New cancer therapy extends the lives of terminally ill dogs and shows potential for use in human patients

Researchers from the Department of Biochemistry and the NUS Center for Cancer Research (N2CR), at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), are pioneering a treatment using stem cell precision engineering technology, to deliver drugs directly to tumor sites in dogs and cats with late-stage cancer and for which no treatment options are available.

To date, the treatment has been administered to nearly 100 dogs and cats with conditions such as perianal adenoma, lung metastases and sarcoma. Most animal patients showed signs of a positive response, including full recovery, cancer remission and good quality of life.

During the treatment of all animal patients involved in the study, no significant side effects were observed – possibly due to the local presence of the therapeutic cells remaining in the tumor environment. For example, one of the dogs that had a tumor around its eye did not lose its vision despite the treatment destroying the tumor – indicating the localization of the treatment at the tumor site, which does not affect the function of the surrounding organs.

While administering the treatment to the animal patients, the research team noted that some dogs with recurring cancers experienced no relapses or side effects. This supports the idea that the engineered therapeutic cells, which were designed to have few side effects and help the body fight cancer, worked as intended.

The research team gathers information from key studies in the field to gather more evidence to explain their findings. Unlike traditional chemotherapy, which often has harmful effects limited by dosage, MSCs are designed to directly treat affected areas in high concentrations, minimizing toxicity elsewhere in the body.

About the treatment mechanism

In the research led by Associate Professor Too Heng-Phon from the Department of Biochemistry and N2CR at NUS Medicine, the team adapted MSCs, which can detect cancer tumours. These modified cells carry a powerful ‘kill switch’ (cytosine deaminase) that produces a high, localized concentration of a cancer-killing drug (5-fluorouracil) in the tumor environment.

The ‘kill switch’ then induces immunity against cancer – by activating the cancer’s innate cGAS-STING and related pathways, which activate the immune response and suppress the tumor.

The development of this therapy to treat canine patients led the team to a better understanding of cancer treatments, as well as its use in human patients, because helping dogs with naturally occurring cancers provides valuable clues about human cancers.

Improvement of treatment

Particularly in late-stage cancer, the team found that remnants of tumors still remained after a few rounds of treatment. To target these remnants more precisely, the team wanted to further improve the treatment:

1. The mechanism was further improved by using the charge of the MSCs to accentuate the charge cGAS-STING and related pathways, recently reported to be critical for the delivery of chemotherapy drugs, including 5-fluorouracil, in activating anticancer immunity.
2. The mechanism was enhanced by the expression of interferon beta, a cytokine known to recruit and facilitate the activation of T cells for anti-cancer immunity. The expression of interferon beta can be tricky: too much of it in the blood can lead to side effects, but the right amount can be extremely powerful and efficient in tackling the cancer.

Assoc Prof Too said: “We make the treatment more efficient by modifying cells that are like ‘hunter killers’, where they settle on the tumors and destroy only these tumors and not other healthy parts of the body. This explains why there are no side effects.

“Drugs in chemotherapy usually lead to some level of side effects. Our treatment uses the body’s biological system, which treats the tumor without significant toxicity – this exceeds what drugs in chemotherapy can do.”

“Exploring optimal disease treatments remains our ongoing endeavor, and NUS Medicine’s technology for efficiently modifying stem cells serves as a ‘future-ready’ platform where recently identified therapeutic genes can be exploited,” he added.

Preparing for human clinical trials

In January 2024, Assoc Prof Too led two senior research fellows from his team, Dr. Sarah Ho and Dr. Woo Jun Yung, to establish AGeM Bio Pte Ltd. With the improved treatment, the research team is seeking validation for the manufacturing processes to prepare the treatment for use in human patients – expected to be completed in the third quarter of 2025.

The team hopes to begin the first phase of human clinical trials in late 2025, where they will work with doctors at the National University Hospital (NUH), to administer intratumoral injections of the engineered MSCs to a small number of patients with relapsed glioblastoma . a debilitating form of brain tumor. After the first phase of the trials, the team will conduct follow-up trials with larger groups of patients in the coming years to gather data on its effectiveness in human patients and improve the treatment.

Dr. Ho said: “To act is to save – that is the mission of our company, AGeM Bio Pte Ltd, where AGeM refers to ‘enhanced gene modification’. With our research we aim to address the unmet need for building cells to save lives rescue – a journey we have been on for more than a decade.”

Dr. Yung added: “While there will be many phases of clinical trials spanning several years before we can have a product the world can use, we are excited to take our research to the next level, which will give us a one step closer to saving people’s lives.”

Both Dr. Ho as Dr. Woo come from the Department of Biochemistry and N2CR at NUS Medicine, and co-founders of AGeM Bio Pte Ltd.

The clinical trial will be led by Clinical Associate Professor Yeo Tseng Tsai, Senior Consultant, Department of Neurosurgery, Department of Surgery, National University Hospital.

He said: “Glioblastoma is a particularly aggressive brain tumor that often recurs after initial treatment. Unfortunately, there is no standard treatment protocol for such recurrent cases. This first phase of our clinical trial represents an important step forward and will assess whether a therapy is demonstrably effective. in animal models can be used safely and effectively in human patients with this condition.”