Revolutionary research breaks the frontline against HIV and cancer | 097

Share:

Listens: 0

Biotechnology Focus Podcast

Science


  Welcome to another episode of Biotechnology Focus radio! I am your host – Michelle Currie – here to give you the Canadian biotech rundown from coast to coast. This week there has been some revolutionary research in HIV, and natural killer cells. FACIT – the fight against cancer innovation trust – has invested in three novel cancer therapeutic discoveries, and Oncolytics Biotech enters a clinical collaboration to combat breast cancer. Keep listening to find out more details!  +++++  Researchers at the BC Centre for Excellence in HIV/AIDS (BC-CfE) and Simon Fraser University (SFU), in partnership with University of British Columbia (UBC) and Western University, develop a way of dating “hibernating” HIV strains, in an advancement for HIV cure research in the province.  Published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), the BC-CfE’s first major scientific contribution to the area of HIV cure research confirms that dormant HIV strains can persist in the body for decades.  Dormant HIV strains, embed their DNA into the body’s cells, tucking themselves away for years – but can reactivate at any time – and are unreachable by antiretroviral treatments and the immune system. This is the reason why HIV treatment needs to be maintained for life.  Dr. Zabrina Brumme, director, Laboratory with BC Centre for Excellence in HIV/AIDS and lead author on the study says that, “If you can’t identify it, you can’t cure it. This research provides further essential clues in the pursuit of an HIV cure—which will ultimately require the complete eradication of dormant or ‘latent’ HIV strains. Scientists have long known that strains of HIV can remain essentially in hibernation in an individual living with HIV, only to reactivate many years later. Our study confirms that the latent HIV reservoir is genetically diverse and can contain viral strains dating back to transmission.”  Dr. Julio Montaner, director of the BC Centre for Excellence in HIV/AIDS  says that, “The BC Centre for Excellence in HIV/AIDS  has consistently been a national and global leader on research on HIV and on the implementation of its pioneering Treatment as Prevention® strategy. The addition of molecular biologist Dr. Zabrina Brumme as director of the innovative BC Centre for Excellence in HIV/AIDS Laboratory ensures the BC Centre for Excellence in HIV/AIDS  will play a significant role in HIV cure research. Curative strategies will need to address this new study’s key findings. I want to acknowledge the study participants and thank them for helping to increase our knowledge on the origins of the latent HIV reservoir.”  Brad Jones, a Ph.D. student with the University of British Columbia (UBC) at BC Centre for Excellence in HIV/AIDS and the first author on the study says that, “By creating family trees of viruses using a technique called molecular phylogenetics, we can reconstruct the evolutionary history of HIV within a person. In essence, we created a highly calibrated ‘time machine’ that gives us a specific time stamp for when each dormant HIV strain originally appeared in a person.”  Through advances in antiretroviral therapy, an individual living with HIV can now live a longer, healthier life on treatment. Treatment works by stopping HIV from infecting new cells. On sustained treatment, individuals can achieve a level of virus that is undetectable by standard blood tests. An undetectable viral load means improved health and that the virus is not transmittable to others—the concept behind Treatment as Prevention®.  Dr. Jeffrey Joy, research scientist at the BC Centre for Excellence in HIV/AIDS and co-author on the study says that “Previous research had already revealed that the HIV reservoir was genetically complex. With our method, we can now understand that complexity with greater granularity, pinpointing exactly when each unique HIV strain originally appeared in a person.”  Dr. Art Poon, assistant professor at Western University’s Schulich School of Medicine & Dentistry, also a co-author on the study, says that, “In order to eradicate HIV from a person’s body, you first need to know the characteristics of HIV in the latent reservoir. We are providing a method for better measuring the timeline of virus latency and evolution within an individual living with HIV.”  “Dating” dormant HIV strains within the viral reservoir involve comparing them to strains that evolved in an HIV-positive person over their entire history of infection.  The BC Centre for Excellence in HIV/AIDS is one of a handful of institutions worldwide capable of such research, thanks to its maintenance of a historical repository of blood specimens from individuals diagnosed with HIV in BC. These specimens date back to 1996 and were originally collected for viral load and drug resistance testing. The BC Centre for Excellence in HIV/AIDS Laboratory has provided HIV drug resistance genotyping for virtually all Canadian provinces and territories since 1998, as well as for many countries worldwide.  