Monthly Archives: June 2017

Awakening Cancer-Fighting Cells of the Immune System Using Radiation Therapy

By: Joseph Longo

T Cell

About half of all cancer patients will be treated with radiation therapy at some point during the course of their disease. Conventional radiation therapy involves the delivery of high doses of radiation to the tumour, usually in multiple smaller doses called fractions. When a cell is irradiated, its DNA becomes damaged. If this damage is left unrepaired, the cell dies. Unlike chemotherapy, which is usually delivered throughout the entire body, radiation therapy is delivered with high precision to a specific area. As a result, DNA damage only occurs in those cells within the radiation field. However, oncologists have noticed that, in a small number of patients with multiple tumours in different locations within the body, the delivery of radiation to one tumour can cause the other tumours outside of the radiation field to shrink in size.

How is this possible? The answer seems to lie within the immune system. When cancer cells die in response to radiation therapy, they release proteins and other molecules into the surrounding environment. These molecules act as “danger signals” that alert and recruit cells from the patient’s immune system. Immune cells known as T cells can recognize certain cancer-specific proteins as “foreign material”, which results in their activation. These activated T cells can then circulate the body and kill any cancer cell that displays that same foreign protein.

What does this mean for a patient receiving radiation therapy? Not only can radiation therapy directly kill cancer cells by causing DNA damage, but, in certain cases, it can also activate and exploit the patient’s immune system to kill cancer cells that may have survived the radiation treatment or spread to other parts of the body. This phenomenon is commonly referred to as the abscopal effect, and has been reported in several different cancer types, including lymphoma, melanoma and hepatocellular carcinoma [1].

In some cancers, the expression of certain proteins on the surface of the cancer cell can mask them from the immune system. Many of these proteins are now the targets for a class of cancer immunotherapy drugs called immune checkpoint inhibitors. The inhibitors work by blocking these cell surface proteins so that T cells can attack and kill the cancer cells. While these immune checkpoint inhibitors have resulted in some dramatic responses in a subset of cancer patients, the number of patients who benefit from immune checkpoint therapies is low [2]. Many clinical trials are now investigating the potential for radiation therapy to increase the number of patients who can benefit from immune checkpoint therapies in a number of different cancer types [3]. In a recent case report, a melanoma patient who progressed while on an immune checkpoint inhibitor, called ipilimumab, was subsequently prescribed palliative radiation therapy and an additional dose of ipilimumab. Remarkably, not only did the patient’s irradiated tumour shrink, but so did the tumours outside of the radiation field [4].

While promising, it should be noted that the abscopal effect of radiation therapy is a rare phenomenon, and more research is needed to fully understand the mechanism by which it occurs and how best to exploit it. In recent pre-clinical studies, it was identified that repeated low doses of radiation in combination with immune checkpoint inhibitors was more effective at activating tumour-specific T cells and inhibiting tumour growth compared to single, higher doses of radiation [5-6]. These studies have important clinical implications, as they suggest that certain radiation doses and fractionation schedules may be more effective at eliciting the abscopal effect than others. The results of on-going clinical trials and further basic research will inform us how best to use radiation therapy in combination with cancer immunotherapies going forward, and have the potential to greatly influence cancer patient care.

This article was written by Joseph Longo. Joseph is currently pursuing a PhD in the Department of Medical Biophysics at the University of Toronto. He studies how statins can be used to treat cancer. To learn more about Joseph and his research, check out our members page.

References

[1] Formenti & Demaria (2009). Systemic effects of local radiotherapy. Lancet Oncol 10:718-726.

[2] Sharma & Allison (2015). Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential. Cell 161:205-214.

[3] Kang et al. (2016). Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer doi: 10.1186/s40425-016-0156-7.

[4] Postow et al. (2012). Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925-931.

[5] Dewan et al. (2009). Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15:5379-5388.

[6] Vanpouille-Box et al. (2017). DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun doi: 10.1038/ncomms15618.

Wielding a Double-Edged Sword: Oncolytic Viruses in Cancer Therapy

By: Martin Smith, PhD

Oncolytic therapy blog pictureYou know the feeling…  It could start with a nagging headache.  Or, it could be the flush feeling of an oncoming fever.  Whatever it may be, many of us can relate to the symptoms of an impending viral infection. But, what if those same symptoms became signals of life saving treatments?  For some patients in trials of a new cancer therapy, headaches and fevers represent markers of hope. Researchers have now engineered viruses to selectively recognize, infect and kill cancer cells in our body.  These viruses, known as oncolytic viruses, are one of the next-generation cancer immunotherapies being studied to treat cancer.

