8-7-2024 (SINGAPORE) researchers from the National University of Singapore’s Yong Loo Lin School of Medicine (NUS Medicine) have pioneered a novel gene therapy that could provide a second chance at life for patients suffering from the deadliest form of brain cancer. The stem cell-based therapy, designed to kill aggressive tumors and activate anti-cancer immunity, is expected to enter clinical trials for glioblastoma patients at the National University Hospital (NUH) by late 2025.
Glioblastoma, an incurable and aggressive brain tumor, typically leaves patients with a life expectancy of only about two years upon diagnosis. This targeted therapy builds upon a similar drug that the NUS Medicine scientists first used to treat dogs and cats with terminal cancers.
The treatment comprises human stem cells carrying cancer-killing genes that naturally gravitate towards tumors. The team behind this breakthrough includes Associate Professor Too Heng-Phon, adjunct senior research fellow Sarah Ho, and post-doctoral fellow Woo Jun Yung from the NUS Medicine’s biochemistry department.
Initially, Professor Too’s team worked on developing the therapy to combat aggressive human tumors until a veterinarian contacted them in 2018 after hearing about their work. The first version of the treatment was successfully used on 65 dogs and cats between 2018 and 2022, with promising results.
The two-part treatment involved injecting the modified stem cells into the animal, followed by the oral administration of off-the-shelf anti-fungal drugs. The researchers developed a technology to insert large amounts of yeast-based genes into the stem cells, which would react with the anti-fungal drugs, enabling the cells to produce a chemotherapy drug called Fluorouracil (5FU).
“The modified stem cells act like suicide bombers, loading the toxic 5FU around the tumor to kill it,” explained Dr. Ho. While 5FU is commonly used in chemotherapy and can cause severe side effects, the localized delivery of the drug in this therapy minimizes serious side effects, though mild ones may occur.
The first version of the treatment focused on killing cancer cells, and 56 out of the 65 dogs and cats who received it lived longer than expected or experienced an improved quality of life.
The second version of the therapy includes an additional ingredient to enhance the recipient’s immunity. The stem cells are engineered to produce Interferon beta, a substance naturally produced by cells that activates the body’s immune system, allowing immune cells to attack the tumor and provide long-term suppression.
“You can’t just kill the cells. You also need to activate the immune system. If not, you will forever be trying to kill every single cell in the tumor environment,” Dr. Ho added.
Since 2023, 30 cancer-stricken dogs and cats have been given this improved treatment at some veterinary clinics, with the team planning a formal study once they have enough patients.
All 95 animals underwent the treatment for free, as a form of compassionate care by NUS Medicine. The current funding for the pets’ treatment will be exhausted by the end of 2024, after which pet owners will have to start paying for the therapy, though at a subsidized rate.
In January, Dr. Ho and Dr. Woo established their biotech start-up AGeM Bio to scale up their animal and human cancer therapies. They will move to their new office and lab in the NUS E7 building, an incubator for NUS technologies, in August.
The improved therapy will be used for the upcoming brain cancer clinical trial for humans, expected to start in the third or fourth quarter of 2025. Pre-clinical studies on mice with brain cancer have shown promising results, with some rodents experiencing complete tumor disappearance a week after receiving the therapy.
The team is currently conducting further pre-clinical studies and preparing a dossier to submit to the Health Sciences Authority. The treatment doses for the clinical trial will be produced at the Advanced Cell Therapy and Research Institute, Singapore.
The first phase of the clinical trial at NUH will test the safety of the treatment with six to 15 patients with recurrent glioblastoma – patients whose tumors have returned after a previous surgery.
“Since it’s a safety trial, it may not be ethical to offer the new treatment for newly diagnosed patients. But for recurrent glioblastoma, there is no standard of care, and so we can do a research trial like this,” explained Clinical Associate Professor Yeo Tseng Tsai, a senior consultant at NUH’s Division of Neurosurgery.
Patients in the clinical trial will undergo another brain surgery to remove as much of the cancerous tumor as possible without causing neurological damage. Three milliliters of modified stem cells will then be injected around the cavity with tumor remnants through 20 jabs, maximizing exposure to the cancer-killing cells. Patients will later take anti-fungal drugs orally, and the surgical site will be sealed with glue to prevent the stem cells from leaking.
If not enough suitable patients can be found within NUH, patients will be recruited from Ng Teng Fong General Hospital or the National Neuroscience Institute.
Alongside his terminally ill brain cancer patients, Dr. Yeo yearns for a successful treatment. “I’m not so optimistic that we will cure glioblastoma. But maybe we can convert it into a chronic disease. So instead of patients living 18 to 24 months, like they do now, maybe they can live five or 10 more years. That would already be a great achievement,” he said.