This research was funded by the Canadian Institutes of Health Research (CIHR) in partnership with the Canadian Foundation for AIDS Research (CANFAR) and the International AIDS Society (IAS) through its support of the Canadian HIV Cure Enterprise (CanCURE), as well as the US National Institutes of Health (NIH) through its support of the Martin Delaney BELIEVE Collaboratory.  +++++  Immune checkpoint inhibitors are waging a revolutionary war on cancer, but new research challenges the central dogma of how this drug treatment works. This research, published in the prestigious Journal of Clinical Investigation, shows for the first time that often-overlooked immune cells called Natural Killer (NK) cells play a crucial role in responding to checkpoint inhibitors.  co-senior author Dr. Michele Ardolino, a scientist at The Ottawa Hospital and assistant professor at the University of Ottawa  explains that, “Checkpoint inhibitors work by waking up the body’s own immune system and unleashing an immune attack on cancer cells. For many years, everyone assumed that checkpoint inhibitors targeted immune cells called T-cells. But our research shows that they also target Natural Killer cells and these cells play a key role in the how this treatment works.”  Dr. Arolino led the study together with Dr. David Raulet, a professor at the University of California at Berkeley.  Dr. Raulet says that “In the cancer immunotherapy field there has been a singular focus on mobilizing anti-tumor T-cells. We believe that NK cells have an important place at the table. Checkpoint therapy combined with other NK-directed immunotherapies may enable us to target many types of tumours that are currently non-responsive to available therapies.”  T-cells and Natural Killer cells can both recognize and kill cancer cells, but they do so in very different ways. NK cells recognize patterns of changes on cancer cells and are the immune system’s first line of defense. A T-cell, on the other hand, recognizes a single abnormal molecule on a cancer cell and initiates a more focused attack.  In the current study, Drs. Ardolino, Raulet and their colleagues investigated the effect of checkpoint inhibitors in various mouse models of cancer. They found that checkpoint inhibitors could shrink tumours even in mice with no anti-cancer T-cells, meaning that some other kind of cell must be responding to the checkpoint inhibitors. When the mice were depleted of Natural Killer cells, it greatly reduced or eliminated the anti-cancer effect of the checkpoint inhibitors. They also showed that Natural Killer cells produce the same checkpoint receptor molecules that T cells do, inferring they can respond directly to checkpoint inhibitors.  co-lead author Jonathan Hodgins, a PhD student at The Ottawa Hospital and the University of Ottawa says that, “This research helps solve a mystery that’s been seen in the clinic, where certain cancers are very susceptible to checkpoint inhibitors even though their T-cells don’t seem to be activated. If we’re right, Natural Killer cells are probably being activated in these patients.”  Previously, Dr. Ardolino, worked in Dr. Raulet’s lab in California before he was recruited to The Ottawa Hospital and the University of Ottawa in 2016. Together they are now investigating approaches to further enhance the cancer-killing ability of Natural Killer cells.  Dr. Ardolino says that, “My dream is that when people come to the hospital with cancer, we’ll be able to take a biopsy and determine not only the mutations in their cancer, but also profile how their immune system is interacting with their cancer. Then we would give the patient the immunotherapy treatments that is most likely to work for them.”  +++++  As a gateway to the cancer research pipeline in Ontario, and a bridge between public and private sectors with an expanding portfolio of breakthrough innovations, Fight Against Cancer Innovation Trust (FACIT) is committed to supporting Ontario entrepreneurs through the latest round of its Prospects Oncology Fund to continuously identify and advance breakthroughs in science and technology.  FACIT has carefully chosen three novel cancer therapeutic discoveries to receive early-stage capital – biotechnology start-up Talon Pharmaceuticals, the Drug Discovery team at the Ontario Institute for Cancer Research (OICR) and the Centre for Commercialization of Regenerative Medicine (CCRM).  The Prospects Fund provides entrepreneurial scientists with the capital resources necessary to achieve critical proof-of-principle studies for their cutting-edge breakthroughs aiming to benefit future patients.  Talon Pharmaceuticals, through its Multiphore drug design platform, is focused on the discovery, development, and commercialization of medicines designed to save lives and improve patient quality of life. They are developing a novel series of small molecules with an undisclosed mechanism of action applying decades of experience with central nervous system (CNS) drug discovery.  