The Research Review Process

By Kathryn Dickinson

In early June 2016, I was fortunate to attend a Canadian Cancer Society grant application review meeting in Toronto, as a community representative. The purpose of these meetings is to rate the grant applications under review, and to generate constructive feedback for their authors. This meeting was to assess highly innovative proposals in the area of Gene Regulation and Cell Biology – one of 6 competitions for innovation in different areas of cancer research. The panel for this meeting was comprised of 16 scientists and 2 community representatives from different regions of Canada, and Canadian Cancer Society staff. The scientists as well as the community representatives volunteered their time. Primary and secondary reviewers had been chosen for each application, and they had assessed the research proposals assigned to them before the meeting. The community representative’s role was to give the view of the community, to observe the integrity of the process and to comment on the quality of the public sections of the applications. It is a lot of work, but was enlightening and felt extremely worthwhile. The proposals covered a wide range of approaches, with relevance to various types of cancer, and in many cases made use of the latest developments in technology.

For each application, once the main reviewers had given their comments and initial ratings for innovation and scientific merit, and after the community representative assigned to the application had spoken, discussion was opened up to the whole panel. The goal was not necessarily to achieve consensus, but to fully air all aspects of an application (related research, methodology, aims, team, budget etc.), identifying both strengths and weaknesses. There were several opportunities for the reviewers to adjust their ratings, both during and at the end of the proceedings. Two panel members had been assigned the role of Scientific Officer, and they recorded discussion highlights to provide feedback to the application’s researchers. The meeting was chaired by a senior scientist, who kept discussions on track, and drew them to conclusion. I felt that the community representatives’ contributions were welcomed and our role appreciated.  The integrity of the process was maintained, for example, by ensuring panel members were excluded from reviewing applications when they had conflicts of interest. The process is well-defined and rigorous, but as this was my second time on a panel, I was able to see that it continues to evolve. For example, an adjustment had been made since last time to make the process more efficient, while still respecting the time and effort of the researchers who had submitted applications.

Both times I have attended review meetings, I have been impressed by the dedication of the panel members, and the positive atmosphere of the meetings. Discussion is good-natured and objective, whether consensus is reached or not. I was also impressed by how well everything is organized, and how much support is available from the Canadian Cancer Society.

Participating in this process as a community representative was a privilege. I am truly grateful to the Canadian Cancer Society, and everyone else involved, for this opportunity. It is due to the researchers who submit applications, those who serve on the review panels, and the donors who provide funding for cancer research, that the Canadian Cancer Society is able to pursue its mission.

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Cancer Immunology pt. 1: The Trouble with Cancer

by Andrew Wight


Treating cancer used to be all about chemotherapy, radiation, and surgery. While these techniques could be effective, they are dangerous, non-specific, and often don’t address the problem of a cancer relapse. That’s why modern research into new cancer therapies is focusing on using our own immune systems to destroy the cancer. In contrast to these older therapies, the immune system is very specific, having the ability to kill cancer cells while leaving neighboring healthy cells unharmed. Moreover, the immune system has memory—the ability to recognize an enemy it has seen before and kill it even better the second time—and so can defend against relapse and metastasis. In this article series, we will give an overview of the immune system: how it works, and how scientists are trying to use it against cancer. Our hope is that new immune-based therapies will usher in a generation of anti-cancer treatments that are safe, effective, and long-lasting.

So if the immune system is so great, why are we only now using it against cancer? There are two reasons for this. First, immunology—the study of the immune system and its interactions with diseases—is a relatively young field, having only really taken off in the 1950s. We’re only now at a state of knowledge where we can hope to make intelligent decisions about immune therapies. Second, of all the challenges that the immune system faces on a daily basis, cancer may be the most difficult and the most complicated. Today’s article will cover a little bit about what makes cancer so tough for the immune system: the problem of self vs. non-self.

