In the coming years, if the needle moves on standard care for osteosarcoma, and glioma's treatment landscape expands to include oncolytic viruses and molecularly targeted agents, dogs will deserve a big shout-out.
“People don't typically see veterinarians as researchers, but as ‘the nice person who takes care of my sick pet,’” muses Amy LeBlanc, DVM, director of the NCI's Comparative Oncology Trials Consortium. “We're very much trained to think across species, though, and often encounter questions along these lines: ‘My dog got this cancer. How is it similar to or different than my grandfather's cancer?’”
Such queries from savvy owners, who want the same treatment options for their pets that people have, are fueling the growth of comparative oncology. Other factors are also at play. “We now have tools to analyze dog tumors in ways we couldn't before, and there's a growing realization that current experimental models aren't optimal for advancing new therapies into humans,” says Deborah Knapp, DVM, of Purdue University in West Lafayette, IN.
Nicola Mason, BVetMed, PhD, of the University of Pennsylvania (Penn) in Philadelphia, agrees. “Many cancers affecting humans also occur naturally in dogs,” she says. “They represent a parallel patient population that could bridge the translational gap where what looks promising in mice doesn't necessarily work in people.”
That the dog is an immunocompetent model is especially favorable given the surge of all things immuno-oncology, “which prompted NCI to really start investing in canine studies,” LeBlanc says. For instance, money from the original Cancer Moonshot was earmarked to create the PRE-medical Cancer Immunotherapy Network for Canine Trials (PRECINCT) consortium in 2017: Five veterinary academic institutions have since been enrolling pet dogs in trials for osteosarcoma, glioma, and lymphoma.
PRECINCT is “a think tank aimed at accelerating promising immunotherapeutic strategies into the human clinic through comparative oncology,” says Mason, who oversees PRECINCT's coordinating center at Penn, where trial data are curated and harmonized.
“Not only do we have better tools and broader acceptance of dogs as a model system, but there's money to support our work, which is always key,” remarks Cheryl London, DVM, PhD, of Tufts University's Cummings School of Veterinary Medicine in North Grafton, MA.
New avenues in osteosarcoma
One of London's projects is a collaboration she and Steven Dow, DVM, PhD, of Colorado State University in Fort Collins, are leading. The focus is osteosarcoma, “which the Children's Oncology Group calls ‘the graveyard of clinical trials’ when it comes to metastatic disease—nothing works at that point,” she says.
Dow and London assessed three drugs—toceranib (Palladia; Zoetis), a multikinase inhibitor; the antihypertensive losartan; and ladarixin (Dompé), an investigational IL8 receptor antagonist—in dogs with osteosarcoma that, despite standard limb amputation and chemotherapy, had spread to the lungs. The goal was to modulate the immunosuppressive tumor microenvironment, “clearing out bad actors” such as inflammatory monocytes and overabundant IL8. “It looks like we may have hit pay dirt,” London says. “The results are exciting, with one complete responder a year and a half out [Clin Cancer Res 2022;28:662–76].” The investigators are now testing the regimen's first-line potential, hoping to prevent metastases and avoid chemotherapy.
Deborah Knapp, DVM, performs an ultrasound on a dog enrolled in a bladder cancer trial.
Losartan plus sunitinib (Sutent; Pfizer), a human equivalent of dog-specific toceranib, is also being evaluated in children and adults with relapsed/refractory osteosarcoma; whether to add ladarixin is under discussion. Trying this novel combination up front to spare children, especially, long-term survivorship issues from dose-intensive chemotherapy “would be good, but moving the needle is hard,” London acknowledges. “The cure rate is roughly 70%, so to merit getting rid of chemotherapy as an anchor, we'd need convincing proof from more dog studies.”
Meanwhile, Mason and LeBlanc are collaborating on a vaccine-based osteosarcoma therapy to halt metastasis. Their approach involves injecting dogs, after primary tumor removal (limb amputation), with an attenuated form of Listeria monocytogenes modified to recognize HER2 on tumor cells. “The idea is for Listeria to then stimulate T-cell responses that will hopefully prevent micrometastases,” Mason explains. “HER2's expression in osteosarcoma is predominantly intracellular, which is likely why antibody-mediated therapies [that] recognize cell-surface HER2 haven't worked well.”
“The vaccine is being tested in children, so we've got a great opportunity to study parallel outcomes,” LeBlanc adds. “Our canine work was not only informative for the ongoing pediatric trial, it also highlighted how biologically rich the data [are] that we can generate in dogs.”
Gunning for Gliomas, bladder cancer
Precise delivery of any therapeutic to brain tumors remains challenging. John Rossmeisl, DVM, of Virginia-Maryland College of Veterinary Medicine in Blacksburg, VA, and Waldemar Debinski, MD, PhD, of Wake Forest University School of Medicine in Winston-Salem, NC, hope their pioneering strategy can help.
