Making cancer treatment less aggressive and more effective
Tracy Heng wants to make cancer treatment gentler and more effective for elderly patients with blood cancer and other blood disorders.
“Bone marrow transplants have transformed survival rates for blood cancers. They replace a diseased blood system with healthy blood-forming cells, but first, doctors have to wipe out a patient’s immune system, which takes a big toll on elderly patients. My goal is to change that,” says Tracy.
Tracy’s research aims to make the treatment less aggressive by lowering the dose of chemotherapy or radiotherapy that resets a patient’s immune system before a blood stem cell transplant.
To make this possible, she’s working to stop donor blood stem cells from being rejected by a patient’s body following a bone marrow transplant, by mixing them with other stem cells that can suppress the immune system.
Tracy is a RD Wright Biomedical Career Development Fellow at Monash University, and a research group leader in the Stem Cells and Translational Immunology Laboratory.
In recognition of her leadership in stem cell research, Dr Tracy Heng has received one of two $50,000 Metcalf Prizes from the National Stem Cell Foundation of Australia.
Bone marrow transplants, used to replace stem cells killed by cancer treatment, are among the few already proven and widely used stem cell treatments.
They are saving lives today by transplanting blood stem cells—also known as haematopoietic stem cells—from a donor to a patient, and are well established for treating blood diseases such as leukaemia, and marrow failure, as well as inherited disorders such as severe immune deficiency and sickle-cell anaemia.
But Tracy thinks we can do better, by lessening the impact of this treatment on the immune system, and helping the newly transplanted cells to be accepted.
Working with an aging immune system
Tracy brings the unique perspective of an immunologist to the field of stem cell science.
“There’s a lot of excitement around the potential for stem cells and stem cell-derived products to treat diseases. But we know now that for stem cell therapies to work successfully, we really need to work with the immune system. I think that aspect was previously overlooked by a lot of stem cell biologists, but I’m hoping I can change that,” says Tracy.
“The human body is very smart. When we introduce donor stem cells to a patient, their body recognises that the cells aren’t their own, and attacks the new cells. To prevent this attack, which can result in loss of the donor cells, the body’s natural immune defence needs to be suppressed. This is generally achieved with high doses of chemotherapy or irradiation, both of which can have severe toxic effects on other organ systems and are poorly tolerated by elderly individuals.”
Bone marrow transplants can be less effective in older patients as their immune system slows down and their bone marrow is less able to take up donor stem cells, regardless of whether they’re from a young or old donor.
This means older patients are not able to recover their immunity after a bone marrow transplant as well as younger patients, leaving them vulnerable to severe infections.
Lessening the impact of bone marrow transplants
Prior to a bone marrow transplant, a patient’s own immune system must be knocked out with a strong dose of either chemotherapy or radiotherapy in order to prepare the body to receive donor blood stem cells. Following the transplant, the patient is monitored while their immune system is piecing itself back together, because of the high risk of infection.
Tracy is looking at whether reducing the course of chemotherapy to a gentler regime can still be effective in older patients. This would reduce the impact on the immune system, allowing patients to recover faster.
“In some cases, high doses of chemotherapy are not required for the bone marrow transplant,” Tracy says. “Lowering the chemotherapy dose would broaden the applicability of this treatment for elderly patients and other patients with non-malignant diseases.”
Helping stem cells to be accepted
While reducing the initial chemotherapy dose will promote faster recovery, it doesn’t help older bone marrow take up stem cells more effectively.
So Tracy is investigating the use of mesenchymal stem cells (MSCs) that have the effect of suppressing the immune system.
MSCs are already the subject of several clinical trials using donor cells or a patient’s own cells. They are being tested for use in stroke, heart attack and multiple sclerosis patients. And they are being used in the clinic to tackle ‘graft-versus-host disease’, a nasty transplant complication in which donor stem cells attack the patient’s body. They can also treat a range of other inflammatory diseases.
When mixed together and administered to a patient, MSCs can promote the uptake of blood stem cells by bone marrow. But shortly after they’ve been injected into to a patient, they disappear.
“MSCs seem like they can do everything, but they don’t live long once inside a patient. They go in, do their job, and die,” says Tracy.
“If we can increase the lifespan of these cells, we can hopefully make the treatment more effective and reduce the need for further rounds of this treatment for patients. That’s what I’m working on now.”
All cells have a certain lifespan—when their time us up, a gene inside them tells them to die. Tracy is switching off these genes in MSCs, hoping that it will allow them to live longer, so that once inside a patient, they will continue to survive and be effective as a longer lasting treatment.
She’s not up to human clinical trials yet – but the mouse models she’s using have a functional human immune system.
“It sounds like something from another world, but it allows us to test our research in something similar to a human to make sure we’re on the right track,” says Tracy.
“It’s all very exciting work, so far we’ve seen very promising results. But it’s always a long process to get it working in humans.”
Moving forward to other applications
Tracy’s research also has the potential to help treat other diseases, including autoimmune and metabolic diseases. And it could prove to be a useful way of managing organ transplants.
“After an organ transplant, patients need to take medication for many years to prevent the body from rejecting the organ. But resetting the immune system to accept the new organ via a blood stem cell transplant could replace the need for ongoing anti-rejection medication,” says Tracy.
Qualifications
2006 Doctor of Philosophy, Monash University
2001 Bachelor of Science (Biomedical) (Honours), Monash University
Career Highlights, Awards, Fellowships, Grants
2016 National Health and Medical Research Council RD Wright Biomedical Career Development Fellowship, 2016-2019
2016 Monash University Faculty Platform Access Grant
2015 Victorian Young Tall Poppy Science Award, Australia Institute of Policy and Science
2015 Monash University Advancing Women’s Research Success Grant
2015 Monash University Faculty Early Career Researcher Fellows Publication Prize
2015 Australian Academy of Science Theo Murphy High Flyers Think Tank: The Stem Cell Revolution
2014 National Stem Cell Foundation of Australia Early Career Researcher Travel Award
2012 Mesoblast Limited Industry Grant, 2012-2016
2011 Australian Research Council Postdoctoral Industry Fellowship, 2011-2015
2011 Australian Research Council Linkage Project Grant, 2011-2014, extended to 2016
2009 Cancer Council Victoria Research Scholarship
Key Publications
Heng, Painter, Immunological Genome Project Consortium (2008). The Immunological Genome Project: networks of gene expression in immune cells. Nature Immunology 9: 1091-4
Mingueneau*, Kreslavsky*, Gray*, Heng* (*equal first), Cruse, Ericson, Bendall, Spitzer, Nolan, Kobayashi, von Boehmer, Mathis, Benoist, Immunological Genome Consortium (2013). The transcriptional landscape of αβ T cell differentiation. Nature Immunology 14:619-32
Mathias, Khong, Spyroglou, Payne, Siatskas, Thorburn, Boyd, Heng (2013). Alveolar macrophages are critical for the inhibition of allergic asthma by mesenchymal stromal cells. Journal of Immunology 191:5914-24
Morison, Homann, Layton, Chidgey, Boyd, Heng (2014). Establishment of transplantation tolerance via minimal conditioning in aged recipients. American Journal of Transplantation 14: 2478–2490
Heng, Goldberg, Gray, Sutherland, Chidgey, Boyd (2005). Effects of castration in two different models of thymic involution. Journal of Immunology 175: 2982-2993