Self/non-self discrimination—the ability for the immune system to identify and distinguish our own cells from those that are invading the body from the outside—is the key for the immune system’s activity. Immune cells use this ability to recognize bacterial cells and cells infected with viruses as ‘non-self’, and then take steps to kill the non-self cells while leaving any nearby ‘self’ cells intact. This self/non-self discrimination is very strictly enforced in the immune system, and with good reason: a breakdown in the ability to distinguish self and non-self cells leads to autoimmune diseases such as multiple sclerosis, arthritis, and type I diabetes. However, this presents a huge difficulty when it comes to cancer. Unlike bacteria and viruses, cancer is a disease where self cells grow uncontrollably, essentially becoming a parasite on the body. However, because they are self cells, the immune system is specifically trained to avoid killing them. Thus, the first challenge in cancer immune therapies is making the immune system able to even recognize the cancer cells as a threat. There are some immune cells, such as the natural killer (NK) cell, that has specifically evolved to deal with this cancer hurdle, and we’ll talk about it in a coming article. Also, extensive work is now underway to develop antibody therapies like Rituximab, which are able to light up a tumor to the immune system. Unfortunately, making the immune system recognize a cancer cell without breaking tolerance to healthy self cells is still a major challenge, and must be overcome if we are ever to achieve the dream of cancer vaccines.

Even if we are able to make the immune system recognize a cancer cell, there is another challenge it must overcome to successfully kill the tumor. As mentioned above, it is possible for the immune system to go haywire, leading to autoimmune diseases. Because of this, our immune systems have evolved something called the regulatory response. The regulatory response is a type of immune response that acts against the conventional immune system, shutting down inflammation and preventing the killing of cells. This regulatory response is important in preventing autoimmune diseases and in cleaning up normal immune responses once their target is dead. Cancer, however, is able to recruit the regulatory response and invoke it to shut down an anti-cancer immune response. Essentially, the cancer sends out a distress cry, claiming to be a self cell and blaming the immune response for starting an autoimmune reaction, and so the regulatory response activates and shuts down the anti-cancer immune response. This regulatory response has proven to be a big problem in the field of cancer immune therapy—again, we need to find a way to block the regulatory response to cancer, while preserving it in other cases to prevent real autoimmune disease. There is some hope, however—recent advances in treatments known as checkpoint inhibitors have been able to relieve some of the regulatory response to cancer, and work here in Ottawa is ongoing to study how to blunt the extremely strong regulatory response that is induced after a cancer surgery.

So now you know what the immune system is up against. Fortunately, as sneaky as cancer can be, the immune system has a number of tricks up its sleeve as well. Tune in next time as we look at the first line of defense against cancer—the innate immune system.

Oncolytic Viruses: A Primer

 

by Connie Son and Andrew Wight


 

Cancer accounts for more than one quarter of deaths in Canada. The current standard of care available to patients includes regimens of chemotherapy and radiotherapy. However, these treatments often cause severe side effects, as both are toxic, and kill tumours and healthy cells alike.

Oncolytic (“cancer-killing”) virus therapy provides a promising new take on cancer therapy by exploiting viruses that selectively target and kill tumour cells while leaving normal cells unharmed. We tend to think of viruses as harmful—after all, they infect and can kill human cells. Amazingly, however, some viruses are very selective in what cells they can infect—the picky eaters of the virus world—and the same mutations that turn a normal cell into cancer also make that cell delicious virus food. Researchers are now taking advantage of different viruses’ hunger for cancer to turn them into a treatment. So how does that work? Oncolytic viruses destroy cancer cells through three different potential mechanisms:

1) by directly infecting and killing cancer cells

2) by triggering anti-tumour immune responses and

3) by replicating in tumour blood vessels, cutting off the tumour’s supply of blood

Viral oncolysis was first observed in 1896, when doctors noticed the number of cancer cells in a leukemia patient decreased during an influenza infection. Around that time, a similar short-lived remission was recorded when a 4-year old leukemia patient got chickenpox. In 1949, the very first clinical trial of oncolytic virus gave infectious hepatitis B virus to 22 patients, putting 4 into remission. In the 1950s and 1960s, research into oncolytic viruses was vibrant and intensive: many human pathogenic viruses, including mumps virus, were tested as potential oncolytic agents. However, injection of impure viral preparations, such as infectious bodily fluids, often led to toxic side effects and even death. Since then, research into safer and better oncolytic viruses has led to significant advances in our understanding of oncolytic virotherapy.

