2012 Research Funded by YTCAF
Each year the AKC Canine Health Foundation send the YTCA Foundation a list of grant requests for funding that they have screened and think would be of interest to breeders and owners of Yorkshire Terriers as well as dog fanciers in general. As an independent entity spun off from the Parent club to preserve our tax exempt status, the YTCAF receives no financial support from the YTCA's participating in efforts such as the Purina Circles program. Instead all of our funding comes from memorials made by individual donors and fund raising efforts such as the online auctions and breeding calendar sales.
The Board members carefully considered the following factors in each request in order to optimize research dollars:
Potential of the research to benefit Yorkshire Terriers in particular and all dogs in general.
Previous research success of the primary investigators
Use of the grant project to help veterinary students, new veterinarians and academicians get started in their chosen field of research (Acorn projects).
The Board voted to support the following CHF grants for 2012.
Michael Deveau, DVM, MS, Texas A&M Research Foundation
Lymphoma is one of the most common neoplasm in canine companion animals accounting for upwards of 25% of all canine cancer and incident rates continue to rise. Chemotherapy results in high remissions rates but poor overall survival durations even with aggressive therapy. Lymphoma is extremely radiosensitive, however, incorporating full and half-body radiation therapy has demonstrated a quid pro quo effect between treatment-related toxicities and tumor control. In human medicine, this approach ahs been abandoned for advanced IFRT techniques utilizing advanced radiotherapy systems designed to kill residual disease while sparing normal tissues. As the technology becomes available in veterinary medicine, this treatment capability will also become available; however, there are no studies in the veterinary literature specifically interrogating this strategy. While demonstrable benefit is the ultimate clinical endpoint, it is critical to ensure safe implementation of IFRT for use in canine patients. To test feasibility and safety, we propose a phase I study in which patients with advanced stage lymphoma will be treated with IFRT using helical tomotherapy. Canine patients identified will be treated with our current standard of care, a 19 week multi-drug chemotherapy protocol. Upon completion, they will be anesthetized to undergo CT examination for radiation therapy planning. Enlarge lymph nodes and the spleen and liver will be contoured as targets and treated to a predetermined dose level. Patients will be subjected to rigorous evaluation at each treatment and at one month intervals for dose limiting toxicities and/or adverse events.
The primary goal of this work is to perform involved-field readiotherapy (IFRT) on canine patients with advanced-staged lymphoma and test its feasibility, tolerability, and safety. This information is a necessary prerequisite to the eventual interrogation of IFRT’s (in combination with chemotherapy) potential superiority to the current standard of care (chemotherapy alone). We have accrued 18 total patients over the course of 2.5 years. Twelve patients have completed therapy with 3 patients on Dose Level 1, 3 patients on Dose Level 2, and 6 patients on Dose Level 3*. This has completed Dose Level 3 leaving the final dose level to fill. Of the 4 remaining patients, 1 patient has been voluntarily withdrawn by clients during the standard of care part, 1 patient was euthanized due to an aspiration event (non-study specific) after fraction 2 of radiation, 1 patient was excluded due to conflicting staging results, and 1 patient for adult onset of seizures (no prior history-confirmed CNS lymphoma) about 14 weeks into the standard of care part.
While patient accrual meets expectations, patient attrition due to factors outside of our control has placed the number of patients completing the radiation therapy part of the trial below expectations. We are currently 1 patient behind from meeting full accrual of Dose Level 4 (assuming no expansion of Dose Level 4). We have submitted a request and have been approved for a 12 month no cost extension.
From a toxicity perspective, only one patient has been withheld therapy due to concerns of inducing a life threatening complication. This patient was on Dose Level 3 and is the reason why the level was expanded. The remaining toxicities experienced by the study patients have resulted in acute transient hematological depressions and gastrointestinal signs all responding to symptomatic management or resolving within two week post IRFT. Six month follow-up is below target primarily due to progressive disease in the patient population. However, of available data, no long term toxicity has been specifically associated or identified as a complication of IFRT at this time.
* Dose Level 3 was expanded from 3 patients to 6 patient due to a dose limiting toxicity.
The primary goal of this work is to perform involved-field radiotherapy (IFRT) on canine patients with advanced-staged lymphoma and test its feasibility, tolerability, and safety. This information is a necessary prerequisite to interrogating IFRT’s (in combination with chemotherapy) potential superiority to the current standard of care (chemotherapy alone). Patient accrual is 2 patients below expectations with 10 patients enrolled at 18 months. Three patients have completed Dose Level 1 and 2 with acceptable toxicity. Two patients have completed Dose Level 3. A dose limiting toxicity presented itself in one of the two patients so Dose Level 3 will be expanded by 4 more patients. There are 2 patients in the queue and recruitment continues to fill the remaining two spots. It is likely Dose Level 4 will be not be opened.
The primary goal of this work is to perform involved-field radiotherapy (IFRT) on canine patients with advanced-staged lymphoma and test its feasibility, tolerability, and safety. This information is a necessary prerequisite to interrogating IFRT’s (in combination with chemotherapy) potential superiority to the current standard of care (chemotherapy alone). Patient accrual is below expectations with 3 patients enrolled at 6 months. The economy has picked up and we have enrolled 3 patients within the last month. We anticipate that accrual will pick up and we will end up on schedule.
