From immunotherapy to mRNA vaccines – the latest science on melanoma treatment explained
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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.
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The Emperor’s New Klotho, Or Something More?
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Unzipping The Genes Of Aging?
Klotho is an enzyme encoded in humans’ genes—specifically, in the KL gene.
It’s found throughout all living parts of the human body (and can even circulate about in its hormonal form, or come to rest in its membranaceous form), and its subgroups are especially found:
- α-klotho: in the brain
- β-klotho: in the liver
- γ-klotho: in the kidneys
Great! Why do we care?
Klotho, its varieties and variants, its presence or absence, are very important in aging.
Almost every biological manifestation of aging in humans has some klotho-related indicator; usually the decrease or mutation of some kind of klotho.
Which way around the cause and effect go has been the subject of much debate and research: do we get old because we don’t have enough klotho, or do we make less klotho because we’re getting old?
Of course, everything has to be tested per variant and per system, so that can take a while (punctuated by research scientists begging for more grants to do the next one). Given that it’s about aging, testing in humans would take an incredibly long while, so most studies so far have been rodent studies.
The general gist of the results of rodent studies is “reduced klotho hastens aging; increased klotho slows it”.
(this can be known by artificially increasing or decreasing the level of klotho expression, again something easier in mice as it is harder to arrange transgenic humans for the studies)
Here’s one example of many, of that vast set of rodent studies:
Suppression of Aging in Mice by the Hormone Klotho
Relevance for Alzheimer’s, and a science-based advice
A few years ago (2020), an Alzheimer’s study was undertaken; they noted that the famous apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for Alzheimer’s, and that klotho may be another. FGF21 (secreted by the liver, mostly during fasting) binds to its own receptor (FGFR1) and its co-receptor β-klotho. Since this is a known neuroprotective factor, they wondered whether klotho itself may interact with β-amyloid (Aβ), and found:
❝Aβ can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD❞
In other words: β-amyloid, the substance whose accumulation is associated with neurodegeneration in Alzheimer’s disease, is a mediator in klotho bringing a known neuroprotective factor, FGF21, to the areas of neurodegeneration
In fewer words: klotho calls the firefighters to the scene of the fire
Read more: Alignment of Alzheimer’s disease amyloid β-peptide and klotho
The advice based on this? Consider practicing intermittent fasting, if that is viable for you, as it will give your liver more FGF21-secreting time, and the more FGF21, the more firefighters arrive when klotho sounds the alarm.
See also: Intermittent Fasting: What’s the truth?
…and while you’re at it:
Does intermittent fasting have benefits for our brain?
A more recent (2023) study with a slightly different (but connected) purpose, found results consistent with this:
Longevity factor klotho enhances cognition in aged nonhuman primates
…and, for that matter this (2023) study that found:
Associations between klotho and telomere biology in high stress caregivers
…which looks promising, but we’d like to see it repeated with a sounder method (they sorted caregiving into “high-stress” and “low-stress” depending on whether a child was diagnosed with ASD or not, which is by no means a reliable way of sorting this). They did ask for reported subjective stress levels, but to be more objective, we’d like to see clinical markers of stress (e.g. cortisol levels, blood pressure, heart rate changes, etc).
A very recent (April 2024) study found that it has implications for more aspects of aging—and this time, in humans (but using a population-based cohort study, rather than lab conditions):
Can I get it as a supplement?
Not with today’s technology and today’s paucity of clinical trials, you can’t. Maybe in the future!
However… The presence of senescent (old, badly copied, stumbling and staggering onwards when they should have been killed and eaten and recycled already) cells actively reduces klotho levels, which means that taking supplements that are senolytic (i.e., that kill those senescent cells) can increase serum klotho levels:
Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans
Ok, what can I take for that?
We wrote about a senolytic supplement that you might enjoy, recently:
Fisetin: The Anti-Aging Assassin
Want to know more?
If you have the time, Dr. Peter Attia interviews Dr. Dena Dubal (researcher in several of the above studies) here:
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Enjoy!
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Peripheral Neuropathy: How To Avoid It, Manage It, Treat It
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Peripheral neuropathy (and what can be done about it)
Peripheral neuropathy is nerve damage, usually of the extremities. It can be caused by such things as:
- Diabetes
- Alcoholism
- Infection
- Injury
The manifestations can be different:
- In the case of diabetes, it’s also called diabetic neuropathy, and almost always affects the feet first.