OICR is a collaborative, not-for-profit research institute accelerating the development of new cancer research discoveries for patients around the world while maximizing the economic benefit of this research for the people of Ontario. OICR’s Drug Discovery team and their collaborators at the National Research Council (NRC) will receive funds towards the development of a potentially superior class of antibody-drug conjugates.  CCRM’s mission is to generate sustainable health and economic benefits through global collaboration in cell and gene therapy, and regenerative medicine. CCRM will receive funds towards the development of a universally compatible source for the next generation of CAR-T therapies.  FACIT’s $35-million in investments over multiple years addresses a critical health care seed-stage gap often experienced by Ontario product developers. De-risking innovation sets up successful projects for either company creation or a larger round of financing by FACIT and its investment partners, with over $340-million in follow-on financings to date. FACIT’s maturing portfolio of technology investments anchors companies and jobs in Ontario and reduces the need for entrepreneurs to look south of the border.  David O’Neill, president of FACIT  says that, “Our team is pleased to invest in and work alongside these entrepreneurial scientists, providing capital, industry networks and commercialization expertise, as they advance their therapies closer to clinical development. Capitalizing on the province’s investment in healthcare and scientific collaboration through our strategic partners at OICR is not only good for creating high-skilled jobs but also ensures research undergoes translation to impact the lives of patients with cancer.”  +++++  Oncolytics Biotech Incorporated enters into a clinical collaboration with SOLTI, an academic research group dedicated to clinical and translational research in breast cancer. This clinical collaboration, being sponsored by Oncolytics and facilitated by SOLTI, is a window of opportunity study in the neoadjuvant setting for breast cancer.  Reolysin, (pel-areo-rep), an intravenously delivered immuno-oncolytic virus turning cold tumours hot is under development by Oncolytics Biotech. Patients will receive the appropriate standard of care for their cancer subtype plus pel-areo-rep (or Reolysin with or without the anti-PD-L1 cancer immunotherapy ate-zoli-zu-mab (also known as Tecentriq)). Patients are biopsied on day one, followed immediately by treatment and a final biopsy after three weeks, on the day of their mastectomy. Data generated from this study is intended to confirm that the virus is acting as a novel immunotherapy and to provide comprehensive biomarker data by breast cancer sub-type, to support Oncolytics’ phase 3 study in metastatic breast cancer and is expected in mid 2019.  Matt Coffey, president and CEO of Oncolytics Biotech says that they are thrilled to enter into this collaboration with SOLTI and sponsor this window of opportunity study.  They expect that this study will provide additional biomarker and immunological data to support our planned phase three study in metastatic breast cancer. This data should confirm the findings of our phase two study and generate a robust biomarker plan designed to potentially enhance our phase three program. Importantly, it will also generate additional data demonstrating how the promotion of a virally induced inflamed phenotype should synergise with checkpoint inhibitors targeting PD-L1 like ate-zoli-zu-mab.”  The study, facilitated by SOLTI, will be coordinated by Dr. Aleix Prat, head of Medical Oncology at the Hospital Clínic of Barcelona, associate professor of the University of Barcelona and the head of the Translational Genomics and Targeted Therapeutics in Solid Tumors Group at August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and member of Oncolytics’ Scientific Advisory Board. SOLTI has a network of more than 300 professionals, mostly medical oncologists, in over 80 hospitals in Spain, Portugal, France, and Italy. Final study design and other details will be announced upon enrollment of the first patient, expected around the end of 2018 or very early 2019.   Dr. Prat says that, “It has been demonstrated that when reovirus infects a tumor, it promotes the release of immuno-stimulatory signals. This, in turn, results in the upregulation of PD-L1 on tumor cells and the recruitment of inflammatory immune cells like Natural Killer-cells and cytotoxic T-cells to the tumor, which are required prerequisites for checkpoint inhibitors to function effectively.  In short, it turns cold tumours hot. They believe pel-areo-rep can demonstrate the necessary inflamed tumour phenotype to prime tumours for PD-L1 blockade, which could potentially represent a promising form of cancer immunotherapy combination with ate-zoli-zu-mab. Results from this study will seek to establish the virus as an important immuno-oncology agent in breast cancer, which could ultimately support the expansion of pel-areo-rep beyond metastatic breast cancer into first-line therapy.”  +++++  Well that wraps up another episode of Biotechnology Focus radio. Thanks for listening! Make sure to check out the articles on the website: biotechnologyfocus.ca. Until the next time, from my desk to yours – this is Michelle Currie.