The study identified a protein interaction that limits the immune response to AML and provides a method to disrupt it.
The study was led by Drs. Jean Wang, Affiliate Scientist at the Ontario Cancer Institute (OCI), the research arm of the University Health Network’s Princess Margaret Hospital, John Dick, leader of the Ontario Institute for Cancer Research’s (OICR) Cancer Stem Cells Program and Senior Scientist at the OCI, and Jayne Danska, Senior Scientist, The Hospital for Sick Children (SickKids) Research Institute.
Their study found that a protein on the surface of AML cells called CD47 binds to a protein called SIRPα, causing macrophages to develop immune tolerance to AML cells. Macrophages are cells of the immune system capable of phagocytosis, an ‘eating’ process that removes pathogens, aged and abnormal cells from the body. The researchers generated mice that expressed SIRPα variants with differential ability to bind to human CD47 and showed that when SIRPα signalling was absent macrophages were able to clear human leukemia stem cells (LSC). This finding is significant, as it is believed that relapse of disease is driven by LSCs that survive conventional chemotherapy.
The researchers then confirmed these results by treating mice that had been engrafted with human AML with a novel protein called SIRPα-Fc that can block CD47 on the leukemia cells. They found that treatment with the protein enhanced phagocytosis of AML cells by macrophages and reduced AML growth in the mice. Additionally, treatment with the protein did not cause increased phagocytosis of normal blood stem cells.
The team is working to develop leukemia therapeutics based on the concept of antagonizing SIRPα signalling and allowing the patient’s own macrophages to remove any LSCs that survive standard therapies.
“This study is an important step forward in our understanding of leukemia stem cells and has opened the door to a new line of therapies that could have a significant clinical impact by preventing relapse of AML. I commend Drs. Wang, Dick and Danska and their colleagues for their outstanding work,” says Dr. Tom Hudson, President and Scientific Director of OICR.
“This work provides a new avenue for treating leukemia by remobilizing the bodies immune defenses against the leukemia cells. Importantly, this approach could kill the ‘roots’ of the leukemia with potentially less toxins then traditional anti-leukemia therapies,” says Dr. Benjamin Neel, Director and Senior Scientist, OCI.
“This study is an excellent example of translating research into a potential clinical application. This collaboration began several years ago by our discovery that CD47-SIRPa interactions were important to the growth of normal blood and leukemia cells, that translated to the development of a blocking protein that exposes LSC to immune attack,” says Danska. “We are optimistic that clinical development of this therapy will contribute to more effective, less toxic treatments for many kinds of leukemia by eliminating LSC.”
OICR is an innovative cancer research and development institute dedicated to prevention, early detection, diagnosis and treatment of cancer. The Institute is an independent, not-for-profit corporation, supported by the Government of Ontario. The annual budget for OICR, its research partners and collaborators exceeds $150 million. This supports more than 1,600 investigators, clinician scientists, research staff and trainees located at its headquarters and in research institutes and academia across the Province of Ontario. It has research hubs in Hamilton, Kingston, London, Ottawa, Thunder Bay and Toronto. OICR has key research efforts underway in small molecules, biologics, stem cells, imaging, genomics, informatics and bio-computing, from early stage research to Phase III clinical trials. For more information, please visit the website at www.oicr.on.ca.
University Health Network
University Health Network consists of Toronto General, Toronto Western, Princess Margaret and Toronto Rehab. The scope of research and complexity of cases at University Health Network has made it a national and international source for discovery, education and patient care. It has the largest hospital-based research program in Canada, with major research in cardiology, transplantation, neurosciences, oncology, surgical innovation, infectious diseases, genomic medicine and rehabilitation medicine. University Health Network is a research hospital affiliated with the University of Toronto. www.uhn.ca.
The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca.
To interview Dr. Jean Wang contact:
Director of Communications
Ontario Institute for Cancer Research
To interview Dr. Jayne Danska contact:
Senior Manager, Media Relations, Communications & Public Affairs
The Hospital for Sick Children (SickKids)