Currently, many viruses with oncolytic properties are tested in clinical trials at the Ottawa Hospital Research Institute and around the world. Some oncolytic viruses, such as mumps and reovirus, are naturally selective for tumour cells. Others, such as measles and herpes simplex virus, are engineered to better target the tumour cells. This genetic engineering both reduces the danger and increases the effectiveness of these viruses, bringing us closer to realizing oncolytic virus therapy as a safer, more effective cancer treatment.

Cancer Research in Ottawa

We’re a busy bunch of scientists here in Ottawa – so busy, in fact, we have a hard time getting away from our research to tell you about it! For those of you curious about what sort of questions are being answered right now in the Capital Region, we’ve compiled a short list of research projects dealing with cancer. This list is far from complete; as always, if you want to know more about something you read here, please don’t hesitate to contact us.

Gray Lab

How does cancer start?

-Mutations in normal cells can accumulate over time and lead to cancer formation.
-Progress in treating and preventing the disease depends on understanding how DNA errors (or mutations) build up in the cancer cells and why they are not repaired correctly.
-Early in his career, Dr. Gray discovered one of the first genes in the human ubiquitin pathway and became interested in ubiquitin’s role in DNA repair.
-Much of their current research focuses on how manipulating ubiquitin levels affects the formation and growth of cancer cells.

 

Vanderhyden Lab

How can we study cancer better?

-Animal models that spontaneously develop cancer enable us to understand the process of tumour formation and aid the investigation of novel prevention and treatment strategies.
-Currently, there are few mammalian models of ovarian cancer, which greatly hinders the ability to test novel therapeutics in a physiologically relevant manner.
-They design mouse models of ovarian cancer to investigate the early events associated with tumour initiation, hormone changes on disease progression and how these respond to common and novel therapeutics treatments.

 

Lorimer Lab

What makes cancer grow?

-A common hallmark of cancer is abnormal and uncontrolled cell growth.
-The Lorimer lab investigates the complex mechanisms involved in cell division with the goal of identifying and evaluating how they might be targeted in cancer therapy.
-Using cells isolated from human brain tumours, they research how cell signaling can also influence the spread of cancer cells and why they are sometimes resistant to chemotherapy.
-They modify signalling pathways in these cells and then determine the effects on cancer cell behaviour.

 

Makrigiannis Lab

How do we fight cancer?

-Natural Killer (NK) cells are a necessary component of the innate immune system that guard against diseases such as cancer.
-In order to fulfill this task, NK cells must be able to discriminate between normal healthy cells and those that have become infected or transformed.
-Their laboratory is interested in dissecting the contribution of different cell surface receptors in the control of NK cell function during challenge of the immune system.

 

Auer Lab

Why does cancer come back?

-Surgery is often necessary in the treatment of solid tumours.
-However, many patients often return months or years later to find their cancer has spread to other organs (metastasis).
-The Auer lab and others have demonstrated that there is a strong suppression of the immune system following surgery and that it is partly responsible for this phenomenon.
-They use viruses to boost the immune system around the time of surgery to eliminate any residual cancer cells.
-Work is ongoing to characterize the immune response to viruses and improve long-term survival in mouse models.

 

Bell Lab

How can we fight cancer with viruses?

-Current cancer therapies for metastatic disease have limited efficacy and high toxicity and thus novel approaches to treatment are sought.
-Viruses have many characteristics which make them desirable as a therapeutic strategy for the treatment of cancer including their ability to infect cells and replicate, induce cell death, release viral particles and spread through human tissues.
-They have shown that a variety of viruses selectively replicate in and kill human cancer cell lines, primary patient samples and eliminate contaminated bone marrow of leukemic cells.
-Research focuses on optimizing and selecting for virus strains with improved efficacy in the treatment of cancer.
-The behavior of tumour microenvironment cells during oncolytic virus therapy, including immune cells and other support cells is also an important are of research.

