
Csoport / Kohorsz |
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Perioperative FLOT plus Durvalumab Cohort
Patients with operable, locally advanced gastric or gastroesophageal junction adenocarcinoma receiving perioperative chemotherapy (FLOT regimen: docetaxel, oxaliplatin, leucovorin, 5-fluorouracil) combined with durvalumab (anti-PD-L1) as standard of care.
Longitudinal biological samples (peripheral blood and tumor tissue) are collected for molecular characterization of tumor-microenvironment interactions and identification of predictive biomarkers of pharmacological resistance.
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Mit mér a tanulmány?
Elsődleges eredményintézkedések
Eredménymérő |
Intézkedés leírása |
Időkeret |
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Identification of immune and angiogenic cellular subsets associated with pathological response to perioperative FLOT plus durvalumab
Időkeret: At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy
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Identification of specific cellular subsets and activation/exhaustion states, assessed by scRNA-seq, TCR/BCR sequencing, and multiparametric spectral flow cytometry of tumor-infiltrating lymphocytes (TILs) and PBMCs, associated with pathological response (Tumor Regression Grade TRG 1-2) or resistance (TRG 3-4) to perioperative FLOT plus durvalumab.
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At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy
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Másodlagos eredményintézkedések
Eredménymérő |
Intézkedés leírása |
Időkeret |
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Association between angiogenic and immune signatures and clinical outcomes
Időkeret: From baseline to approximately 2 months after completion of adjuvant therapy (up to approximately 9 months)
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Correlation of angiogenic and immune profiles (serum cytokine/chemokine panels by Luminex xMAP, pathomic biomarkers from whole-slide HE images, and flow cytometry data) with clinical outcomes including Tumor Regression Grade (TRG), early recurrence, and short-term survival.
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From baseline to approximately 2 months after completion of adjuvant therapy (up to approximately 9 months)
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Validation of a pathomic biomarker related to angiogenesis and immune response
Időkeret: At baseline (endoscopic biopsy) and at surgical resection (approximately 3-4 months after treatment initiation)
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Validation of a previously developed pathomic biomarker derived from whole-slide HE digital histology, related to vascular architecture and immune cell spatial distribution, as a predictor of response to perioperative FLOT plus durvalumab in gastric and GEJ adenocarcinoma.
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At baseline (endoscopic biopsy) and at surgical resection (approximately 3-4 months after treatment initiation)
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Characterization of immune evasion mechanisms in non-responders
Időkeret: At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy
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Characterization of immune evasion mechanisms in the tumor microenvironment of non-responders (TRG 3-4) based on single-cell analyses (scRNA-seq, TCR/BCR-seq) of TILs and PBMCs, including identification of exhausted T cell populations, immunosuppressive cell subsets, and altered antigen presentation pathways.
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At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy
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Együttműködők és nyomozók
Nyomozók
- Kutatásvezető: Carlo Castori, MD, UOC Chirurgia Esofago Gastrica - Istituto "Humanitas" di Milano
Publikációk és hasznos linkek
Általános kiadványok
- Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Lohr C, Bernhard H, Schuch G, Rethwisch V, von Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Weniger J, Belle S, Gaiser T, Oduncu FS, Guntner M, Hozaeel W, Reichart A, Jager E, Kraus T, Monig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957. doi: 10.1016/S0140-6736(18)32557-1. Epub 2019 Apr 11.
- Albano F, Severini FL, Calice G, Zoppoli P, Falco G, Notarangelo T. The role of the tumor microenvironment and inflammatory pathways in driving drug resistance in gastric cancer: A systematic review and meta-analysis. Biochim Biophys Acta Mol Basis Dis. 2025 Aug;1871(6):167821. doi: 10.1016/j.bbadis.2025.167821. Epub 2025 Apr 7.
- Janjigian YY, Al-Batran SE, Wainberg ZA, Muro K, Molena D, Van Cutsem E, Hyung WJ, Wyrwicz L, Oh DY, Omori T, Moehler M, Garrido M, Oliveira SCS, Liberman M, Oliden VC, Smyth EC, Stein A, Bilici M, Alvarenga ML, Kozlov V, Rivera F, Kawazoe A, Serrano O, Heilbron E, Negro A, Kurland JF, Tabernero J; MATTERHORN Investigators. Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer. N Engl J Med. 2025 Jul 17;393(3):217-230. doi: 10.1056/NEJMoa2503701. Epub 2025 Jun 1.
Tanulmányi rekorddátumok
Tanulmány főbb dátumok
Tanulmány kezdete (Becsült)
Elsődleges befejezés (Becsült)
A tanulmány befejezése (Becsült)
Tanulmányi regisztráció dátumai
Először benyújtva
Először nyújtották be, amely megfelel a minőségbiztosítási kritériumoknak
Első közzététel (Tényleges)
Tanulmányi rekordok frissítései
Utolsó frissítés közzétéve (Tényleges)
Az utolsó frissítés elküldve, amely megfelel a minőségbiztosítási kritériumoknak
Utolsó ellenőrzés
Több információ
A tanulmányhoz kapcsolódó kifejezések
Kulcsszavak
Egyéb vizsgálati azonosító számok
- GASTRO-IMMUNE-FLOT-2026
Terv az egyéni résztvevői adatokhoz (IPD)
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