Approximately 80,000 Americans are diagnosed with bladder cancer each year. Although new immunotherapies known as immune checkpoint inhibitors are very promising, they are only effective in about 25% of patients with this cancer. Despite numerous studies, there is still no clear understanding of why the majority of patients with bladder cancer do not respond, nor are there clear ways to predict which patients will respond. Understanding the mechanisms of resistance to checkpoint inhibition has been frustrating and expensive, leaving both patients and doctors wishing for a better way.
With support from the V Foundation, Nicola J. Mason, B.Vet.Med., Ph.D., at the University of Pennsylvania School of Veterinary Medicine, is trying to find a better way to match checkpoint therapies with patients most likely to respond to them by studying bladder cancer in dogs. Her goal is twofold: to provide new treatments for dogs suffering from bladder cancer and to discover new biomarkers to identify which human and canine patients are most likely to benefit from these immunotherapies.
A win-win approach to cancer research
Mason’s project is funded through the V Foundation’s canine comparative oncology grant program, which supports researchers from human and veterinary medicine using a comparative approach that could lead to better cancer therapies for humans and pet dogs.
For years, mice have been used to study cancer. Although many important discoveries have been made using mice, they are model systems and frequently don’t show the same types of side effects that people experience in response to cancer therapies. Pet dogs are 85% similar to humans genetically and develop spontaneous tumors, including bladder cancer, that share many biological and behavioral characteristics with human cancer. Furthermore, pet dogs have intact immune systems and are likely to be highly valuable in determining responses to immunotherapies.
Developing state-of-the-art tools to study canine cancer
Bladder cancer in dogs is surprisingly similar to bladder cancer in people. These tumors tend to have a similar genetic makeup, the same subtypes and similar responses to chemotherapy. Mason is leading an interdisciplinary team of researchers from the University of Pennsylvania Veterinary and Medical schools to examine the biology of canine bladder cancer from several different angles.
“We are developing advanced tools for studying bladder cancer in dogs,” said Mason. “Having immune reagents that parallel those used to treat and assess response to treatment in people should help us address this question of why some human bladder cancer patients respond to immunotherapy while others do not. Eventually we may be able to use this information to help more patients respond to this treatment.”
They are specifically looking at checkpoint inhibitors, which are designed to unleash the full power of T-cells to fight cancer by blocking certain immune checkpoints that would normally keep the body’s T-cells from overreacting during an immune response. The researchers have developed their own checkpoint inhibitors for use in dogs because canine versions are not yet available for clinical use. So far, they have developed the canine equivalents of two human checkpoint inhibitors, which they plan to test soon. Before treatment, they will take biopsies of bladder tumors that have developed spontaneously in pet dogs to analyze genetic mutations and the types of cells present in the tumor microenvironment. After treatment with the checkpoint inhibitor, they will take another biopsy to see how the tumor changes in response to the therapy.
“We predict that the response to checkpoint inhibition will positively correlate with tumor mutational burden, and it may also be associated with the baseline immune profile of the tumor,” Mason said.
For quick and inexpensive analysis of a tumor’s mutational burden, they have developed a next-generation sequencing panel that can identify mutations occurring in genes that are commonly mutated in cancer. They are currently validating this tool, which corresponds to panels used to study tumor cell mutations in people.
In another aim of this study, the researchers are examining biomarkers that could be used to predict cancer response or resistance to checkpoint inhibitors. For this, they worked with the life science company NanoString to design a gene expression panel that can be used to evaluate the genes that make up the immune landscape (immunome) of cancer samples. The panel closely parallels one designed to evaluate the immunome in human cancer samples. The canine panel allows the researchers to examine 800 genes covering about 47 different immunological pathways and will be employed to analyze gene expression before and after checkpoint inhibitor treatment. They are also developing immunofluorescent strategies to determine the types of immune cells that infiltrate the tumors after checkpoint inhibition.
Looking beyond bladder cancer
The tools the researchers are developing with V Foundation funding can also be used to study other types of cancer. For example, the researchers are beginning to look at the mutational burden of hemangiosarcoma, a deadly cancer in dogs that is similar to a rare cancer in people called angiosarcoma. Although it is a very serious cancer, angiosarcoma is extremely difficult to study in people because there are so few patients. The researchers also plan to examine immune responses to checkpoint inhibition in other cancers and determine if clinical response correlates with tumor mutational burden and baseline immune status of the tumor.
“In these cancers, it is possible that we will find that the mutational load and immune response to checkpoint inhibition in dogs and humans are similar,” said Mason. “This will open up many new avenues for using the dog as a model to understand responses to checkpoint inhibitors and provide insights into basic tumor biology and immunology. This will benefit both the dogs and people.”