 

Diallo Lab

How can we improve virus therapy?

-Not all tumours are able to be targeted and killed by oncolytic viruses, thus they are resistant to this therapy.
-Research in the Diallo Lab focuses on the discovery and characterization of drug compounds that boost the activity of the oncolytic virus.
-Additionally, these compounds increase the susceptibility of cancer cells to the virus.
-This also has great potential to improve virus and vaccine manufacturing.

Welcome to the RIOT!

Hello Ottawa, Canada, and the world! OttawaRIOT, the Canadian Cancer Society’s Research Information Outreach Team, is live! We’re a group of students and researchers in Ottawa who want to share with you what amazing research is going on to help the fight against cancer. In the coming weeks, check back here to find engaging and exciting articles that will explain what cancer is, and what science is doing about it. Everyone talks about cancer research; if you want to get informed on what is actually going on, right here in Canada, you’ve come to the right place.

First, by way of introduction, here are the members of OttawaRIOT:

Casey Lansdell

Position

Master’s candidate in Dr. Auer’s lab enrolled in the Biochemistry program at the University of Ottawa.

Education

Casey is a graduate from Trent University (Peterborough, ON) with a Bachelor of Science in Forensic Science (Honours).

Current Projects

Her current research project is further investigating the mechanisms of surgery- induced suppression of tumuor- specific T- cell function.

Casey currently lives with her boyfriend Drew and her cat Zoe, but enjoys travelling out to Verona, ON to visit her family, where she can relax and go fishing.

Andrew Wight

Position

Ph.D. candidate (microbiology & immunology) in the Makrigiannis lab.

Education

Andrew completed his B.Sc. honours in Microbiology & Immunology at the University of King’s College/Dalhousie University in 2012.

Current Projects

Andrew is currently investigating the mechanisms behind adaptive natural killer cell responses, and their applicability in treating viral infections and cancer.

Andrew lives in Ottawa with his wife Irenee, and enjoys choral singing, knitting and spinning, and boardgames of any sort.

Dr. Lee-Hwa Tai

Position

Post-doctoral Fellow in Dr. Auer’s lab.

Education

Dr. Tai’s expertise in basic immunology comes from her doctoral studies (McGill University 2005-2010), which studied how the immune system ‘sees’ viruses.

Current Projects

Her current postdoctoral work is in the field of cancer immunology and immunotherapy and consists of using animal tumor models and cancer patient samples to study the effects of standard-of-care and experimental therapies in the treatment of postoperative metastatic disease.

In her spare time, Lee chases after her two sons, ages five years and five months.

Megan Tu

Position

Ph. D. candidate (microbiology & immunology) in the Makrigiannis lab.

Current Projects

Megan studies the role of class I MHC receptors in protection from cancer.

Connie Son

Position

Honours Student in Dr. Diallo’s lab

Education

Connie is currently studying biochemistry with option in microbiology and immunology at University of Ottawa. Her passion for research sparked when she first participated in a school science fair during her secondary education in Saint John, New Brunswick. In the summer prior to starting her BSc, she started her research career in an immunology lab, and she immediately fell in love with lab work.

Current Projects

Connie’s research project involves screening different types of tumors to find the correlation between in vivo and ex vivo infectivity of tumors with oncolytic rhabdovirus MG1. Ultimately, she hopes to find a biomarker that helps select the appropriate patients for clinical trials of an oncolytic virotherapy.

Katherine Baxter

Position

Master’s candidate in Dr. Auer’s lab, enrolled in the Microbiology and Immunology program at the University of Ottawa.

Education

Katherine is a graduate from the University of Ottawa with a Bachelor of Science (honours) in Biopharmaceutical Sciences, specialization in Genomics

Current Projects

Her current research project is investigating the use of oncolytic vaccines during the perioperative treatment of pancreatic cancer.