- In the case of alcoholism, it is more generalized, but tends towards affecting the extremities first.
- In the case of infection, a lot depends on the nature of the infection and the body’s response.
- In the case of injury, it’ll naturally be the injured part, or a little “downstream” of the injured part.
- This could be the case of a single traumatic injury (e.g. hand got trapped in a slammed door)
This could be the case of a repetitive injury (carpal tunnel syndrome is a kind of peripheral neuropathy, and is usually caused by consistent misalignment of the carpal tunnel, the aperture through which a bundle of nerves make their way from the forearm to the hand)
Prevention is better than cure
If you already have peripheral neuropathy, don’t worry, we’ll get to that. But, if you can, prevention is better than cure. This means:
- Diabetes: if you can, avoid. This may seem like no-brainer advice, but it’s often something people don’t think about until hitting a pre-diabetic stage. Obviously, if you are Type 1 Diabetic, you don’t have this luxury. But in any case, whatever your current status, take care of your blood sugars as best you can, so that your blood can take care of you (and your nerves) in turn. You might want to check out our previous main feature about this:
- Alcoholism: obviously avoid, if you can. You might like this previous edition of 10almonds addressing this:
- Infection: this is so varied that one-liner advice is really just “try to look after your immune health”.
- We’ll do a main feature on this soon!
- Injury: obviously, try to be careful. But that goes for the more insidious version too! For example, if you spend a lot of time at your computer, consider an ergonomic mouse and keyboard.
- There are many kinds available, so read reviews, but here’s an example product on Amazon
Writer’s note: as you might guess, I spend a lot of time at my computer, and a lot of that time, writing. I additionally spend a lot of time reading. I also have assorted old injuries from my more exciting life long ago. Because of this, it’s been an investment in my health to have:
A standing desk
A vertical ergonomic mouse
An ergonomic split keyboard
A Kindle*
*Far lighter and more ergonomic than paper books. Don’t get me wrong, I’m writing to you from a room that also contains about a thousand paper books and I dearly love those too, but more often than not, I read on my e-reader for comfort and ease.
If you already have peripheral neuropathy
Most advice popular on the Internet is just about pain management, but what if we want to treat the cause rather than the symptom?
Let’s look at the things commonly suggested: try ice, try heat, try acupuncture, try spicy rubs (from brand names like Tiger Balm, to home-made chilli ointments), try meditation, try a warm bath, try massage.
And, all of these are good options; do you see what they have in common?
It’s about blood flow. And that’s why they can help even in the case of peripheral neuropathy that’s not painful (it can also manifest as numbness, and/or tingling sensations).
By getting the blood flowing nicely through the affected body part, the blood can nourish the nerves and help them function correctly. This is, in effect, the opposite of what the causes of peripheral neuropathy do.
But also don’t forget: rest
- Put your feet up (literally! But we’re talking horizontal here, not elevated past the height of your heart)
- Rest that weary wrist that has carpal tunnel syndrome (again, resting it flat, so your hand position is aligned with your forearm, so the nerves between are not kinked)
- Use a brace if necessary to help the affected part stay aligned correctly
- You can get made-for-purpose wrist and ankle braces—you can also get versions that are made for administering hot/cold therapy, too. That’s just an example product linked that we can recommend; by all means read reviews and choose for yourself, though. Try them and see what helps.
One more top tip
We did a feature not long back on lion’s mane mushroom, and it’s single most well-established, well-researched, well-evidenced, completely uncontested benefit is that it aids peripheral neurogenesis, that is to say, the regrowth and healing of the peripheral nervous system.
So you might want to check that out:
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What’s the difference between ADD and ADHD?
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Around one in 20 people has attention-deficit hyperactivity disorder (ADHD). It’s one of the most common neurodevelopmental disorders in childhood and often continues into adulthood.
ADHD is diagnosed when people experience problems with inattention and/or hyperactivity and impulsivity that negatively impacts them at school or work, in social settings and at home.
Some people call the condition attention-deficit disorder, or ADD. So what’s the difference?
