Acute myeloid leukemia (AML) is a cancer of the blood cells. Almost three out of four of adults with AML die within five years of being diagnosed with the disease, so there is a great need for new ways to treat it.
One emerging approach is to use a subset of cells from the immune system called DNT cells to target and kill the mal-formed blood cells produced by the disease. The DNT cells can be extracted from patients or from healthy donors, multiplied outside the body, and given to patients with AML as a therapy. Early results with this DNT cell-based therapy have been promising, however some cancer cells from AML patients are not successfully targeted by the DNT cell therapy.
A team led by Senior Scientists Dr. Housheng Hansen He at Princess Margaret and Dr. Li Zhang at Toronto General Hospital looked for genetic differences that would explain why some patients don’t respond to DNT cell therapy.
Their study used a powerful tool called CRISPR to edit the genes in AML cell samples. In an experimental model, they made changes to 1,000 genes at a time, and then tested whether the therapeutic T-cells were able to target the cancer.
Using this approach, the team identified a group of genes—which are components of the SAGA deubiquitinating complex—as important for enabling AML cells resistance to T-cell therapy. These genes have many functions, but their ability to make changes to proteins that bind to a cell’s DNA may be important for treatment resistance.
The team was also able to identify genes that can serve as markers for whether the cancer would respond to DNT cell therapy. “We found that when a protein known as the CD64 was expressed on the cancer cells, they were effectively targeted and killed by DNT cells. Likewise, when CD64 was absent, the cancer was resistant to the therapy,” says Dr. Zhang.
These findings provide important first steps towards optimizing DNT cell therapy and for predicting whether the therapy will help individual patients. Future clinical trials will test whether CD64 can be used to identify the individuals with AML that are most likely to benefit from DNT cell therapy, while basic research studies are needed to explore the role of the SAGA complex in therapy resistance and how to target it.
This work was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Ministry of Colleges and Universities, and The Princess Margaret Cancer Foundation. Dr. He holds the Joey and Toby Tanenbaum Brazilian Ball Chair in Prostate Cancer.
Fraser Soares, Branson Chen, Jong Bok Lee, Musaddeque Ahmed, Dalam Ly, Enoch Tin, Hyeonjeong Kang, Yong Zeng, Nayeema Akhtar, Mark D Minden, Housheng Hansen He, Li Zhang. CRISPR screen identifies genes that sensitize AML cells to double negative T cell therapy. Blood. 2020 Dec 3. doi: 10.1182/blood.2019004108
Driving can serve as a lifeline for older adults, enabling them to run errands, attend doctor’s appointments and maintain social connections. This independence can be jeopardized as mental capacity and mobility decline, making driving unsafe.
While fully automated vehicles are a potential solution to help older adults maintain their independence, the success of this strategy depends on whether older adults accept and use the technology.
A team of researchers the KITE Research Institute, the research arm of the Toronto Rehabilitation Institute, sought to understand how age, driving style, driving conditions and exposure to automated vehicle technology impacted older adults' acceptance of automated vehicles.
The research team was led by Senior Scientist Dr. Alex Mihailidis and included Senior Scientist Dr. Jennifer Campos and PhD candidates Shabnam Haghzare and Katherine Bak.
Thirty-six participants ranging in age from 65 to 90 completed driving scenarios in the KITE Research Institute’s state-of-the-art DriverLab simulator. Three driving scenarios were replicated: heavy rain, high traffic and clear daytime. For each of these scenarios, two driving sessions were completed: one that was controlled by the participant; and one controlled by the computer to simulate a self-driving car.
Before and after each session, participants filled out questionnaires that assessed their comfort with, and acceptance of automated vehicles.
The researchers also assessed differences in the driving style—such as breaking and accelerating—between the participant and the automated vehicle. The results showed that greater differences in driving styles (especially for deceleration), were associated with more negative attitudes towards self-driving vehicles in participants. Additionally, participants over the age of 80 had lower expectations of the reliability of automated vehicles.
“It is projected that age-related frailties will be the leading cause of fatal road accidents by 2025,” says Dr. Mihailidis. “While fully automated vehicles could potentially help older adults maintain their independence while keeping our roads safe, our findings suggest we need to customize the automated driving experience to the user to help build trust in this technology.”
This work was supported by Canadian Institutes of Health Research, AGE-WELL NCE Inc., UBER Canada, the Schwartz Reisman Institute for Technology at the University of Toronto and Toronto Rehab Foundation.
