More than 16,000 Australians will be diagnosed with melanoma each year. Most of these will be caught early, and can be cured by surgery.

However, for patients with advanced or metastatic melanoma, which has spread from the skin to other organs, the outlook was bleak until the advent of targeted therapies (that attack specific cancer traits) and immune therapies (that leverage the immune system). Over the past decade, these treatments have seen a significant climb in the number of advanced melanoma patients surviving for at least five years after diagnosis, from less than 10% in 2011 to around 50% in 2021.

While this is great news, there are still many melanoma patients who cannot be treated effectively with current therapies. Researchers have developed two exciting new therapies that are being evaluated in clinical trials for advanced melanoma patients. Both involve the use of immunotherapy at different times and in different ways.

The first results from these trials are now being shared publicly, offering insight into the future of melanoma treatment.

Immunotherapy before surgery

Immunotherapy works by boosting the power of a patient’s immune system to help kill cancer cells. One type of immunotherapy uses something called “immune checkpoint inhibitors”.

Immune cells carry “immune checkpoint” proteins, which control their activity. Cancer cells can interact with these checkpoints to turn off immune cells and hide from the immune system. Immune checkpoint inhibitors block this interaction and help keep the immune system activated to fight the cancer.

Results from an ongoing phase 3 trial using immune checkpoint inhibitors were recently published in the New England Journal of Medicine.

This trial used two types of immune checkpoint inhibitors: nivolumab, which blocks an immune checkpoint called PD-1, and ipilimumab, which blocks CTLA-4.

Some 423 patients (including many from Australia) were enrolled in the trial, and participants were randomly assigned to one of two groups.

The first group had surgery to remove their melanoma, and were then given immunotherapy (nivolumab) to help kill any remaining cancer cells. Giving a systemic (whole body) therapy such as immunotherapy after surgery is a standard way of treating melanoma. The second group received immunotherapy first (nivolumab plus ipilimumab) and then underwent surgery. This is a new approach to treating these cancers.

Based on previous observations, the researchers had predicted that giving patients immunotherapy while the whole tumour was still present would activate the tumour-fighting abilities of the patient’s immune system much better than giving it once the tumour had been removed.

Sure enough, 12 months after starting therapy, 83.7% of patients who received immunotherapy before surgery remained cancer-free, compared to 57.2% in the control group who received immunotherapy after surgery.

Based on these results, Australian of the year Georgina Long – who co-led the trial with Christian Blank from The Netherlands Cancer Institute – has suggested this method of immunotherapy before surgery should be considered a new standard of treatment for higher risk stage 3 melanoma. She also said a similar strategy should be evaluated for other cancers.

The promising results of this phase 3 trial suggest we might see this combination treatment being used in Australian hospitals within the next few years.

mRNA vaccines

Another emerging form of melanoma therapy is the post-surgery combination of a different checkpoint inhibitor (pembrolizumab, which blocks PD-1), with a messenger RNA vaccine (mRNA-4157).

While checkpoint inhibitors like pembrolizumab have been around for more than a decade, mRNA vaccines like mRNA-4157 are a newer phenomenon. You might be familiar with mRNA vaccines though, as the biotechnology companies Pfizer-BioNTech and Moderna released COVID vaccines based on mRNA technology.

mRNA-4157 works basically the same way – the mRNA is injected into the patient and produces antigens, which are small proteins that train the body’s immune system to attack a disease (in this case, cancer, and for COVID, the virus).

However, mRNA-4157 is unique – literally. It’s a type of personalised medicine, where the mRNA is created specifically to match a patient’s cancer. First, the patient’s tumour is genetically sequenced to figure out what antigens will best help the immune system to recognise their cancer. Then a patient-specific version of mRNA-4157 is created that produces those antigens.

The latest results of a three-year, phase 2 clinical trial which combined pembrolizumab and mRNA-4157 were announced this past week. Overall, 2.5 years after starting the trial, 74.8% of patients treated with immunotherapy combined with mRNA-4157 post-surgery remained cancer-free, compared to 55.6% of those treated with immunotherapy alone. These were patients who were suffering from high-risk, late-stage forms of melanoma, who generally have poor outcomes.

It’s worth noting these results have not yet been published in peer-reviewed journals. They’re available as company announcements, and were also presented at some cancer conferences in the United States.

Based on the results of this trial, the combination of pembrolizumab and the vaccine progressed to a phase 3 trial in 2023, with the first patients being enrolled in Australia. But the final results of this trial are not expected until 2029.

It is hoped this mRNA-based anti-cancer vaccine will blaze a trail for vaccines targeting other types of cancer, not just melanoma, particularly in combination with checkpoint inhibitors to help stimulate the immune system.

Despite these ongoing advances in melanoma treatment, the best way to fight cancer is still prevention which, in the case of melanoma, means protecting yourself from UV exposure wherever possible.

Sarah Diepstraten, Senior Research Officer, Blood Cells and Blood Cancer Division, WEHI (Walter and Eliza Hall Institute of Medical Research) and John (Eddie) La Marca, Senior Research Officer, Blood Cells and Blood Cancer, WEHI (Walter and Eliza Hall Institute of Medical Research)

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Semaglutide (sold as Ozempic, Wegovy and Rybelsus) was initially developed to treat diabetes. It works by stimulating the production of insulin to keep blood sugar levels in check.