In short, what was previously called ADD is now known as ADHD. So how did we get here?
Let’s start with some history
The first clinical description of children with inattention, hyperactivity and impulsivity was in 1902. British paediatrician Professor George Still presented a series of lectures about his observations of 43 children who were defiant, aggressive, undisciplined and extremely emotional or passionate.
Since then, our understanding of the condition evolved and made its way into the Diagnostic and Statistical Manual of Mental Disorders, known as the DSM. Clinicians use the DSM to diagnose mental health and neurodevelopmental conditions.
The first DSM, published in 1952, did not include a specific related child or adolescent category. But the second edition, published in 1968, included a section on behaviour disorders in young people. It referred to ADHD-type characteristics as “hyperkinetic reaction of childhood or adolescence”. This described the excessive, involuntary movement of children with the disorder.
It took a while for ADHD-type behaviour to make in into the diagnostic manual. Elzbieta Sekowska/Shutterstock In the early 1980s, the third DSM added a condition it called “attention deficit disorder”, listing two types: attention deficit disorder with hyperactivity (ADDH) and attention deficit disorder as the subtype without the hyperactivity.
However, seven years later, a revised DSM (DSM-III-R) replaced ADD (and its two sub-types) with ADHD and three sub-types we have today:
- predominantly inattentive
- predominantly hyperactive-impulsive
- combined.
Why change ADD to ADHD?
ADHD replaced ADD in the DSM-III-R in 1987 for a number of reasons.
First was the controversy and debate over the presence or absence of hyperactivity: the “H” in ADHD. When ADD was initially named, little research had been done to determine the similarities and differences between the two sub-types.
The next issue was around the term “attention-deficit” and whether these deficits were similar or different across both sub-types. Questions also arose about the extent of these differences: if these sub-types were so different, were they actually different conditions?
Meanwhile, a new focus on inattention (an “attention deficit”) recognised that children with inattentive behaviours may not necessarily be disruptive and challenging but are more likely to be forgetful and daydreamers.
People with inattentive behaviours may be more forgetful or daydreamers. fizkes/Shutterstock Why do some people use the term ADD?
There was a surge of diagnoses in the 1980s. So it’s understandable that some people still hold onto the term ADD.
Some may identify as having ADD because out of habit, because this is what they were originally diagnosed with or because they don’t have hyperactivity/impulsivity traits.
Others who don’t have ADHD may use the term they came across in the 80s or 90s, not knowing the terminology has changed.
How is ADHD currently diagnosed?
The three sub-types of ADHD, outlined in the DSM-5 are:
- predominantly inattentive. People with the inattentive sub-type have difficulty sustaining concentration, are easily distracted and forgetful, lose things frequently, and are unable to follow detailed instructions
- predominantly hyperactive-impulsive. Those with this sub-type find it hard to be still, need to move constantly in structured situations, frequently interrupt others, talk non-stop and struggle with self control
- combined. Those with the combined sub-type experience the characteristics of those who are inattentive and hyperactive-impulsive.
ADHD diagnoses continue to rise among children and adults. And while ADHD was commonly diagnosed in boys, more recently we have seen growing numbers of girls and women seeking diagnoses.
However, some international experts contest the expanded definition of ADHD, driven by clinical practice in the United States. They argue the challenges of unwanted behaviours and educational outcomes for young people with the condition are uniquely shaped by each country’s cultural, political and local factors.
Regardless of the name change to reflect what we know about the condition, ADHD continues to impact educational, social and life situations of many children, adolescents and adults.
Kathy Gibbs, Program Director for the Bachelor of Education, Griffith University
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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Guava vs Pineapple – Which is Healthier?
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Our Verdict
When comparing guava to pineapple, we picked the guava.
Why?
Pineapple is great, but guava just beats it in most ways:
In terms of macros, guava has nearly 4x the fiber and nearly 5x the protein, for the same carbs, giving it the notably lower glycemic index. An easy win for guava in this category.
In the category of vitamins, guava has a lot more of vitamins A, B2, B3, B5, B9, C, E, K, and choline, while pineapple has marginally more vitamin B1. Another clear win for guava.
When it comes to minerals, guava has more calcium, copper, magnesium, phosphorus, potassium, selenium, and zinc, while pineapple has more iron and manganese. One more win for guava.