Haghzare S, Campos JL, Bak K, Mihailidis A. Older adults' acceptance of fully automated vehicles: Effects of exposure, driving style, age, and driving conditions. Accid Anal Prev. 2021 Feb;150:105919. doi: 10.1016/j.aap.2020.105919. Epub 2020 Dec 10.
The UHN Office of Research Trainees (ORT) is proud to announce the release of the latest issue of The ORT Times!
It is bittersweet for us to announce that this month's edition of the UHN ORT Times will be our last. With every end comes a new beginning, and we are excited about this new chapter where the ORT will focus on more timely and rapid communications, including bi-weekly email updates and utilizing social media. Using these platforms, we will continue to share helpful content including career development workshops, research training opportunities within and outside of UHN, and trainee and alumni spotlights.
We look forward to connecting with you on Twitter and LinkedIn or by email at ort.admin@uhnresearch.ca.
Since our inaugural edition of the ORT Times in November 2011, the ORT Times has served as a monthly email e-newsletter for UHN trainees and the research community as a whole. To view past issues of the ORT Times, please visit uhntrainees.ca.
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Princess Margaret Cancer Centre’s Dr. Tak Mak and Stanford University’s Dr. Mark Davis have been awarded the 2021 Szent-Györgyi Prize for Progress in Cancer Research. Drs. Mak and Davis received the award for their discovery of the structure of the T-cell receptor (TCR) and their research into the underlying mechanisms of T-cell function and development.
Their discoveries have laid the foundation for a novel T-cell-based immunotherapy approach, known as CAR (chimeric antigen receptor) T-cell therapy, which has been approved for the treatment of several types of blood cancer.
The award, presented by the National Foundation for Cancer Research (NFCR), honours scientists who have made discoveries that have led to advances in cancer prevention, diagnosis or treatment. The prize was established in 2006 in honor of NFCR’s cofounder, Dr. Albert Szent-Györgyi, who received the 1937 Nobel Prize in Physiology or Medicine.
“We would like to see more and continued support to basic cancer research that is the true driving force for the development of novel cancer therapies,” stated Sujuan Ba, Ph.D., co-chair of the 2021 Prize selection committee and president and CEO of NFCR. “What Mak and Davis have achieved is an outstanding example of how the discoveries made from basic cancer research can lay a solid foundation for the further development of life-saving clinical applications.”
This pioneering research was set in motion by Dr. Mak in 1984, who successfully cloned the human TCR β gene, and at the same time by Dr. Davis, who cloned the murine TCR gene. Based on these and other complementary discoveries in T-cell biology, scientists were able to finally engineer T-cells that recognize and destroy cancer.
Drs. Mak and Davis will be presented the award in Washington D.C. at a ceremony that is tentatively scheduled in October 2021, depending on the status of the COVID-19 pandemic.
Congratulations to Drs. Mak and Davis for this prestigious honour and for their life-changing contributions to cancer research and our understanding of the immune system.
Source: NFCR press release.
A study from University Health Network, Canada’s largest research hospital, reveals the percentage of symptomatic and asymptomatic health care workers infected with the novel coronavirus.
“A key question that we wanted to answer was ‘how many asymptomatic health care workers are unknowingly infectious or have been exposed to the virus,’” says Dr. Deepali Kumar, senior author and a Clinician Investigator at the Toronto General Hospital Research Institute (TGHRI).
To answer this question, two tests were used: swab tests, to see if the virus was present and able to spread; and blood antibody tests, to see if past exposure to the virus had occurred.
The results revealed that, of symptom-free staff, around 0.5% had positive swab tests. This means that around one out of every 200 staff were potentially infectious. When staff had symptoms, that number jumped to 3.4%, or around seven out of every 200 individuals.
Using blood antibody tests, the research team found that between 1.4 to 3.4% of symptom-free staff tested positive, depending on which antibody test was used. “This means that somewhere between three and seven staff out of every 200 had been infected with the virus without ever reporting symptoms,” says Dr. Victor Ferreira, the first author of the study and a Scientific Associate at TGHRI, where he works with Senior Scientist and co-author Dr. Atul Humar.
Symptoms that were considered were fever, headache, new or worsening cough, shortness of breath, sore throat, runny nose, pink eye, diarrhea, loss of sense of smell or muscle aches.
“Our findings reaffirm the importance of remaining vigilant in the screening of health care and other front line workers regardless of whether they experience COVID-19-like symptoms,” says Dr. Ferreira.
