Studying animal models to enhance the overall understanding of cancer is a longstanding and valuable practice that, until recently, had been fairly uniform. The traditional model, the laboratory mouse, has occupied the oncologic arena since the 1980s, offering researchers a way to observe tumor growth and drug response in a natural environment, as opposed to in a petri dish. This approach, known as comparative medicine, more realistically represents how cancer behaves in humans and yields insight as to how scientists can effectively treat the disease.
It wasn’t until late 2005 that a bigger, potentially better animal model entered the comparative medicine scene. Publication of the canine genome enabled comparison of dogs and humans at a molecular and genetic level, revealing biological similarities in each. In October 2017, the National Institutes of Health (NIH) recognized the untapped potential of the canine model in cancer research with a five-year $2.5 million grant awarded to Weill Cornell Medicine and Tufts University scientists to study new therapeutic strategies in dogs with lymphoma.
Dogs experience naturally occurring lymphoma that resembles the way that the disease manifests in humans. It is estimated that up to 80,000 dogs are diagnosed with lymphoma per year in the United States alone, with increased incidence in golden retrievers, whose lifetime risk for lymphoma is 1:8, as compared to a 1:50 risk in humans.
Dr. Kristy Richards
“I want to cure cancer in people, and dogs provide a great opportunity for research that can help us move lymphoma therapies to the clinic for humans faster,” says the Lymphoma Program’s Kristy Richards, PhD, MD, who will lead the research as a co-principal investigator.
“We’re using the NIH grant to study immunotherapies and targeted treatment regimens in combinations that haven’t yet been tried in humans. The idea is to get to a therapy that can cure diffuse large B-cell lymphoma (DLBCL) in dogs. If it works well in dogs, we have better rationale to move the therapy forward in people.”
The immune system is the body’s in-house security guard that protects against infection and disease, but some forms of disease, like cancer, have evolved to evade the immune system’s defense mechanisms. Immunotherapies, which harness the power of a patient’s own immune system to fight cancer, rely upon an intact immune system, which lab mice grown in sterile cages and never challenged by sickness do not possess. Dogs, thanks to their propensity to eat, lick and roll around in whatever unsanitary substance they please, have thoroughly educated immune systems, a prime environment for testing immunotherapies.
But that is far from the only advantage of the canine model. “We can do things with the dog model that we can’t do with the mouse model, or even with the human model,” says Dr. Richards.
About two-thirds of human DLBCL patients enter remission following six cycles of standard chemotherapy regimen rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Dogs on lower, more frequent doses of the same treatment regimen almost always enter remission – but they also almost always relapse. If they were to receive the human dose intensity, they would suffer significant impairments to quality of life, such as decreases in physical activity and appetite, and vomiting and diarrhea.
Since standard chemotherapy cures nearly 70 percent of humans with DLBCL, current clinical trials of less toxic, non-chemotherapy based regimens are limited to the one-third of people who eventually relapse. Novel treatments used in these trials must be proven effective as single agents before being combined in what would ultimately require extensive (and therefore expensive) study.
The fact that dogs are not cured by standard therapies makes them the perfect candidates for testing of new, targeted therapies with fewer toxic side effects, permitting use of doses similar to those used in humans. Through use of these novel agents, dogs help science to leapfrog ahead of years’ worth of human trialing, while science helps dogs to live longer, happier lives.
Treating people’s pet dogs also encourages a humanistic approach. Much like in human oncology, scientists work to develop therapies that take more into consideration than just killing cancer cells, like quality of life, for example.
In fact, one of Dr. Richard’s favorite aspects about her research is that she gets to help the dogs that she’s studying.
“If we can manage to do something good for human medicine at the same time that we’re helping the model organism that’s helping us to study it, that’s a great thing,” she says.
Dr. Richards says that enlisting the help of the canine model to study lymphoma is a concept that is “arriving, but has not yet arrived.” Support from the NIH, as well as from organizations like Puppy Up and Paws 4 a Cure that raise funds to conduct clinical trials for dogs, plays a major role in validating the benefits of the canine lymphoma model, but further research is required to actually reap those benefits.
At a poster session of the 2014 ASCO meeting, results of a phase I trial were presented from an ongoing, multi-center, phase I/II study testing the combination of romidepsin and lenalidomide in patients with relapsed lymphoma and myeloma. Although romidepsin and lenalidomide have both been individually approved by the FDA for the treatment of lymphoma and multiple myeloma, the combination represents a novel experimental development, based on potentially synergistic mechanism of action, and non-overlapping toxicity of the two biologic agents.
The phase I portion of the trial evaluated toxicity, maximum tolerated dose, and clinical activity of the romidepsin and lenalidomide combination. Romidepsin was given intravenously on days 1, 8, and 15 and lenalidomide was given orally on days 1-21 of a 28-day cycle. From the 13 evaluable patient responses, there was an overall response rate of 54%, complete response rate of 15%, and partial response of 39%.
From these early results the investigators concluded that the combination of romidepsin and lenalidomide is well tolerated and lacks any unexpected toxicity. Responses were consistent across multiple lymphoma subtypes, and the upcoming disease specific phase II cohorts will include B-cell lymphomas, T-cell lymphomas, and multiple myeloma.
On May 30, 2014, at the 50th annual meeting of the American Society of Clinical Oncology (ASCO) I had the pleasure of presenting updated, preliminary results from the multi-center, national cooperative group CALGB 50803 phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. This trial represents an important step as we move away from traditional cytotoxic chemotherapy towards a future with novel, better-tolerated regimens for treatment of patients with follicular lymphoma.
Patients in this trial received oral lenalidomide on days 1-21 of each 28-day cycle for a total of twelve cycles plus four weekly infusions of rituximab during cycle 1 followed by four additional infusions at the start of cycles 4, 6, 8, and 10. The primary objective was to measure the patient’s complete response rate. Overall, we found that the regimen was well tolerated, with very low rates of infection or other significant adverse events. Preliminary data from patients evaluable for complete response suggests that over 90% of patients responded, including roughly 70% complete responses. At two years, 89% of patients continued to respond. These efficacy data are consistent with what is typically seen with cytotoxic chemotherapy-based regimens and they support further evaluation of lenalidomide plus rituximab compared to chemotherapy in an ongoing phase III trial.
New Developments in Lymphoma 