Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, has been categorized based on the cancer cell of origin as either activated B-cell (ABC) DLBCL or germinal center B-cell (GCB) DLBCL. Each subtype is associated with a certain degree of tumor vulnerability and a corresponding response to therapy.
The more that clinicians know about how a patient’s disease develops, the better equipped they are to devise an informed and precise treatment plan. Yet, between 10-20 percent of DLBCL cases are unclassified, providing little guidance for strategic intervention.
To shed light on the unclassified disease subtype and further define the composition of the ABC and GCB subtypes, the Weill Cornell Medicine and NewYork-Presbyterian Hospital Lymphoma Program’s Dr. John P. Leonard took part in an international research initiative led by the National Cancer Institute at the National Institutes of Health, with findings recently published in the New England Journal of Medicine.
Whereas prior studies of genetic subtyping investigated individual mutations, this research was among the first to examine how mutations in multiple genes may relate to disease pathogenesis and therapeutic response.
Researchers used next-generation sequencing technology to analyze nearly 600 DLBCL patient biopsy samples, contributed in part through the Lymphoma Program’s efforts in collaboration with the Alliance for Clinical Trials in Oncology. Based on the co-occurrence of genetic alterations that they observed, the team discovered four new genetic subtypes of DLBCL – MCD, BN2, N1 and EZB – enhancing science’s understanding of the genetic framework of this aggressive cancer.
“These findings will take us one step closer to potentially employing targeted agents as part of treatment for specific DLBCL subtypes,” says Dr. Leonard. “If we can specifically identify these lymphoma types and incorporate new agents that target relevant pathways, we will advance rational clinical trials with the aim to improve outcomes for patients based on the biology of their disease.”
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.
“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.
A group of more than 20 Brazilian oncologists traveled to Weill Cornell Medicine and NewYork-Presbyterian Hospital from South America to attend the 2017 Update in Hematologic Malignancies, a two-day interactive educational symposium organized and presented by members of the Weill Cornell Lymphoma Program’s research and clinical faculty.
The meeting, directed by Dr. Sarah Rutherford, featured didactic lectures on chronic lymphocytic leukemia (CLL) and Richter’s Transformation (RT) by Drs. John Allan and Richard Furman, discussions of controversies and challenging cases in mantle cell, follicular and diffuse large B-cell lymphomas (MCL, FL, DLBCL) led by Drs. Rutherford and Peter Martin, a lymphoma-specific hematopathology update from Dr. Amy Chadburn, and a tour of Dr. Leandro Cerchietti’s research laboratory.
Programs like this one foster partnerships that can propel us toward our goal of improving health outcomes for the nearly 100,000 people around the world who are affected by lymphoma. Our team is able to establish collaborative international relationships to teach and learn from medical practitioners of a diverse background, all while solidifying our role as a trusted, global authority on lymphoma research and care.
“The relationship we have established with the Brazilian oncologists is fulfilling for all of us,” says Dr. Rutherford. “We enjoy teaching them and helping to manage complex cases that they face in Brazil. We also remain in touch with them after the conference – providing guidance on patients and even traveling to Brazil to participate in meetings. We look forward to continuing this collaboration given our shared mission of providing the best possible care for patients with lymphoma.”