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Research Highlight | Jul 1, 2018

Montreal immunotherapy team studying ways to overcome treatment resistance in patients with melanoma

Immunologist Dr. John Stagg (Université de Montréal, CR-CHUM) tells us how he and his team will contribute to a Montreal Cancer Consortium (MCC) initiative that is focused on bringing new hope to melanoma patients.

In recent years, researchers have made significant progress developing new treatments for melanoma. These treatments include the use of checkpoint inhibitors that allow the immune system to fight cancer cells, as well as new “smart drugs” designed to target specific gene mutations common in melanoma patients. But while these treatments are successful in about half of melanoma patients, the other half quickly builds resistance to them. This resistance is what Dr. Stagg’s research group is studying as part of the TFRI sub-project titled Development of novel-pre-clinical treatment strategies to improve immune checkpoint inhibitor therapy and to overcome resistance in melanoma.

Here Dr. Stagg explains the project, its role within the groundbreaking Montreal Cancer Consortium (MCC), and how his team hopes to make immunotherapies more effective for melanoma patients.

Q: First of all, tell us about the project and its main objectives. 
A: Our project has three main goals. Our first objective is to investigate how targeted therapy with BRAF/MEK inhibitors modulate the tumour microenvironment and the systemic immune landscape in melanoma patients. Our second goal is to identify novel melanoma antigens recognized by the immune system that can be used for therapeutic vaccination, which is one of the most promising strategies in immuno-oncology. The third objective of the project is to use pre-clinical models to evaluate the therapeutic activity of novel immune checkpoint inhibitors and novel targeted therapy. Specifically, we will evaluate the synergistic effects of targeting the adenosine, GSK-3 and MNK-1/2 pathways to overcome resistance to anti-PD-1/CTLA-4 therapy.

Q: How do you plan to achieve these goals?
A: To understand how the immune system interacts with BRAF/MEK inhibitors, we will use tumour biopsies and blood samples, which will be analyzed before, at resection, and upon progression of the treatment using state-of-the-art platforms in genomics, proteomics and immune-monitoring. For the second part, which involves the identification of melanoma antigens, we will use a unique pipeline that hinges next-generation sequencing, high-throughput mass spectrometry, bioinformatics and machine learning.

Q: How could the findings from this project improve life for these patients?
A: The proportion of melanoma patients receiving precision medicine has increased significantly in the past few years with the development of targeted and immune therapies. A better understanding of the immune landscape of melanoma during and after targeted therapy could alert oncologists when to switch treatment regimens from targeted therapies to checkpoint inhibitors. Multi-platform analyses of patients’ samples will further inform us on the most relevant pathways involved in treatment resistance and pre-clinical models will serve to test the activity of novel treatments. Finally, since lessons learned from melanoma have led to the approval of immunotherapies in over 10 different types of cancer, our project could thus lead to discoveries applicable to other types of cancer.

Q: How will collaboration with researchers within the MCC make it possible to achieve these objectives?
A: This project will build a strong network between clinical oncologists, platform leaders and pre-clinical experts by consolidating existing research strengths and forging new multi-centre collaborations across research-intensive hospitals and institutes in Montreal. This will serve to collectively co-ordinate implementation of advanced technology in genomics, proteomics, immune monitoring and pre-clinical models to advance the next generation of precision medicines in melanoma.

Q: How can this project advance the implementation of precision medicine in Canada?
A: Our project has gathered together top basic scientists and clinicians who have pioneered the development of new melanoma treatments, including with targeted and immunotherapies. Importantly, our team can rapidly take new discoveries to patients in the form of clinical trials.