The Modiano Lab is working to understand what causes cancer and what drives its behaviors -- translating that knowledge into better treatments and, ultimately, fewer cases of cancer in animals and in human patients. We asked Jaime F. Modiano, VMD, PhD, Perlman Professor of Oncology and Comparative Medicine and Director, Animal Cancer Care and Research Program at the College of Veterinary Medicine and Masonic Cancer Center at the University of Minnesota to share how his team is translating lab findings to canine trials, updates on current immunotherapy studies in canine osteosarcoma, and what is he most excited about for the future of osteosarcoma research.
I have always been curious about the natural world, and especially relations among animals. I was determined to be a scientist from a young age, and veterinary medicine provided an opportunity to combine "science" and "animals" in a single field. My undergrad research experiences with John Gold and Jim Womack added an emphasis on genetics, and the opportunity to train as a grad student with Peter Nowell, the discoverer of the Philadelphia chromosome, was probably the highlight of my educational experience. However, the single event that led me back to studying cancers of dogs (rather than focusing on how these events impact humans) was a project that my wife initiated as part of her residency training. She wanted to understand mechanisms that lead to what appears to be higher risk of certain tumors in dog breeds. Her grant got funded, and here we are, almost 30 years later, still working to understand how tumors are similar and different across different species.
We are very sensitive about using the word "models." We understand models are imperfect, and so our emphasis has been on finding the right experimental system to answer the right question. We are extremely conservative when it comes to using live animals for research, whether the animals are healthy blood donors (human, dog, cat, or other), purpose-bred laboratory mice, or dogs with naturally occurring diseases. We always ask ourselves, what is the best way to answer the question? Sometimes, the complexity of the system requires using mice - and when we believe a project is ready to be translated to the clinic, we consider including companion dogs in our experiments.
We have developed unique mouse "models" to study various aspects of the immune system and to understand how it adapts or responds to cancer, including mice that lack critical genes that are important to initiate immune responses and mice that lack the molecules that direct T cells to "self." We have also brought several cancer treatments to the clinic for dogs with osteosarcoma, a life threatening soft tissue sarcoma called hemangiosarcoma, and malignant lymphomas. Many of these treatments have emphasized activation of the immune system, albeit at different points of entry in the activation sequence. At the present time, we are investigating combination therapies against osteosarcoma that use one compound to alter the immune environment (eBAT or VSV) and a second compound that inhibits two critical checkpoints of immune activation, with the expectation that we can create a favorable environment and the right set of signals to support anti-tumor immune responses.
Our recent efforts have emphasized developing diagnostic tests that can help to guide therapy by predicting prognosis (the proof of concept, published a little over a year ago was done in osteosarcoma) and perhaps more exciting, to understand how cancer-permissive environments form as a consequence of aging, how we can identify them to stratify healthy individuals according to their overall risk level, and how we can intervene to disrupt that risk and delay or prevent the formation of cancer altogether. One project we have been mulling about is how we could apply these concepts to inform the actual risk of kids that have predisposing heritable mutations (like those born to Li Fraumeni families) to develop osteosarcoma. We think we have the tools to do that now.
The University of Minnesota provides a great environment to conduct translational studies in companion animals that can inform the pathway for human therapeutic development. The Clinical Investigation Center (CIC), which is part of the Office of the Associate Dean of Research and is directed by Dr. Antonella Borgatti, is a centralized resource for veterinary clinical trials - whether the major focus of those trials is a direct veterinary application or a downstream human application. Cancer is a big focus of the CIC, but it is not the only one. There is a lot of activity from other specialties, and even within cancer, we have a wide diversity of studies. The CIC provides the infrastructure to conduct trials, with a team of exceptionally skilled and highly trained techs under the leadership of two superb veterinarians. The concept is to provide rigor and consistency that meet the highest regulatory standards, with enough flexibility to accommodate the unique needs of every study.
The founding director of the CIC, Dr. Washabau, was a board-certified veterinary internist. The second director, Dr. Conzemius, was a board-certified veterinary orthopedic surgeon. And the current director, Dr. Borgatti, is a board-certified veterinary oncologist. And while those of us who work on cancer really appreciate having someone who shares our interest in the leadership position, we have always found the support we needed in the CIC. In my opinion, this is an optimal approach to support the totality of the enterprise and I am extremely grateful for all the work that Dr. McCue, our Dean of Research has done to continue growing and improving this service.
