How Clinical Trials in Dogs with Lymphoma Can Lead to New Therapies for Humans

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.

Vet giving dog a check up

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.

KRichards
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.

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New Treatment Combination Poses Potential Way to Combat Chemo-Resistant DLBCL

Each year, roughly 20,000 Americans are diagnosed with diffuse large B-cell lymphoma (DLBCL), an aggressive cancer of abnormal B-cells. Most people with DLBCL are cured with the standard chemotherapy regimen rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), but 30-40 percent of cases are resistant to chemotherapy for reasons that may be related to the way that genes are regulated within the cancer cells.

Prior WCM laboratory research demonstrated that certain genes within chemotherapy-resistant DLBCL cells are often inappropriately turned off and that long-term exposure to low doses of oral hypomethylating agent azacitidine (also known as CC-486) can turn those genes back on, thereby re-sensitizing the cells to chemotherapy.

Lymphoma Program chief Dr. Peter Martin, Dr. Leandro Cerchietti, Dr. John P. Leonard, Dr. Maria Revuelta and Dr. ldefonso Ismael Rodriguez-Rivera, and colleagues from around the country, set out to test a novel therapeutic alternative for these chemo-resistant cases with a phase I, open-label, multicenter trial of oral azacitidine plus R-CHOP in people with high-risk, previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed lymphoma. The trial was conducted in collaboration with Alliance Foundation Trials (AFT), a research organization that develops cancer clinical trials with pharmaceutical companies, scientific investigators and the Alliance for Clinical Trials in Oncology (ACTO) institutional member network.

Patients in the trial received CC-486 for seven days prior to R-CHOP initiation, then for 14 days prior to each of five following R-CHOP cycles. The research team found that the combination of CC-486 plus R-CHOP was safe and well tolerated, and that it produced a higher-than-anticipated complete response (CR) rate, or disappearance of signs of cancer, exceeding 85 percent. Dr. Cerchietti’s lab also identified key changes in genes and gene expression consistent with the anticipated CC-486 effect. Dr. Martin presented the team’s findings at the American Society of Hematology Annual Meeting and Exposition on December 9, 2017, in Atlanta, GA.

Weill Cornell Medicine

“We are at an exciting moment in time: CC-486 is emerging simultaneously with a peak in collaborative efforts between scientists, physicians and patients,” said Dr. Martin. “We are working day and night to move this concept forward, including the possible opening of randomized trials.”

FDA Approves Subcutaneous Administration of Rituximab for Three Lymphoma Types

On June 22, 2017, the United States Food and Drug Administration (FDA) approved subcutaneous injection of rituximab plus hyaluronidase human for people with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). Subcutaneous administration refers to the method of delivering a drug under the skin rather than directly into a vein as performed during intravenous (IV) administration.

insulin injection

Administration of rituximab under the skin tends to take less than 10 minutes, whereas the traditional IV method can last several hours. The technique also allows for fixed dosing, which can reduce preparation time and excess drug waste, and may be more cost effective than IV infusion.

The approved treatment is to be employed only after patients have received at least one cycle of intravenous rituximab.

Approval comes based on the results of a series of clinical trials demonstrating comparable safety and efficacy outcomes across subcutaneous and intravenous administration.