However, designing and implementing a multicenter clinical trial is a process affected by numerous clinical and client constraints. These constraints negatively impact patient accrual. Currently the cost and time component associated with pr oviding only the standard of care option with IFRT alienates a faction of clients who would participate given less costly chemotherapeutic options and time investments. Since the primary goals of the study are to determine the MTD and characterize the long-term toxicity profile and not overall efficacy, if accrual remains low, we may need to modify our participation criteria to include those clients who treat any traditional definitive chemotherapy agent (such as single gent doxorubicin, CCNU, Vincristine, etc.) where the intent of the client is to prolong survival over prednisone or no treatment along.
The primary goal of this work is to perform involved-field radiotherapy (IFRT) on canine patients with advanced staged lymphoma and test its feasibility, tolerability, and safety. This information is a necessary prerequisite to interrogating IFRT’s (in combination with chemotherapy) potential superiority to the current standard of care (chemotherapy alone). Patient accrual has improved and are within expectations with 8 patients enrolled at 12 months. Two patients have completed Dose Level 1 with acceptable toxicity and no infield failure as of this report (~ 1 month post IFRT). The third patient for Dose Level 1 will be completed by the of January, 2013. This will close Dose Level 1 and open Dose Level 2. There are four patients within the queue to fill Dose Level 2.
MAF-D12CA - 026: Development of CD20-Specific Antibody Fragment for Targeted Therapy of Canine B-Cell Lymphoma
Nicola J. Mason, B Vet Med, PhD, University of Pennsylvania
Blood cell lymphomas affect about 30 dogs in every 100,000. Diffuse large B cell lymphoma (DLBCL) is a common type affecting dogs and is similar to non-Hodgkin’s lymphoma in humans. Current treatment induces remission in about 75 percent of patients but the majority relapse and the lymphoma is drug resistant within six to nine months of diagnosis. In human medicine a drug called Rituximab is used to treat various types of lymphoma. The researchers in this study will work to develop a drug similar to Rituximab that works on canine lymphoma patients. The results of this work could lead to the development of the first targeted treatment of canine B cell lymphoma and may significantly improve the outcome for dogs with b cell lymphomas.
FINAL REPORT – October 1, 2013
One of the research projects that the YTCA Foundation has helped support is “Developing a New Delivery System for Lymphoma Treatment” D12CA-026, a grant sponsored by the Morris Animal Foundation. As noted in the Final Report submitted by principle investigator Nicola J. Mason, BVetMed, Ph.D., of the University of Pennsylvania, lymphoma is a cancer of the blood that effects both humans and dogs. In dogs the most common type of lymphoma is that which affects the B cells, part of the specific mammalian immune system. Even though chemotherapy treatments promote remission in 85% of the cases, the disease usually comes back and the canine patients succumb to the cancer.
As one of the two lymphocytes (B and T cells) in specific immunity, B cells target extracellular pathogens, i.e. infectious agents in the fluid surrounding cells like bacteria, viruses, fungi, as well as toxins. In response to these pathogens, the B cells produce specific proteins called antibodies that bind to the pathogens and help the other immune system cells kill them off. When these B cells become cancerous, a good portion of the immune system is thus inactivated resulting in eventual death of the dog.
In human oncology there is an antibody drug called Rituximab that will target the cancerous B cells, but this drug doesn’t work in canines. The goal of this grant was to find another approach to fighting canine B cell lymphoma by using genetic engineering and biotechnology to produce fragments of antibody proteins that would specifically target the CD20 surface markers on the cancerous canine B cells and thus lead to their destruction.
Although the researchers have been unsuccessful to date in creating these antibody fragments, their work has produced new tools that can help identify antibodies that do recognize canine B cells. Additionally in the collegial atmosphere of “basic” science that seeks to share the answers to questions rather than profit from them, the researchers at the University of Pennsylvania are making their work available to other researchers to use in their studies on canine cancer. All of these efforts will hopefully generate new treatments for canine lymphomas that affect so many dogs.
Lymphoma affects approximately 30 of every 100,000 dogs, Current treatment consists of a combination of chemotherapy drugs, which induces remission in about 75 percent of patients. However, most dogs relapse within six to nine months of diagnosis. Rituximab, an antibody-targeting drug, has substantially improved survival times for people with various types of B-cell lymphoma. However, rituximab cannot be used in dogs because it is a human antibody and will therefore be rapidly destroyed by the dog's immune system. Furthermore, rituximab does not recognize or bind to canine B cells. Funded by Morris Animal Foundation, researchers at the University of Pennsylvania are developing a novel system to identify canine-derived antibody fragments similar to rituximab that will recognize canine cancer cells. In the first phase of the study, researchers isolated canine-derived, antibody fragments from "libraries" of antibody fragments. In order to begin screening these libraries for candidate fragments, researchers have generated target cells that express a specific canine B cell surface molecule, the same surface molecule that rituximaab targets in humans. They are in the process of cloning these cells for use in their screening tests. Antibody fragments in libraries that bind tightly to these cells will then be candidates for further study. Development of a canine-derived antibody fragment may allow targeted delivery of cell-killing agents to the malignant B cells, thereby allowing for increased chemotherapy doses, reduced side effects and improved outcome for dogs with B cell lymphoma.