March 1, 2021
Research breakthrough paves way for more cancer patients to benefit from immunotherapy, regardless of ancestry
OICR Investigator, Dr. Naoto Hirano, expands arsenal of immunotherapy technologies, opening new frontiers in immunotherapy for cancer patients and beyond
Adoptive cell therapy is a promising cancer treatment that uses our immune system to eliminate cancer cells. These treatments, however, are only effective for a small subset of individuals with specific types of cancer and specific inherited genes. Dr. Naoto Hirano’s recent breakthrough paves the way for novel immunotherapies to help more patients, regardless of their genetic ancestry, live longer and healthier lives.
In a study published in Nature Biotechnology, Hirano and his collaborators developed a new technology that rigorously and robustly identifies the immune cells that are capable of recognizing and eliminating cancer cells. This technology allows researchers to develop new immunotherapies for cancer patients that are not limited by the differences – or heterogeneity – of tumour cells, thus expanding the potential impact of immunotherapy for patients around the world.
Hirano’s technology applies to an immunotherapy approach called T cell receptor (TCR) gene therapy that is based on genetically-engineered immune cells (T cells) recognizing and binding to specific molecules, called peptide-loaded human leukocyte antigens (HLA), on the surface of cancer cells. Although there has been progress in TCR therapy, there are more than 28,000 different variations of HLA found in humans and current TCR therapies only work for a few of these variations.
“Historically, TCR treatments have been developed for those who had the most common and well-studied HLA alleles, which often meant that these immunotherapies only worked for people from Caucasian ancestry,” says Hirano, who is a Senior Scientist at the Princess Margaret Cancer Centre and OICR Clinician Scientist. “It was an important goal for us to develop a technology that could work for a broad range of HLA alleles. We’re proud of what we developed because it could help many more cancer patients in the future.”
The technology presented in this study involves a methodology that can – in a single step at a low expense – form a functional protein structure, called a dimer, that is comprised of any peptide and HLA molecule, regardless of type, and can bind to and identify a variety of T cells. The method improves the binding affinity between T cells and HLA molecules nearly 200-fold relative to prior methods, which could allow researchers to better identify and engineer the T cells for novel immunotherapies.
The technology has been licensed to TCRyption Inc. for further development, translation, and large-scale implementation. In the future, it may be applied to fields other than cancer research and care, including autoimmune diseases such as rheumatoid arthritis and type 1 diabetes.
“I’m grateful for the cancer research community’s support over the years, which has enabled me to focus on important and challenging issues,” says Hirano, who was named the University Health Network’s Inventor of the Year last year for developing these analysis techniques. “Only with the support for rigorous experimentation, deep expertise, and innovative thinking, were we able to make this breakthrough.”
Note: N.H. has received research funding from Takara Bio and served as a consultant for Takara. The University Health Network has filed a patent application related to this study on which N.H. is named as a lead inventor. N.H. is cofounder and has equity in TCRyption to which the technologies used in this study have been licensed.
December 2, 2020
Researchers at the University of Guelph and McMaster University create combination immunotherapy approach to treat breast tumours and other cancers
Over the last few decades, scientists have made significant progress in harnessing the immune system to treat cancers. Despite these advances, many types of cancer can still evade the immune system and current immunotherapies. Dr. Sam Workenhe is developing better treatment options for patients with these hard-to-treat diseases.
In his recent study, published in Nature Communications Biology, Workenhe and collaborators at the University of Guelph and McMaster University discovered a new combination immunotherapy approach for breast tumours and other cancers. Their approach leverages cancer-killing viruses, called oncolytic viruses, and chemotherapy to trigger tumour inflammation, stimulating the body’s immune system to control tumour growth. Their combination leveraged the oncolytic virus, oHSV-1, and the chemotherapy agent, Mitomycin-C.
The research team demonstrated the effectiveness of this treatment approach in mouse models of breast cancer. They found that that mice treated with this combination therapy lived approximately two months longer than untreated ones – a significant difference relative to the short lifespan of these mouse models.
“Simply put, we wake up the immune system,” says Workenhe, Assistant Professor at the University of Guelph’s Ontario Veterinary College and an OICR Joseph and Wolf Lebovic Fellowship Program awardee. “Our study proves that aggressive tumours without immune cells can be made to render an immune response. Understanding how to design treatments that can potentially activate the immune system against cancer can revolutionize the current standards of care.”
Additionally, the study delineated the anticancer mechanisms of their approach, detailing how each element kickstarts an immune response against the tumours. Workenhe, who is a trained veterinarian and a virologist, is now applying these findings to further study immune responses and inflammatory cell death in tumours.
