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.
Chimeric antigen receptor (CAR) T-cell therapy is an emerging form of immunotherapy that leverages the strength of a patient’s own immune system to fight cancer.
Immune cells called T-cells are extracted from the patient’s blood and modified in the laboratory to produce chimeric antigen receptors, surface-level proteins that enable the T-cells to recognize and fight targeted antigenic tumor cells. The newly engineered T-cells are then cultivated in a lab before infusion back into the patient’s body, where they further multiply and go to work attacking cells that possess the antigen that they were programmed to destroy.
At the OncLive State of the Science Summit on Treatment of Hematologic Malignancies, Dr. John Leonard, who served as co-chair for the May 4 event, expressed promise in the use of CAR T-cell therapy for patients with acute lymphoblastic leukemia (ALL), in particular.
Dr. Leonard said that in a small group of clinical trial recipients with ALL, the immunotherapy has produced excellent, seemingly durable responses, and more data on CAR T-cells for patients with hard-to-treat lymphomas, like resistant forms of diffuse large B-cell lymphoma (DLBCL), are forthcoming.
While patient selection is a crucial part of interpreting the data and planning for the future, Dr. Leonard believes that the main challenges in the development of CAR T-cell therapy relate to factors of patient selection such age, comorbidities, and aggressive cancers with prohibitive wait times for engineered cells, which can take as long as several weeks depending on the specific CAR product being used.
“I think there’s no doubt that some patients benefit, but at least in the near-term, it’s going to be a relatively small number of patients that will get CAR T-cells for lymphoma,” he said.
Check out what else Dr. Leonard had to say about CAR T-cells in this video from OncLive:
Dr. Ghione is a visiting hematology fellow from Torino, Italy who is working with the Weill Cornell Lymphoma Program for six months.
Rituximab is a drug that is used to treat B-cell non-Hodgkin lymphomas. It is a type of immunotherapy called a monoclonal antibody, and it works by targeting CD20, a protein present on the surface of the B-cells.
In the United States, rituximab is administered by intravenous (IV) infusion, often over several hours. In March 2014, a formulation of rituximab for subcutaneous injection (under the skin rather than directly into the vein) was approved by the European Medicines Agency, and Health Canada approved the subcutaneous formulation in September 2016. At my home institution – the University of Torino — we have been using subcutaneous rituximab routinely. Advantages for patients include the faster administration time, usually less than 10 minutes. Institutions may prefer subcutaneous rituximab because it is administered as a fixed dose, which can reduce the preparation time and waste.
The first study to compare the two formulations was conducted in Europe from 2009 to 2012 in 124 people receiving rituximab maintenance for follicular lymphoma. The purpose of this study was to identify a comparable dose and to compare safety. The second study, called “SABRINA” was conducted in Europe, Canada, and Thailand, with the participation of 127 people with previously untreated follicular lymphoma who were receiving chemotherapy plus rituximab. Patients responded equally to treatment with both formulations (intravenous versus subcutaneous), and no differences were found in terms of safety. In comparing the side effects, IV administration was linked to more gastrointestinal-based events (such as diarrhea and nausea), while skin reactions (usually redness at the injection site) were more common with subcutaneous rituximab.
In another large study, called “MABEASE,” 576 people with diffuse large B-cell lymphoma participated in a clinical trial in which they were randomized to receive CHOP chemotherapy with either subcutaneous or intravenous rituximab. Again, the efficacy of the two formulations was similar and the subcutaneous administration was associated with increased administration-related reactions (mainly rash).
Finally, a clinical trial called “PrefMab” enrolled more than 700 people with diffuse large B-cell lymphoma and follicular lymphoma with the aim of evaluating patient satisfaction using both administration methods. One group of participants started with intravenous infusion and then switched to subcutaneous, and vice-versa for the second group. In general, patients preferred the subcutaneous formulation. Specifically, 80% of the patients preferred the subcutaneous formulation, 10% still preferred the intravenous one and 10% had no preference. This preference was largely due to the reduction of time spent in the hospital and the comfort of the administration.
In addition to efficacy, safety, and patient preference, the financial impact of the new formulation is worth considering. Two groups have conducted economic studies on this subject. The Roche study found that the subcutaneous formulation was associated with reduced costs due to less staff time (nurses, technicians and pharmacists), shorter time in the bed/chair in the infusion center, and a reduction in wasted drug and materials related to the infusion. The Italian study reported an overall saving of 6.057 euros ($6.464 USD) for each rituximab administration. The financial impact might differ in different healthcare systems.
Subcutaneous rituximab is not currently available in the United States, but the Food and Drug Administration (FDA) accepted a Biologics License Application in November 2016. This means that probably the formulation will be soon available in the U.S. market.
Chimeric antigen receptor (CAR) T-cell therapy is an emerging form of immunotherapy that leverages the strength of a patient’s own immune system to fight cancer.
In the United States, rituximab is administered by intravenous (IV) infusion, often over several hours. In March 2014, a formulation of rituximab for subcutaneous injection (under the skin rather than directly into the vein) was approved by the European Medicines Agency, and Health Canada approved the subcutaneous formulation in September 2016. At my home institution – the University of Torino — we have been using subcutaneous rituximab routinely. Advantages for patients include the faster administration time, usually less than 10 minutes. Institutions may prefer subcutaneous rituximab because it is administered as a fixed dose, which can reduce the preparation time and waste.
New Developments in Lymphoma 