This type of drug is increasingly being prescribed for weight loss, despite the fact it was initially approved for another purpose. Recently, there has been growing interest in another possible use: to treat addiction.

Anecdotal reports from patients taking semaglutide for weight loss suggest it reduces their appetite and craving for food, but surprisingly, it also may reduce their desire to drink alcohol, smoke cigarettes or take other drugs.

But does the research evidence back this up?

Animal studies show positive results

Semaglutide works on glucagon-like peptide-1 receptors and is known as a “GLP-1 agonist”.

Animal studies in rodents and monkeys have been overwhelmingly positive. Studies suggest GLP-1 agonists can reduce drug consumption and the rewarding value of drugs, including alcohol, nicotine, cocaine and opioids.

Out team has reviewed the evidence and found more than 30 different pre-clinical studies have been conducted. The majority show positive results in reducing drug and alcohol consumption or cravings. More than half of these studies focus specifically on alcohol use.

However, translating research evidence from animal models to people living with addiction is challenging. Although these results are promising, it’s still too early to tell if it will be safe and effective in humans with alcohol use disorder, nicotine addiction or another drug dependence.

What about research in humans?

Research findings are mixed in human studies.

Only one large randomised controlled trial has been conducted so far on alcohol. This study of 127 people found no difference between exenatide (a GLP-1 agonist) and placebo (a sham treatment) in reducing alcohol use or heavy drinking over 26 weeks.

In fact, everyone in the study reduced their drinking, both people on active medication and in the placebo group.

However, the authors conducted further analyses to examine changes in drinking in relation to weight. They found there was a reduction in drinking for people who had both alcohol use problems and obesity.

For people who started at a normal weight (BMI less than 30), despite initial reductions in drinking, they observed a rebound increase in levels of heavy drinking after four weeks of medication, with an overall increase in heavy drinking days relative to those who took the placebo.

There were no differences between groups for other measures of drinking, such as cravings.

In another 12-week trial, researchers found the GLP-1 agonist dulaglutide did not help to reduce smoking.

However, people receiving GLP-1 agonist dulaglutide drank 29% less alcohol than those on the placebo. Over 90% of people in this study also had obesity.

Smaller studies have looked at GLP-1 agonists short-term for cocaine and opioids, with mixed results.

There are currently many other clinical studies of GLP-1 agonists and alcohol and other addictive disorders underway.

While we await findings from bigger studies, it’s difficult to interpret the conflicting results. These differences in treatment response may come from individual differences that affect addiction, including physical and mental health problems.

Larger studies in broader populations of people will tell us more about whether GLP-1 agonists will work for addiction, and if so, for whom.

How might these drugs work for addiction?

The exact way GLP-1 agonists act are not yet well understood, however in addition to reducing consumption (of food or drugs), they also may reduce cravings.

Animal studies show GLP-1 agonists reduce craving for cocaine and opioids.

This may involve a key are of the brain reward circuit, the ventral striatum, with experimenters showing if they directly administer GLP-1 agonists into this region, rats show reduced “craving” for oxycodone or cocaine, possibly through reducing drug-induced dopamine release.

Using human brain imaging, experimenters can elicit craving by showing images (cues) associated with alcohol. The GLP-1 agonist exenatide reduced brain activity in response to an alcohol cue. Researchers saw reduced brain activity in the ventral striatum and septal areas of the brain, which connect to regions that regulate emotion, like the amygdala.

In studies in humans, it remains unclear whether GLP-1 agonists act directly to reduce cravings for alcohol or other drugs. This needs to be directly assessed in future research, alongside any reductions in use.

Are these drugs safe to use for addiction?

Overall, GLP-1 agonists have been shown to be relatively safe in healthy adults, and in people with diabetes or obesity. However side effects do include nausea, digestive troubles and headaches.

And while some people are OK with losing weight as a side effect, others aren’t. If someone is already underweight, for example, this drug might not be suitable for them.

In addition, very few studies have been conducted in people with addictive disorders. Yet some side effects may be more of an issue in people with addiction. Recent research, for instance, points to a rare risk of pancreatitis associated with GLP-1 agonists, and people with alcohol use problems already have a higher risk of this disorder.

Other drugs treatments are currently available

Although emerging research on GLP-1 agonists for addiction is an exciting development, much more research needs to be done to know the risks and benefits of these GLP-1 agonists for people living with addiction.

In the meantime, existing effective medications for addiction remain under-prescribed. Only about 3% of Australians with alcohol dependence, for example, are prescribed medication treatments such as like naltrexone, acamprosate or disulfiram. We need to ensure current medication treatments are accessible and health providers know how to prescribe them.

Continued innovation in addiction treatment is also essential. Our team is leading research towards other individualised and effective medications for alcohol dependence, while others are investigating treatments for nicotine addiction and other drug dependence.

Read the other articles in The Conversation’s Ozempic series here.

Shalini Arunogiri, Addiction Psychiatrist, Associate Professor, Monash University; Leigh Walker, , Florey Institute of Neuroscience and Mental Health, and Roberta Anversa, , The University of Melbourne

This article is republished from The Conversation under a Creative Commons license. Read the original article.