Neoadjuvant precision therapy for non-small cell lung cancer: A platform for discovery

Tracking immunotherapy response to personalize treatment for lung cancer patients

In the past decade, immunotherapy and other genetically determined precision therapies have revolutionized lung cancer care. For instance, a new treatment that combines immunotherapy with chemotherapy before surgery for patients with resectable lung cancer has been established as new standard of care across Canada, after it was found that this combination eliminates all lung cancer cells before surgery in one quarter of patients. But while these responses are extremely promising, they also mean that three quarters of patients treated with chemotherapy and immunotherapy before surgery do not completely respond to the treatment.

A pan-Canadian team of researchers newly funded by the Marathon of Hope Cancer Centres Network (MOHCCN) is setting out to better understand why this occurs. Their goals are to discover ways to predict which patients are most likely to benefit from these new precision treatments and how best to treat those who do not.

“Our goal is to understand which medications are best suited to each patient,” says project lead Dr. Jonathan Spicer, a Scientist in the Cancer Research Program at the Research Institute of the McGill University Health Centre (RI-MUHC). “We are using the unique opportunity to understand exactly how these therapies work in responders and non-responders by taking a deep dive into the resulting cancer genetics and tumour immune environment after surgical resection.”

The team, which includes experts from Québec, Ontario, British Columbia, Manitoba, and Nova Scotia, will use funding from the Network’s Pan-Canadian Project Program to perform whole-genome and -transcriptome sequencing of tumour samples. The sequencing and associated clinical data will be contributed to the MOHCCN Gold Cohort, which is on track to become the largest and most complete cancer case resource in Canada.

In addition to using this data to better understand response to these combination therapies, the team will collaborate to perform a wide array of analyses, such as high-resolution single-cell imaging of tumour samples and microbiome sequencing. They will use this wealth of data not only to identify features that predict whether a tumour is likely to respond to immunotherapy, but also to learn why responses differ between patients.

Another aspect of the project aims to study how certain tumour cells manage to survive the pre-operative therapy (so-called ‘persister cells’). By understanding how these cells persist through therapy, the researchers hope to use this information to devise new treatments that achieve complete eradication of such cancers.

"This effort truly establishes a large platform of discovery that is optimally positioned to generate the essential data required to develop more effective and curative treatments,” explains Dr. Spicer.

They will also be looking at how to monitor lung cancers in a less invasive way, using a technique called liquid biopsies. These blood tests measure the presence of small fragments of tumour DNA in the blood (also known as circulating tumour DNA or ctDNA), as well as other blood components. The goal is to establish ctDNA measurements as a means to identify patients that are responding particularly well to chemo-immunotherapy, and who may therefore be able to de-escalate subsequent treatments such as surgery and radiation, avoiding unnecessary toxicity.

This project will build on existing relationships between lung cancer researchers and clinicians across Canada while also helping to create new ones. By working together on this ambitious project, the team will be able to profile a large number of patient tumours, contributing valuable data to the MOHCCN Gold Cohort. They will also draw on different members’ areas of expertise to obtain a comprehensive picture of how lung cancers respond to immunotherapy and discover how best to treat each patient with a personalized approach.