These results come from the first phase of the study called Research Platform to Screen and Protect Healthcare Workers study—or RESPECT for short, which enrolled front-line health care workers at UHN between March and June 2020. Given the success of the first phase, RESPECT 2.0 has since been initiated and expanded to include broader clinical personnel, research personnel and other workers, such as those in the food industry.
“This observational study has important implications for infection control, as well as staff and patient safety. And it could not have been possible without the multidisciplinary team of physicians, researchers, nurses and other allied health professionals that contributed. Thank you to everyone at TeamUHN that made this possible,” says Dr. Brad Wouters, UHN’s EVP of Science and Research.
The study was funded by the Mount Sinai Hospital and University Health Network Academic Medical Organization, the Ontario Institute for Cancer Research, the Government of Ontario, and the Toronto General & Western Hospital Foundation. T Pugh is a Tier 2 Canada Research Chair (CRC); M Cybulsky and B Wouters are Tier 1 CRCs.
Victor H. Ferreira, Andrzej Chruscinski, Vathany Kulasingam, Trevor J. Pugh, Tamara Dus, Brad Wouters, Amit Oza, Matthew Ierullo, Terrance Ku, Beata Majchrzak-Kita, Sonika T. Humar, Ilona Bahinskaya, Natalia Pinzon, Jianhua Zhang, Lawrence E. Heisler, Paul M. Krzyzanowski, Bernard Lam, Ilinca M. Lungu, Dorin Manase, Krista M. Pace, Pouria Mashouri, Michael Brudno, Michael Garrels, Tony Mazzulli, Myron Cybulsky, Atul Humar, Deepali Kumar. Prospective observational study and serosurvey of SARS-CoV-2 infection in asymptomatic healthcare workers at a Canadian tertiary care center. 16 Feb 2021. PLOS ONE. doi.org/10.1371/journal.pone.0247258
A recent study sheds light on the underlying reasons why transplant patients on a commonly used immunosuppressant may be more susceptible to infections. The work also identifies a group of genes that could be targeted to develop ways to avoid this unwanted side effect.
The study was published in the journal Hepatology and co-led by Drs. Mamatha Bhat, a Scientist at the Toronto General Hospital Research Institute (TGHRI) and the Ajmera Transplant Centre, and Paul Kubes, Director of the Snyder Institute for Chronic Diseases at the University of Calgary. Postdoctoral fellows Carsten Deppermann and Moritz Peiseler served as co-first authors. Collaborators included Drs. Atul Humar and Deepali Kumar at the Ajmera Transplant Centre and TGHRI.
“The immunosuppressant that we focused in this study, known as tacrolimus, is the most commonly used drug to prevent organ rejection. The drug accumulates in the liver, which is an important site in the body for identifying and fighting infection,” says Dr. Bhat.
The study revealed that the function of a group of immune cells found in the liver, known as Kupffer cells, are affected by tacrolimus. Kupffer cells help fight infections by capturing bacteria from the blood as it is filtered through the liver.
As a first step, the researchers explored the link between tacrolimus and infection by analyzing data from over 2,700 transplant patients. The analysis revealed that the patients with the highest levels of tacrolimus in their blood were at increased risk of staphylococcal infection, which is caused by the bacteria known as Staphylococcus aureus.
Next, using an experimental model of staphylococcal infection, the researchers showed that tacrolimus reduced the ability of the Kupffer cells to capture and destroy bacteria. The research team also looked at which genes were being turned on or off in Kupffer cells in response to tacrolimus. They found that the activity of a group of genes belonging to the TREM-1 pathway were substantially reduced when Kupffer cells are exposed to tacrolimus.
“The TREM-1 pathway is known to be involved in a process known as phagocytosis, which is used by immune cells to engulf or ‘eat’ bacteria. By shutting down the TREM-1 pathway, tacrolimus may compromise the ability of Kupffer cells to use phagocytosis to fight infection,” says Dr. Kubes.
Dr. Bhat adds, “We also explored whether tacrolimus affects other cells of the innate immune system—the same branch that Kupffer cells are part of. We did not find any substantial effects, suggesting that tacrolimus affects Kupffer cells in a very specific manner.”
These findings lay the foundation for new strategies to protect Kupffer cells from harm by tacrolimus. Dr. Bhat concludes that “While immunosuppressants are required to treat and prevent organ rejection, our work suggests that there may be ways to reduce side effects and protect patients from infection.”
