Increased survival with eye melanoma in clinical trial

Date:
August 30, 2021
Source:
University of Gothenburg
Summary:
Once it has spread (metastasized), uveal (intraocular or eye)
melanoma - - an unusual form of cancer -- has a very high mortality
rate.

Researchers and doctors show that, in a small group of patients
with metastatic uveal melanoma, a new combination treatment can
bring about tumor shrinkage and prolonged survival.



FULL STORY ==========================================================================
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 Staahlberg, 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 Skaane. 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.

========================================================================== Story Source: Materials provided by University_of_Gothenburg. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Lars Ny, Henrik Jespersen, Joakim Karlsson, Samuel Alse'n,
Stefan Filges,
Charlotta All-Eriksson, Bengt Andersson, Ana Carneiro, Hildur
Helgadottir, Max Levin, Ingrid Ljuslinder, Roger Olofsson Bagge,
Vasu R.

Sah, Ulrika Stierner, Anders Staahlberg, Gustav Ullenhag, Lisa M.

Nilsson, Jonas A. Nilsson. The PEMDAC phase 2 study of pembrolizumab
and entinostat in patients with metastatic uveal melanoma. Nature
Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-25332-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210830100002.htm

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