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Research Highlight | October 16, 2019

Early results from two studies provide insight into who may benefit from immunotherapies

Immunotherapy is a cancer treatment that harnesses the power of our own immune system to fight cancer. But despite its proven life-saving potential, researchers are still trying to understand why it’s only effective in a small subset of cancer patients.

To shed light on this key area of cancer research, TFRI-funded researchers across the country are looking at different ways in which our immune system interacts with cancer – before, during and after immunotherapy. Their goal is simple: to find biomarkers that could indicate who will benefit from this treatment while also searching for clues that could help make it more effective for more patients.

In this context, two recent studies partly funded by the TFRI are showing results that provide key insights into how immunotherapy works, and who may benefit from it.

Study 1: Early results from immunotherapy drug trial are INSPIRE-ing

Two TFRI-funded groups have been contributing to a promising clinical study based at the Princess Margaret Cancer Centre in Toronto over the past two years. It is called INSPIRE – Investigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation.

The study evaluates how patients with five different types of cancer – head and neck squamous cell carcinoma, triple negative breast cancer, high grade serous ovarian cancer, malignant melanoma and mixed solid tumours – respond to a specific type of immunotherapy, an anti-PD1 drug called pembrolizumab. The main objective of INSPIRE is to investigate whether specific genomic and immune biomarkers in patients may predict for response or resistance to this treatment.

While analyses of correlative samples from this study are still ongoing, early results from the first 80 patients are showing some promising results.

“Several biomarkers have been identified as being potentially predictive of response to pembrolizumab,” said Dr. Lillian Siu, a senior medical oncologist at Princess Margaret who leads the group. “For example, the frequency of tumour-infiltrating 4-1BB + PD-1+ CD8 T cells in tumour at baseline pre-treatment was positively associated with clinical response. Likewise, the fold-expansion of intra-tumoral CD8 T cells from baseline to about six to nine weeks post-treatment is another example of a potential biomarker of response to pembrolizumab.”

These biomarkers have the potential to change lives. According to Dr. Siu, if validated, they may contribute to the selection of patients who are most likely to respond to immune checkpoint inhibitors, sparing those who are least likely to respond from these expensive drugs that may also cause immune-related toxicities.

The study also serves as a model that larger, pan-Canadian immunotherapy studies may adopt in the future.

“INSPIRE brought together researchers and investigators from different disciplines in our institution to meet regularly to exchange knowledge between bench and bedside,” said Dr. Siu. “This led to the standardization of many processes for complex correlative studies using immunotherapy, which could be adopted by other institutions to perform larger studies.”

Study 2: Profiling immune checkpoints in non-small cell lung cancer

In recent years, therapies that block immune checkpoints (ICP) have emerged as potential treatment options for patients with non-small cell lung carcinoma (NSCLC), the most common type of lung cancer. But not all patients can benefit.

That’s why a team of researchers led by immunotherapy specialist Dr. Réjean Lapointe (Centre de recherche du Centre hospitalier de l’Université de Montréal) and partly funded by the TFRI has developed a novel resource that helps to paint a clearer picture of how these checkpoints interact with NSCLC in patients.

To create this tissue microarray (TMA), the team used a novel biopsy technique that allowed them to get samples from immune-dense regions of NSCLCs. They then profiled these tumours by mapping infiltrating immune cell (IIC) subsets, ICPs, proliferation, and effector T-cell markers.

According to the paper, published in The Journal for Immunotherapy of Cancer (March 2019), this detailed profile of immune checkpoints in NSCLCs provides new insights into crucial elements of our immune system, allowing the team to identify prognostic biomarkers that correlate to better survival.

“In this hypothesis-generating study, we revealed that redundant immune-checkpoint interactors associate with positive outcomes for patients with NSCLC,” said Dr. Lapointe. “We also found combinations that efficiently stratify patients and defined prognostic combinations that may be able to guide the use of blockade therapies in the future.”

Study 1

An interim report on the investigator-initiated phase 2 study of pembrolizumab immunological response evaluation (INSPIRE)

Authors

Derek L. Clouthier, Scott C. Lien, S. Y. Cindy Yang, Linh T. Nguyen, Venkata S. K. Manem, Diana Gray, Michael Ryczko, Albiruni R. A. Razak, Jeremy Lewin, Stephanie Lheureux, Ilaria Colombo, Philippe L. Bedard, David Cescon, Anna Spreafico, Marcus O. Butler, Aaron R. Hansen, Raymond W. Jang, Sangeet Ghai, Ilan Weinreb, Valentin Sotov, Ramy Gadalla, Babak Noamani, Mengdi Guo, Sawako Elston, Amanda Giesler, Sevan Hakgor, Haiyan Jiang, Tracy McGaha, David G. Brooks, Benjamin Haibe-Kains, Trevor J. Pugh, Pamela S. Ohashi & Lillian L. Siu 

Funding

This study was partly funded by a Terry Fox Translational Program Grant to the Immunotherapy Network (iTNT) and a Terry Fox Program Project Grant to New era of precision medicine in triple-negative breast cancer

Study 2

Immune-enrichment of non-small cell lung cancer baseline biopsies for multiplex profiling define prognostic immune checkpoint combinations for patient stratification

Authors

Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Anne-Marie Mes-Masson, Nidhameddine Kchir, Kamel Hamzaoui, Igor Jurisica & Réjean Lapointe 

Funding

This study was partly funded by a Terry Fox Translational Program Grant to the Immunotherapy Network (iTNT)