This work was supported by the Toronto General & Western Hospital Foundation, the American Society of Transplantation, the Canadian National Transplant Research Program, the Canadian Liver Foundation, the German Research Foundation (DFG), the Canadian Institutes of Health Research, Alberta Innovates Health Solutions, and the Heart & Stroke Foundation of Canada. P. Kubes is a Tier 1 Canada Research Chair in Leukocyte Recruitment in Inflammatory Disease.
Deppermann C, Peiseler M, Zindel J, Zbytnuik L, Lee WY, Pasini E, Baciu C, Matelski J, Lee Y, Kumar D, Humar A, Surewaard B, Kubes P, Bhat M. Tacrolimus impairs Kupffer cell capacity to control bacteremia: why transplant recipients are susceptible to infection. Hepatology. 7 Feb 2021 (epub 6 Aug 2020). doi: 10.1002/hep.31499.
Scientists at the Toronto General Hospital Research Institute (TGHRI) have found that a new drug therapy—based on a protein known as interferon—can promote viral clearance in outpatients with COVID-19.
Over 750,000 Canadians have contracted COVID-19—the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
While many clinical trials have focused on finding ways to reduce the severity of COVID-19 in hospitalized individuals, few trials have identified treatments that can be used outside the hospital setting. To expand drug treatment options, TGHRI Senior Scientist Dr. Jordan Feld led a phase II clinical trial involving patients with mild to moderate COVID-19 symptoms.
“Treating outpatients is important,” says Dr. Feld, “If we can quickly lower viral levels in these patients, they are less likely to develop severe disease and, perhaps more importantly, have a lower risk of infecting others.”
The research team tested a form of interferon—a protein involved in the body’s defence against viruses—known as peginterferon lambda. This protein is a modified interferon that stimulates the body’s natural immune response.
Dr. Feld and other researchers have studied peginterferon lambda as a treatment for viral hepatitis, which led the team to explore the use of the drug to treat COVID-19.
The trial included 60 adults recently diagnosed with COVID-19. The researchers randomly assigned 30 patients to receive peginterferon lambda and the other 30 to receive a placebo. They found that a single injection of peginterferon lambda rapidly reduced the amount of SARS-CoV-2 detected in nasal swabs. By seven days after treatment, viral levels were over 260-fold lower in patients treated with peginterferon lambda than patients treated with placebo. In comparison, recently approved antibody treatments result in only about 3-fold reductions in viral levels.
“Accounting for the amount of virus detected at the start of the trial, patients who received peginterferon lambda were over four times more likely to clear the virus within a week than patients who received the placebo,” explains Dr. Feld. Of the patients who started the trial with high viral levels, 79% cleared the virus with treatment, compared to only 38% with placebo.
The researchers also found that peginterferon lambda was safe and well tolerated. Side effects were similar between patients who received the drug and those who received the placebo.
Unlike some COVID-19 treatments, the activity of peginterferon lambda does not depend on the genetic makeup of the virus. This is especially important with the recent spread of new virus variants from the UK and South Africa, which appear to be more infectious.
The team is now testing peginterferon lambda in hospitalized COVID-19 patients and hopes to soon run a phase III clinical trial to test the drug in a larger outpatient population.
“We know that peginterferon lambda promotes viral clearance. Now, we need to investigate whether this translates into clinical benefits,” says Dr. Feld. “Even with the vaccine coming, we need therapies now. If early antiviral treatment lowers a patient’s risk for developing serious disease or for spreading the virus, it could help turn the tide on this pandemic.”
This work was supported by the Toronto COVID-19 Action Initiative, the University of Toronto, the Ontario First COVID-19 Rapid Research Fund, the Toronto General Hospital Research Institute and the Toronto General & Western Hospital Foundation.
Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux C, Borgia SM, Boggild AK, Powis J, McCready J, Tan DHS, Chan T, Coburn B, Kumar D, Humar A, Chan A, O’Neil B, Noureldin S, Booth J, Hong R, Smookler D, Aleyadeh W, Patel A, Barber B, Casey J, Hiebert R, Mistry H, Choong I, Hislop C, Santer DM. Tyrrell DL, Glenn JS, Gehring AJ, Janssen HLA, Hansen BE. Peginterferon Lambda for the Treatment of COVID-19 in Outpatients: A Phase 2, Placebo-Controlled Randomized Trial. Lancet Respir Med. 2021 Feb 5. doi: 10.1016/S2213-2600(20)30566-X.
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