Once it has spread (metastasized), uveal (intraocular or eye) melanoma — an unusual form of cancer — has a very high mortality rate. In a study published in Nature Communications, researchers and doctors at the University of Gothenburg and Sahlgrenska University Hospital show that, in a small group of patients with metastatic uveal melanoma, a new combination treatment can bring about tumor shrinkage and prolonged survival.

Uveal melanoma, an infrequent form of malignant melanoma, starts in the pigment cells of not the skin, but the eye. For skin melanoma, immunotherapy using “checkpoint inhibitors” has proved effective in many cases, but this has not applied to intraocular melanoma. Some 80 people get uveal melanoma in Sweden annually, and half of them get metastases, often in the liver. Patients with metastatic uveal melanoma frequently die shortly after diagnosis.

This is a Phase II trial in which 29 patients with metastatic eye melanoma received a combination of two inhibitor drugs that target HDAC (histone deacetylase) and PD-1 (a checkpoint protein on T cells) respectively. In four of these patients, the tumors shrank significantly, and for several patients the course of the disease was slowed down. Unusually, some of the patients are still alive today, three years after the study began.

“Our hope was that the HDAC inhibitor would reprogram hidden cancer cells so that they could be detected by the immune cells, thus making the immunotherapy with PD-1 inhibitors effective,” explains Lars Ny, senior lecturer at the University of Gothenburg and physician specializing in oncology at Sahlgrenska University Hospital.

 Resistance with a genetic explanation

“On the whole, the clinical trial met our expectations, although this doesn’t seem to be a curative treatment either. To find out why there were such major differences in how well patients responded, we performed genetic analyses. These showed that the treatment worked better against the tumors where the BAP1 gene was active and intact. This gene is often inactivated in metastases, but now we find that it’s associated with a better response to immunotherapy,” says Jonas Nilsson, professor at Sahlgrenska Academy at the University of Gothenburg, who is active at both the Sahlgrenska Center for Cancer Research and the Harry Perkins Institute of Medical Research in Perth, Australia.

The research team is now continuing to investigate why loss of the BAP1 gene causes resistance to immunotherapy, and what other changes in blood components may predict improved survival after immunotherapy in uveal melanoma patients.

One of the tumors, which had a deviant mutation pattern, was found to originate from the iris of the eye, which meant that it had been damaged by ultraviolet (UV) light from the sun. The scientists believe that the resulting tumor is more likely to show a relatively good response to immunotherapy. The response also seems to depend on tumor burden, ie how many tumors the patient has and how large they are. In collaboration with Anders Ståhlberg, the researchers were able to measure circulating free tumor DNA and the tumor marker serum lactate dehydrogenase (LDH) in blood samples. Evidently, these were correlated with the outcome: the less circulating free tumor DNA or LDH in the blood found before treatment, the longer the patients survived after it.

Trial with a long history

Since 2014, the same research team has also been working on another study that may provide a new treatment for metastatic eye melanoma. In this study, SCANDIUM (Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases), patients with uveal melanoma that has metastasized are randomly assigned to receive either the treatment prescribed by their doctor or an experimental therapy known as isolated hepatic perfusion (IHP). The latter involves surgically isolating the patient’s liver from the systemic circulation and perfusing quantities of cytotoxic drugs through it.

“When the SCANDIUM trial started, it felt very bittersweet. It was important to know whether this treatment worked — as we believed, based on retrospective studies. It was also good that the operations were performed so that we could get biopsies to study the disease. But, of course, it wasn’t good that patients were randomly excluded from the only thing that, at the time, was known to bring about a brief treatment response, when the patients had liver metastases. Our feeling was that, to come up with a treatment capable of challenging IHP, we needed to focus our research on eye melanoma,” Nilsson relates.

From lymphoma to uveal melanoma

Based on their own findings that epigenetic treatment was capable of affecting various immunoregulatory genes in lymphoma, Jonas and Lisa Nilsson decided to test whether these treatments could affect the same genes in eye melanoma. Henrik Jespersen, then a doctoral student supervised by Lars Ny and Jonas Nilsson, recalls what happened.

“I came into the lab and asked Jonas what he was doing at the flow cytometer. He said he just wanted to see if he could get results to form the basis for a new clinical trial that Lars and I could run.”

It turned out that while BET (bromodomain and extra-terminal motif) inhibitors lacked the capacity to stimulate the immunogenicity of uveal melanomna, HDAC inhibitors were able to do this.

Ny relates that when he was having lunch with Jonas and Lisa Nilsson, they told him about their results.

“They proposed combining HDAC inhibitors with PD-1 inhibitors to see whether that might work better for uveal melanoma patients. Thinking it sounded intriguing, I offered to raise the question with, the pharmaceutical company Merck (known as MSD outside of the U.S. and Canada), which I was going to have a meeting with anyway, later in the week, about another study. And the company was extremely interested in the new idea!”

Successful collaboration

It took two and a half years before the trial could start, in collaboration with Merck/MSD and Syndax. The latter had an HDAC inhibitor that was tested on humans only in initial studies in the U.S. and was not available in Europe. Then, when the study began in 2018, it took ten months to recruit the 29 participating patients.

“Seeing patients respond in an investigator-sponsored study that’s included as part of your thesis is something special. Being the person who both administered the treatment and then contributed to lab analyses was also a lesson for life,” Jespersen says.

Lars Ny adds his comments.

“I’m proud of the superb collaboration we have with the patient association and in the Swedish melanoma study group, and that colleagues all over the country were willing to recruit patients for the study from Norrland to Skåne. These modern treatments also have side effects, but nowadays we have quite a lot of experience with immunotherapy, so we were able to eliminate the side effects even if some had to stop the treatment.

The research will continue even after the article is published. The research group is interested in finding out why BAP1 loss results in resistance to immunotherapy and what changes in blood components may further predict better survival after immunotherapy in uveal melanoma patients. Some of these studies will take place in collaboration with Jonas Nilsson’s other lab, in Perth.

Title: The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma, https://www.doi.org/10.1038/s41467-021-25332-w

Contacts:

Lars Ny, Senior Lecturer at Sahlgrenska Academy, University of Gothenburg, specialized physician, phone 46 700 206 198, email lars.ny@oncology.gu.se

Jonas Nilsson, Professor at Sahlgrenska Academy, University of Gothenburg, and the Harry Perkins Institute of Medical Research, University of Western Australia in Perth, phone 61 432 623 539, email jonas.nilsson@perkins.org.au

Press contact, Sahlgrenska Academy, University of Gothenburg, email press@sahlgrenska.gu.se