Viruses can be deadly, and some have devastated the human race.  However, others are being used for oncolytic virus therapy can actually be quite useful.  When virions encounter a living organism something amazing happens. The virus particle will recognize and bind to signals on the surface of the host cell.  Once bound, the virus enters the cell where it hijacks the internal cellular machinery to replicate – making more copies of itself.  Unchecked, replication of the virus can cause the cell to explode . This releases the cell contents, including many new virus particles, which go on to repeat the infection cycle.  This self-perpetuating behavior is common in the virus life cycle and is exactly what cancer researchers want to take advantage of when programming oncolytic viruses to preferentially target cancer cells.

Cancer cells function differently than healthy cells. Scientists have selected viruses that find cancer cells because of their altered function (1).  Or, they have engineered special systems into the virus to recognize specific cancer markers.  Oncolytic viruses happily bind and enter the host and replicate to produce numerous copies of themselves inside the cell.  Gravid with new virus particles, the host cancer cell explodes, spewing out large numbers of cancer killing viral particles to continue the fight.  The cancer cells release their insides during the explosion, activating the immune system to recognize and attack other cancer cells (2).  This activation of the immune system is what leads to common symptoms of viral infection (an infographic illustrating oncolytic viruses can be found here).

It sounds perfect, right? Researchers across the world are definitely excited about oncolytic viruses.  Early stage clinical trials are critical to determine the safety and efficacy (3).  With safety being of utmost importance here, it is important to remember that viruses can be hard to control.  Doctors will consider short-term side effects tolerable as long as they remain manageable.  The long-term behaviour of viral therapies will also be important to understand.  For example, some viral infections can actually lead to cancer.  The human papilloma virus (HPV) has been shown to cause cervical cancer as well as head and neck cancer years after infection.  There is no doubt that determining the effects of oncolytic viruses will be very important as the scientific community approaches drug development.

A cautious approach will be very important in using oncolytic viruses.  The pros and cons associated with the use of these viruses forge a veritable double-edged sword.  Perhaps it is time we pulled that sword from stone and used it in the fight against cancer.

This article was written by Dr. Martin Smith. Dr. Smith completed his PhD at the University of Waterloo studying how proteins can cause cancer. He currently works for the Ontario Brain Institute where he studies brain disease. To learn more about Dr. Smith and his research check out our members page.

References:

(1) Ilkow et al., From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer, PLOS Pathogens, 2014; 10(1); 1-8.

(2) Chiocca and Rabkin, Oncolytic Viruses and Their Application to Cancer Immunotherapy, Cancer Immunol. Res., 2014; 2(4); 295-300.

(3) Aghi and Martuza, Oncolytic viral therapies – the clinical experience, Oncogene, 2005; 24, 7802-7816.

Teaching Cancer Research to the Next Generation: A Recap of Let’s Talk Cancer 2017

OLYMPUS DIGITAL CAMERAHello everyone! There has been a lot of activity over here at RIOT recently. We thought we would share with you some updates on an incredible event that we just held this past April!

An important aspect of what we do at RIOT is to increase awareness on the progress in cancer research, and that includes reaching out to the younger generation! So, over the past two years, we have been travelling around the GTA, teaching high school classes on cancer biology and what cancer research is like as a potential career option. It’s been an awesome journey for us to meet such bright and motivated students as well as the outstanding teachers that show such an amazing level of commitment and dedication to their students.

These rewarding experiences led us to create a one-day symposium in collaboration with Let’s Talk Science for high school students known as Let’s Talk Cancer. With the support of community donors like SimpliHome, we have been successful in hosting Let’s Talk Cancer events for other RIOT teams across Ontario for the past two years now. Together, we wanted to create a positive and greater learning experience for the exceptionally curious students.

Our event was held in the iconic “Great Hall” at The University of Toronto campus. The space really captured the essence of a historic academic institution with a whimsical nod at Hogwarts! We started the day with an awe-inspiring speech by a young cancer survivor, who shared her personal experiences battling breast cancer. It was humbling to listen to her words, she brought immense perspective to the students and really highlighted the importance of cancer research to all of us.

The day was then filled with lectures from scientific leaders and experts in the various fields of cancer research. We invited scientists to speak on their own research that ranged from ‘Clonality’ and ‘Tumor Microenvironment’ to ‘Personal Oncogenomics’ and ‘Drug Development’. Each lecture was followed by a lively Q&A and then a hands-on activity to engage the students to apply what they learned. A winning team of students, from one of our activities, even had the unique opportunity to tour a stem cell lab! We ended the day with an energetic talk given by a cancer community advocate, who empowered the students with tools to get active and involved in their own community.

Today, cancer touches the lives of people of all ages directly or indirectly. This includes our younger generation – and they want to do something about it, whether it be in advocacy or pursue a career in research and/or medicine. Researchers are still learning more about the complexity of cancer day by day and it is going to take our next generation to make new and lasting discoveries. We hope events like Let’s Talk Cancer inspires the next generation of scientific leaders in our community.

Check out more pictures from the event below!