“A lot of people are excited about engineering viruses to inflame the tumour and improve cancer treatment,” says Workenhe. “The implications of these findings for human cancer therapy may be huge.”
This post was adapted from a University of Guelph news story.
November 25, 2020
Despite disruptions, cancer researchers across Ontario are continuing to make scientific progress in labs and at home. Here, Vivian discusses her master’s project, discovering drug targets for future immunotherapies.
August 28, 2020
OICR-supported researchers and collaborators discover indicators in the blood that may predict which patients will respond to the immunotherapy drug, pembrolizumab
Adapted from UHN’s Media Release.
Immunotherapy can shrink tumours and prolong survival for certain cancer patients, but clinicians don’t yet know which patients will benefit from these treatments. OICR-supported researchers and collaborators at the Princess Margaret Cancer Centre have made a discovery that could help identify those patients who may benefit and match them with potentially life-saving therapies.
In their study, recently published in Nature Cancer, the research group found that the changing levels of tumour fragments, or circulating tumour DNA (ctDNA), in a patient’s blood can be used to predict whether they will respond to the immunotherapy drug pembrolizumab.
The study lays the foundation for researchers to develop an easy, non-invasive and quick blood test to determine who will benefit from the drug and how well their disease is responding to treatment.
“While we have known for some time that cancer disease burden can be monitored by measuring tumour DNA in the blood, we are excited to report that the same concept can be applied to track the progress of patients being treated with pembrolizumab,” says co-first author Cindy Yang, PhD Candidate in Dr. Trevor Pugh’s lab at the Princess Margaret Cancer Centre and OICR. “This will hopefully provide a new tool to more accurately detect response and progression in patients undergoing immune checkpoint inhibitor therapy. By detecting progression early, patients may have the opportunity to undergo subsequent lines of treatment in a timely fashion.”
The benefits of blood tests
Conventionally, imaging scans – such as computerized tomography (CT) scans – and other methods are used to monitor a patient’s cancer. This study suggests a simple and quicker blood test as an alternative to these scans.
“Although important, computerized tomography (CT) and other scans alone will not tell us what we need to know quickly or accurately enough,” says senior author Dr. Lillian Siu, Senior Scientist and medical oncologist at the Princess Margaret Cancer Centre.
Dr. Scott Bratman, radiation oncologist and Senior Scientist at the Princess Margaret Cancer Centre and co-first author of the study, points out that it may take many months to detect whether a tumour is shrinking with various imaging scans.
“New next-generation sequencing technologies can detect and measure these tiny bits of cellular debris floating in the blood stream accurately and sensitively, allowing us to pinpoint quite quickly whether the cancer is active.”
This study represents one of the many emerging applications of using ctDNA to guide treatment decisions. It is one of the first to show that measuring ctDNA could be useful as a predictor of who responds well to immunotherapy across a broad spectrum of cancer types.
The prospective study analyzed the change in ctDNA from 74 patients, with different types of advanced cancers, being treated with pembrolizumab. Of the 74 patients, 33 had a decrease in ctDNA levels from their original baseline levels to week six to seven after treatment with the drug. These patients had better treatment responses and longer survival. Even more striking was that all 12 patients who had clearance of the ctDNA to undetectable levels during treatment were still alive at a median follow-up of 25 months.
Conversely, a rise in ctDNA levels was linked to a rapid disease progression in most patients, and poorer survival.
“Few studies have used a clinical biomarker across different types of cancers,” says Siu, who also co-leads OICR’s OCTANE trial. “The observation that ctDNA clearance during treatment and its link to long-term survival is novel and provocative, suggesting that this biological marker can have broad clinical impact.”
Innovation and translation
This study is part of a larger flagship clinical trial, INSPIRE, which has enrolled more than 100 patients with head and neck, breast, ovarian, melanoma and other advanced solid tumours. INSPIRE brings together researchers from many disciplines to investigate the specific genomic and immune biomarkers in patients that may predict how patients will respond to pembrolizumab.
INSPIRE is made possible by collaborations across institutes and industries with expertise from those applying genomics to research and those applying genomics in the clinic.
“INSPIRE is an incredibly collaborative initiative that is a blend of big genomics – looking at large trends across many individuals – and highly-personalized genomics – looking at mutations within each patient sample,” says Pugh, co-senior author, Senior Scientist at Princess Margaret and Senior Investigator and Director of Genomics at OICR. “This is a modern approach to the translation of clinical genomics.”
“As a PhD student, this project gave me the unique opportunity to work in a highly collaborative intersection with industry, clinical, and academic partners,” says Yang. “It is very exciting to see translational research in action.”
Read the UHN Media Release.