Knowing that IL13RA2 and EPHA2 are expressed in roughly 90% of canine and human gliomas but not in normal brain, Debinski figured out how to target both membrane receptors “through their specific ligands, which we tagged with genetically modified bacterial toxins,” he says. Upon ligand–receptor binding, the cytotoxins are internalized by and kill glioma cells (Neuro Oncol 2021;23:422–34).
John Rossmeisl, DVM, with Emily
The concept made it to phase III evaluation in people but “failed due to trial design flaws, nonspecific targeting, and technical issues with drug delivery,” says Rossmeisl, who began working in dogs to improve convection-enhanced delivery (CED) of the cytotoxic cocktail. CED “involves infusing treatment under constant pressure at an extremely low rate over a prolonged time period,” he explains. “Predicting where the drug goes in the brain is tricky, so we spent time refining the technique. We now use specialized catheters and imaging tracers to better map drug distribution.”
The researchers have expanded their target coverage to include EPHB2 and EPHA3 receptors, “because all four are expressed in different glioma microenvironments,” Debinski says. They've also engineered a single agent, instead of a cocktail, as the payload. This means “we can deliver one entity to go after glioma's heterogeneous abnormalities,” Rossmeisl notes. “Our lead candidate is far more potent than earlier constructs, with no side effects so far.”
Within 3 years, “we'll compile the necessary data to move on to human trials,” Debinski adds. “Along the way, many dogs will have benefited from a highly effective treatment.”
Veterinary oncologists “have almost always investigated any human drug that looks good, purely for vet use,” says Timothy Bentley, DVM, also of Purdue. “A newer development for us is doing more trials in dogs to better refine studies in people—humans are the whole point, but we get new therapies for dogs as a bonus.”
Bentley has been collaborating with Rene Chambers, DVM, MD, of the University of Alabama at Birmingham, on a canine trial assessing M032, an oncolytic herpes simplex virus (oHSV) for glioma. Like talimogene laherparepvec, or T-VEC (Imlygic; Amgen), an option for melanoma—and the only approved oHSV to date—M032 “is modified to selectively replicate in and kill cancer cells,” Bentley explains. “It's also engineered to produce IL12, stimulating immune system action and increasing efficacy.”
Timothy Bentley, DVM, examines Dakota.
M032 has been greenlighted for human trials, but “the FDA requested that we first study its dose escalation in pet dogs with spontaneous gliomas, following surgery,” Bentley says. Preliminary findings indicate that it doesn't harm dogs and may extend their survival (Neurosurg Focus 2021;50:E5). The investigators are establishing an optimal dose and also testing M032 in combination with indoximod (Lumos Pharma), an investigational IDO inhibitor.
Overall, “we've made inroads, but there's still much to do to get comparative oncology more on the cancer research community's radar,” Knapp concludes. “I think we'll get the most traction within specific disease groups.”
For instance, bladder cancer “is another tumor type where we know rodent models aren't predictive enough,” Knapp says. On the other hand, comparing human and canine invasive urothelial carcinoma, “the molecular subtypes line up very nicely.” Studying dogs with the disease and the canine homolog of BRAFV600E, her group reported similar cross-species outcomes with vemurafenib (Zelboraf; Genentech) treatment. “We now have a relevant model to better understand BRAF-targeted therapies, including how resistance develops, which is huge,” she says (Mol Cancer Ther 2021;20:2177–88).
“We're just starting to delve into the shared cancer biology between canines and humans,” Rossmeisl observes. “You're going to see an explosion of studies using the dog as a translational model, which will expose a larger audience to comparative oncology, hopefully sparking new ideas.” –Alissa Poh
Dogs with naturally occurring cancers have become a highly relevant model in which “our ability to interrogate therapeutic responses” is key, notes Nicola Mason, BVetMed, PhD, of the University of Pennsylvania in Philadelphia. As with humans, by learning “as much as we can about how these therapies influence our canine patients’ [intact] immune system, we can understand why some respond and others don't.”
Through the NCI-funded PRECINCT consortium, Mason and fellow investigators have worked with NanoString Technologies to create the nCounter Canine IO Panel, a pan-cancer immune profiling platform. She's using it in a multisite trial of a HER2-targeted, Listeria-based vaccine for canine osteosarcoma. “The data we're getting from these dogs [are] very informative,” she says, “suggesting that immunologic fitness is very important and may be necessary for a positive outcome.”
The canine IO panel “parallels human immune profiling platforms,” Mason adds. “If we identify a molecular signature of interest in dogs, we can see if it's also present in people.”
All PRECINCT findings, as well as dog data from multiple other sources, are deposited in the NCI's Integrated Canine Data Commons. “It's our closest equivalent to The Cancer Genome Atlas,” says Deborah Knapp, DVM, of Purdue University in West Lafayette, IN. “Anyone can use this repository. It has comprehensive case and sample information, as well as cloud-based tools to pull in and analyze human data alongside.”
Such resources “have changed…our ability to understand what we're looking at” data-wise, says Cheryl London, DVM, PhD, of Tufts University in North Grafton, MA. “That'll help us accumulate the evidence needed to convince clinicians a promising dog therapy is worth trying in people.” –AP
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