Investigating the effects of immunogenic chemoradiation in shaping the immune landscape of esophageal cancers

Projektinformationen

IC_IL_EC_2017

ID Finanzhilfevereinbarung: 752698

DOI

10.3030/752698

Projekt abgeschlossen

EK-Unterschriftsdatum 24 März 2017

Startdatum 1 März 2018

Enddatum 19 Mai 2020

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 168 277,20

EU-Beitrag

€ 168 277,20

Koordiniert durch

OSPEDALE SAN RAFFAELE SRL
Italy

Periodic Reporting for period 1 - IC_IL_EC_2017 (Investigating the effects of immunogenic chemoradiation in shaping the immune landscape ofesophageal cancers)

Berichtszeitraum: 2018-03-01 bis 2020-02-29

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

"Esophageal cancer is among the top 10 deadliest cancers worldwide, with the adenocarcinoma (EAC) variant representing the predominant histological subtype in western countries. The standard therapy for esophageal adenocarcinoma is pre-operative neoadjuvant chemo-radiation and surgery. Only about 20% of patients achieve a pathological complete response (pCR) and increased 5-year survival after NACR. Understanding the mechanisms of response to NACR is pivotal to better stratify patients and inform the design of more efficacious therapies.
Evidence suggests that the neoadjuvant chemo-radiatiotherapy stimulates anti-cancer immune responses, which may contribute to the long-term effects of successful treatments.
Tumor-specific responses of T lymphocytes, cells of the immune system, are directed against proteins from DNA mutations in the tumor, that are recognized as ""non-self"".
This project investigates whether the apathologic complete response to neoadjuvant chemo-radiotherapy treatment achieved in a fraction of patients with esophageal cancer may result from the stimulation of tumor-specific immune responses that contributes to cancer cell elimination.
This proof-of concept study may lead to the definition of novel and more efficacious immunotherapeutic approaches for EAC, including the design of cancer vaccines to newly diagnosed cases to block disease progression, with a strong impact in ameliorating the patients quality of life.
The overall objective of this project are to investigate the molecular and cellular mechanisms of immune response against esophageal cancer upon neoadjuvant chemo-radiotherapy, by comparing responder and non-responder patients for the molecular pathways in the tumor, the infiltration of cells of the immune system in the tumor and the regognition of tumor DNA mutation by the patients immune system."

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

"Esophageal adenocarcinoma tumor biopsies were collected by endoscopy from 32 patients cases with esophageal adenocarcinoma after patients informed consent. Tumor biopsies before neoadjuvant chemo-radiation therapy from 18 patients were analyzed by sequencing of the DNA and RNA. These data were analyzed to predict mutated tumor proteins (""tumor neoantigens"") presented by the patients HLA molecules to the immune system. These results will contribute, after further validation on more esophageal cancer samples, to the definition of new molecular markers of response to neoadjuvant chemoratiotherapy.

We implemented a method to test the recognition of tumor neoantigens, i.e. mutated tumor proteins, by the patients immune system. We investigated whether the patients with complete response to neoadjuvant chemo-radiotherapy have more TNAs recognized by patients lymphocytes that contribute to cancer elimination

Tumot biopsies collected before treatment from 50 patients were coloured for 8 protein markers to identify several types of cells of the immune system infiltrating the tumor, both pro-tumoral and anti-tumoral immune cells. tThese results were validated by flow cytometry analysis for 42 protein markers to identify better the cells of the immune system in the tumor before treatment."

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Genomic analysis (DNA and RNA sequencing) from treatment-naïve esophageal adenocarcinoma samples prospectively obtained from consecutive patients, integrated with the analysis of multiple immune markers and in vitro assays with patients immune cells, has been performed within this project e for the first time.
These preliminary results support an immune-mediated mechanism of response to NACR elicited in a fraction of EAC patients, suggesting possible ways to stratify patients and direct them to more tailored neoadjuvant and/or adjuvant treatments.
One of the innovations developed in the project has been analysed by the European Commission's Innovation Radar. This innovation is: “Biomarkers of response to neoadjuvant chemo-radiation in esophageal adenocarcinoma to improve early prognosis and design personalized immunotherapies”.
This innovation would benefit the society by improving the therapeutic efficacy against esophageal cancer, the 7th most deadliest malignancies worldwide and with an incidence on over 500.000 world cases in 2018 (GLOBOCAN).

Presentation at the European Union Corner at Meet Me Tonight 2018 in Milan