The VIGOR trial is complete and the paper describing the outcome was recently submitted, so I will describe the outcome a bit generally. The backstory is that, while she was still at the University of Tennessee, Dr. Amy LeBlanc had started a collaboration with Dr. Steve Russell at Mayo to test an oncolytic vesicular stomatitis virus in dogs. Much of the work was done by Dr. Shruthi Naik, who was then a postdoc in Dr. Russell's lab. Fast forward to Dr. Leblanc moving to the NCI and making a connection between Dr. Russell and Dr. Naik's group and our group, and magic happened. The virus is engineered to exploit its tropism for cancer cells (it seems to love osteosarcoma cells more than others!) and to spare non-malignant cells from its oncolytic activity. The premise is that the virus, which is highly immunogenic, will infect the tumor environment, kill tumor cells to expand, and by doing so, it will expose itself AND bits of the tumor to the immune system, activating an immune response. There is a lot of preclinical data to support the scientific premise of oncolytic virotherapy, and we knew from the work of Drs. Naik, LeBlanc, and Russell that VSV could be used safely and that it had biological activity. Several things had to fall into place for this trial. The first was robust funding from the state of Minnesota through its competitive Partnership for Biotechnology, which leverages resources from the U of M and the Mayo Clinic. The second was successful fundraising by Vyriad (a Mayo spinoff that is developing VSV and other oncolytics for cancer), and their recognition of the value of a comparative study in dogs. The third was the arrival of Dr. Kelly Makielski, a super-talented postdoc (now Assistant Professor) who guided the study through all its complexity with support from our Cancer Biology NH training grant. The fourth was the relentless support we got from the CIC to overcome many regulatory obstacles. The fifth was the unique environment at the U of M, where we had the brainpower to address the clinical, genomic, and immunologic complexity of the project. The sixth was the enduring support of donors who helped to support the study financially. And the final one was the amazing resilience and dedication of all of our team. Nothing would happen without the hard work of a lot of amazing individuals.
Our hypothesis was that using the virus while there was tumor burden (a delay of therapy approach) would provide the best opportunity to alter the immune environment in the tumor and activate the immune system. We would follow that with removal of the primary tumor (amputation) and then apply conventional chemotherapy with sufficient time having elapsed between the immune stimulus (VSV) and chemotherapy so as not to disrupt any ongoing immune response. This approach also gave us the opportunity to confirm that the virus would home to the tumor (it does) and would change the immune environment (it does).
The results from the study tell us that, at least at the dose we used, VSV is not a panacea, but it seems to be effective to generate durable remissions (and by "durable" we mean, until the dogs die of something else!) in a subset of dogs that share in common some degree of pre-existing immunity.
VIGOR opened the door to the ongoing METEOR trial, where we are testing VSV in combination with a drug we call ONcoImmune aCCelerator (ONIx) as treatment for dogs that failed first line therapy (surgery + chemo) and have measurable pulmonary metastasis. ONIx is a peptide developed by Dr. Aaron Ring, at Yale, that inhibits the interactions between CD47 and SIRP-alpha and between PD-1 and PD-L1/PD-L2. We are using a slightly modified dose and schedule for VSV to increase the likelihood of disrupting the local tumor environment and creating a pro-immune state where ONIx can enhance the activity of macrophages and professional antigen presenting cells, as well as of anti-tumor (and anti-virus) T cells and NK cells.
I am extremely excited about the evolving recognition that osteosarcoma represents a huge constellation of diseases (maybe a different disease in each patient), at least genetically and immunologically. These tumors all seem to converge into a tissue organization that achieves the lowest energy state for "osteosarcoma" formation and maintenance. So, it would appear that there may be no single "driver" or sets of drivers for osteosarcoma. Instead, the cells adapt in a highly selective environment to become the complex tissue we call "osteosarcoma." This is probably not news to many people who have been working on this disease for many years - and especially to those who look at osteosarcoma samples under the microscope. But we've had to work our way back to this because the molecular revolution pushed us to look for the elusive driver. This gets us back to the concept of identifying and understanding the events that create a tumor permissive environment, and to think about how we can attack that while recognizing that we would be proposing potentially radical interventions in kids (and dogs) that appear otherwise healthy. It is a tall order, but we are excited that the dog-loving community has expressed willingness to test the idea and worked with us to start the Canine Osteosarcoma Early Detection (COED) study, which seeks to address the first goal by developing a test that can detect the high risk (tumor-permissive) environment with clinically acceptable sensitivity and specificity.
