Dogs are man’s best friend and dog owners are always embarrassed when their beloved pets get terminally ill. Canine cancer is the leading cause of death in dogs and when they are diagnosed with a late stage or terminal disease, there are often no treatment options available. In a recent study, however, a new form of chemoimmunotherapy has been shown to be a promising treatment in changing the course of dogs’ lives.
Scientists at the NUS Center for Cancer Research (N2CR) Translational Research Program (TRP) at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) have used precision-engineered stem cell technology to treat cancerous canines. In a study led by Associate Professor Too Heng-Phon from N2CR TRP and the Department of Biochemistry at NUS Medicine, the team modified mesenchymal stem cells (MSCs), which can seek out cancerous tumors. These modified cells carry a powerful ‘kill-switch’ (cytosine deaminase) that produces a high, localized concentration of the cancer-killing drug (5-fluorouracil) in the tumor environment and then induces anti-cancer immunity. The development of this therapy to treat canine patients is leading the team towards a better understanding of cancer treatment as well as its use in patients, as helping dogs with natural cancers provides valuable clues about human cancers.
Assoc. prof. Too said, “To repurpose stem cells for cancer treatment, it is common to use viruses to introduce therapeutic genes into cells. However, we designed a non-viral gene delivery platform that introduces a large amount of therapeutic genes into stem cells, effectively killing growing cancer cells out of control. With this therapy proven to be safe and showing promising clinical benefits in animal patients, we hope to develop effective treatment options to help cancer patients as well, who can improve their health without compromising their quality of life.”
Application of technology to canine cancer patients
The technology developed by the NUS Medicine team was first applied to canine patients in Singapore in 2018, in collaboration with Dr. Jean Paul Ly, CEO and founder of Animal Wellness. The research team then collaborated with multiple veterinary partners and institutions, treating a total of 65 dogs, as well as two cats, with conditions such as perianal adenoma, lung metastases and sarcoma. Patients first received precisely engineered MSCs via direct injections at the tumor site or through the bloodstream, followed by oral tablets containing a drug commonly used to treat fungal infections (5-flucytosine) over several days. After one week, the cycle was repeated for another two weeks before the end of the first cycle of treatment. The team then monitored the condition of the patients and repeated the course where necessary.
Among the animal patients who received treatment for three to eight weeks, 56 showed signs of a positive response, including 14 who showed complete recovery from treatment. Two patients with animals remain cancer-free at least 30 months after treatment, while 46 patients showed good quality of life for two to 32 months, with treatment. During treatment in all animal patients included in the study, no significant side effects were observed — likely due to the localized presence of therapeutic cells that remain within the tumor environment.
Despite significant advances in the treatment of human cancer, there is a large backlog in the development of oncology therapies for animal patients. Until 2009, all animals were treated with generic human chemotherapy drugs on an off-label basis since there were no animal-specific cancer drugs approved by the US Food and Drug Administration (FDA). dr. Lee Yee Lin, founder and chief veterinarian of the Gentle Oak Veterinary Clinic in Singapore, with whom the research team collaborated and who is one of the authors of the study, said: “Therapies and advances in allopathic medicine are usually first developed for humans, before however , as part of the trial for this study, dogs with cancer without other possible treatment options are the primary recipients of the therapy — and many of them have shown promising results with improved quality of life. The hope is that the therapy will become one of the standard options available to dogs in the near future , so more patients can benefit from it.”
One of the team’s collaborators, Associate Professor Antonio Giuliano, Department of Veterinary Clinical Sciences, City University of Hong Kong, will also take the therapy into clinical animal studies in 2023.
Providing therapy as an accessible and affordable option for human patients
Stem cell therapy differs from other cell and gene therapies that use viruses to introduce genes into cells. Instead of using a virus, the modification involves using a chemical carrier, which is safer and faces fewer regulatory constraints in treatment development. Compared to other cell and gene therapies, the therapy design has a significantly shorter cycle time and much lower manufacturing costs, paving the way for a more accessible and affordable option for cancer patients in the future.
dr. Ho Yoon Khei, Senior Research Associate, N2CR TRP and Department of Biochemistry at NUS Medicine, and first author and lead scientist of the study, said: “Currently, we can develop this therapy for up to 18 human patients each week. More than the results shown beneficial to our pets, we hope to expand the therapy to human patients in the future and improve health care outcomes for those with cancer — especially when they have no more treatment options.”
The research team is working with local and global health institutions to assess the safety and efficacy of the therapy in veterinary medicine and is discussing plans for clinical trials on patients in Singapore and the Asia-Pacific region. It is expected to start in 2024.
Professor Chong Yap Seng, Lien Ying Chow Professor of Medicine, Dean of NUS Medicine, added: “Our research work at NUS Medicine aims to create real, meaningful health benefits for the populations we serve, and ultimately, drive better healthcare outcomes for all . We believe this therapy developed by N2CR will have a major impact on the health and well-being of patients with solid tumors and late-stage cancer.”
N2CR is one of 10 Translational Research Programs (TRPs) at NUS Medicine which aims to create a strong and coherent scientific base to achieve impactful and meaningful research results for the school and the Singapore healthcare system. In addition to cancer, other areas are cardiovascular disease, digital medicine, healthy longevity, human potential, immunology, infectious diseases, precision medicine, synthetic biology and nanomedicine. These 10 key focus areas, which are multidisciplinary and health- and disease-based, will create greater synergy and collaboration between basic scientists and clinician scientists, strengthen programmatic research, and deliver research outputs to address clinically relevant questions and applications that align with national priorities.