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Improving brain tumor treatment

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A new view of glioblastoma could help predict patient outcomes

This collaborative project aims at dramatically improving our understanding of glioblastoma (GBM) towards predicting responses to standard and experimental therapies.

GBM is the most common and aggressive brain tumor, affecting three to five individuals in every 100 000 people. The average age at diagnosis is 60 years and available treatments, involving surgery followed by radio- and chemotherapy, are associated with a median survival of only 15 months. In addition, GBM generally develops resistance to therapy, and only a few patients experience prolonged survival.

The goal of this project is to understand how the tumor microenvironment (TME), particularly immune system components, differ between tumors sampled at diagnosis and at recurrence, and how this correlates with patient response to standard and experimental treatments. In addition, patients with extraordinarily long survival will be analyzed and compared with patients experiencing a shorter course of disease.

Work on this project is supported by Wellcome Leap as part of the Delta Tissue program and is led by the Wyss Center, in collaboration with the University of Geneva, Geneva University Hospital and the Paris Brain Institute.  

The problem
Brain tumors are not usually analyzed as a whole. As a result, the complexity of the tumor and its microenvironment is not captured in its entirety

Investigations are typically performed on very thin GBM slices, only about 10 microns thick, and fail to capture the 3D complexity of the TME. In addition, standard analyses rarely analyze how the TME changes over time upon treatment. GBM comprise many different types of cells, each with their own genetic makeup. This tumor cell diversity enables cells to adapt to their environment.

A contributing factor to GBM resistance to current treatments is likely the immunosuppressive TME. The TME is composed of immune cells, blood vessels, molecules released by tumor cells as well as hypoxic areas. Altogether, this milieu is immunosuppressive, allowing the tumor to escape the immune response and progress.

Stéphane Pagès
Stéphane Pagès, PhD, Director of Neuroimaging at the Wyss Center
“To address this challenge, we are bringing together a dynamic group of scientists. Our colleagues at the Paris Brain Institute are experts in tissue preparation and computational analysis and, at the Wyss Center, we have deep expertise with fast and high-resolution lightsheet microscopy. Along with our collaborators from the University of Geneva and Geneva University Hospital, our aim is to understand the role of specific genes and proteins in the development of the tumor.”

A new approach
Revealing the 3D structure of large GBM samples to find correlates of prolonged survival

The team is using high-resolution 3D microscopy to map the spatial distribution of immune cells, tumor cells, genetic markers, blood vessels and hypoxic zones in entire human GBM.

By accurately mapping the TME in tumors from the same patient obtained before and after treatment, the goal is to build a model to help predict response to therapies. In addition, by comparing patients with short versus long survival, it will help identify parameters of the TME associated with longer survival, opening avenues for the development of novel therapies.

The experimental pipeline: A series of technologies, not yet applied to human brain tumors, will be used to map the spatial distribution of molecular markers, cells and blood vessels 


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Tissue preparation and labelling
Mesospim microscope credit stephane Pages
High resolution 3D imaging
Screenshot 20200123 164040
Data analysis and modelling

Experimental therapies

The local immunosuppressive effect of the GBM TME is thought to play a role in tumor progression. A new generation of immunotherapies attempts to reverse this immunosuppression by boosting the immune response. However, these strategies do not yet benefit the majority of patients.

A phase I/II clinical trial testing a GBM-derived peptide vaccine combined with an immune checkpoint inhibitor is enrolling patients with recurrent GBM at the University of Geneva and Geneva University Hospital. This immunotherapy trial aims at stimulating the patient’s immune system, and in particular T cells, towards tumor cells.

The team will map tumors from two patient cohorts in the trial, one being treated with the peptide vaccine alone and one with the vaccine combined with the immune checkpoint inhibitor pembrolizumab, an antibody used to potentiate vaccine-elicited T cell responses. This will help understand the effects of the peptide vaccine on the GBM TME and potentially identify parameters associated with patient outcome.

Richie
Richie Kohman, PhD, Chief Scientific Officer at the Wyss Center
“This is a great example of how the Wyss Center is combining its expertise in tissue imaging with clinical collaborators to make a real impact on pressing medical challenges. It’s our unique model that can enable bold projects such as this one to be accomplished.”
Valrie 01
Valérie Dutoit, PhD, Co-Research Group Leader at the University of Geneva
"We hope that the project will lead to a better understanding of the role of the tumor microenvironment in patients’ response to standard or experimental intervention and help to identify those patients likely to respond."

The insights provided by this project will provide a better understanding of the role of the TME in the response of patients to standard or experimental treatments, help to identify those patients with prolonged survival and open new avenues for developing novel treatment options.


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