Salivary gland transplantation: a breakthrough after twenty years of research

In December 2022, the University Medical Center Groningen (UMCG) performed a unique treatment. For the first time, a patient was treated with salivary gland organoid cells, grown from his own stem cells. This therapy is the result of more than twenty years of research led by Rob Coppes, professor of Radiotherapy at the UMCG.

“It’s unique that you can develop an idea in one place and then eventually apply it in a clinical trial in the same place,” says Coppes. The idea for this research came about in the early 2000s at a conference in Oxford. “I saw a poster presentation about an experiment where cells were injected into the spinal cord of laboratory animals. The research showed a small improvement, and that planted a seed.”

The real breakthrough came a few years later through a chance meeting. “Our department merged with the stem cell biology department. During conversations at the coffee machine I discovered that they had techniques that we could use. Together we submitted a grant proposal to KWF. In 2003 the research officially started.”

 Organoids

The first steps were promising, but full of challenges. “In 2008, we showed that it was possible to isolate and culture stem cells from salivary glands,” Coppes explains. “In that phase alone, we needed three mice to treat one mouse. Of course, that is not feasible in the clinic. An important breakthrough came from the research of Hans Clevers’ group on organoids at the Hubrecht Institute. “Organoid technology took us much further. We lacked a few growth factors to grow high-quality organoids. It then took us six years to develop the method according to Good Manufacturing Practice (GMP) guidelines. After approval by the CCMO, the central medical ethics review committee, we were able to treat the first patient in December 2022.”

Dry mouth

Xerostomia, a dry mouth due to reduced saliva production, is a common side effect of radiation for tumors in the head and neck area. Without functioning salivary glands, patients suffer from various complaints, such as loss of taste, difficulty speaking, swallowing and serious dental problems. “It has a huge impact on the quality of life,” Coppes emphasizes. “Without saliva, you don’t die, but life does become more unpleasant.”

The treatment is currently focused on a specific group of patients with a tumor in the oral cavity or near the tongue. “In these patients, the tumor is surgically removed, including one of the salivary glands. We receive a piece of the removed gland, grow it in the lab and make organoids from it. In the case of metastasis on the other side, the patient undergoes radiation. The same salivary gland on the other side is then severely damaged and no longer functional. The idea is that we replace the grown salivary gland after the radiotherapy.”

Cooperation

Interdisciplinary collaboration was essential to make this research a success. “We collaborated with biomedical sciences, radiotherapy, stem cell biology, oral surgery, the ATMP department to do everything according to regulations and later with radiology. We were lucky that all these departments within the UMCG were willing to cooperate and had sufficient capacity.”

In addition to the enormous impact for the patient, Coppes gets a lot of satisfaction from the scientific process. “The best thing about this research is that you learn so much about how life works. Sometimes you discover by-catches that are unexpectedly valuable. For example, we now know exactly where the stem cells are in salivary glands. We have applied this knowledge to adjust radiation methods so that the stem cells are spared as much as possible. That helps patients before they even know what they are missing.”