One big thing in pineapple’s favor is that it contains bromelain, which is an enzyme* found in pineapple (and only in pineapple), that has many very healthful properties, some of them unique to bromelain (and thus: unique to pineapple)
*actually a combination of enzymes, but most often referred to collectively in the singular. But when you do see it referred to as “they”, that’s what that means.
However cool that is, we think it unfair to weight it against guava winning in every other category, so we still say guava gets the overall win.
Of course, enjoy either or both; diversity is good!
Want to learn more?
You might like:
Let’s Get Fruity: Bromelain vs Inflammation & Much More
Enjoy!
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What To Do If Having A Stroke Alone?
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It’s Q&A Day at 10almonds!
Have a question or a request? We love to hear from you!
In cases where we’ve already covered something, we might link to what we wrote before, but will always be happy to revisit any of our topics again in the future too—there’s always more to say!
As ever: if the question/request can be answered briefly, we’ll do it here in our Q&A Thursday edition. If not, we’ll make a main feature of it shortly afterwards!
So, no question/request too big or small 😎
❝Thank you for the video about what to do if you have a heart attack alone, what about what to do if you have a stroke alone?❞
(for anyone who missed that video, here it is)
That’s a good question, especially as stroke risk is rising in the industrialized world in general, and the US in particular.
However, let’s start with the caveat that if you are having a stroke, there’s a good chance you will forget what we are about to say, what with the immediate effects it has on the brain. That said…
The general advice when it comes to looking after someone else who is experiencing a stroke, is, “don’t”.
In other words, call emergency services, and don’t do anything else, e.g:
- don’t give them anything to eat or drink
- don’t give them any medications
- don’t let them go to sleep
- don’t let them talk you out of calling emergency services
- don’t let them drive themselves to hospital
- don’t drive them to hospital yourself either*
*This is for two reasons:
- an ambulance crew has skills and resources that you don’t, and can begin treatment en-route, and also,
- not all hospitals have appropriate resources to treat stroke, so the ambulance crew will know to drive to one that does, instead of driving to a random hospital and hoping for the best
So, flipping this for if it’s you having the stroke, and you’re cognizant enough to remember this:
- do call an ambulance; stay on the line and don’t do anything else unless instructed by the emergency services.
In order to do that, of course it’s important to recognize the symptoms; you probably know these but just in case, the mnemonic is “FAST”:
- Face: is there weakness on one side of their face?
- Arms: if they raise both arms, does one drift downwards?
- Speech: if they speak, is their speech slurred or otherwise unusual?
- Time: to call emergency services
It’s great to not get caught out by surprise, so you might also want to check out:
6 Signs Of Stroke (One Month In Advance)
Take care!
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7 Days Of Celery Juice: What’s The Verdict?
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Laura “Try” tries many popular trends, and reports on the benefits (or problems, or both). In this case, it’s 7 days of celery juice… Not as a fast, though, i.e. she doesn’t just have celery juice for 7 days, but rather, it’s how she kicks off each morning, with half a liter (16oz) on an empty stomach.
What she found
First, she bought a masticating juicer and organic celery. So, those are expenses to consider, especially the one-off expense of the juicer, and the ongoing expense of organic celery—estimated $90/month).
In terms of taste, she was surprised it wasn’t as bitter as expected, but from the second day onwards, she did use the juicer’s filter to remove the frothy sludge, and she also switched to juicing only the stalks, not the leaves—which are more bitter.
10almonds note: the leaves are more bitter because that’s where the polyphenols are more densely concentrated. The leaves are better for you than the stalks. Enjoy the leaves. Really: if you chop them finely you can use them as herbs in your cooking, and if you’re making a salad, just chop them into that too.
The reason she picked the quantity of half a liter is because this is what she found recommended to coat the stomach lining—on the promise of increased stomach acid production, reduced bacteria overgrowth, as well as antiviral, antifungal, and anti-inflammatory properties. As she’s just one woman without a personal lab, she couldn’t test and thus verify any of these though—but she did still have benefits to report:
She did experience clearer skin, more energy, and better sleep after a few days.
Ultimately, she decided to continue to do it just at the weekends, due to its positive effects, despite the cost and time consumption.
For more personal insights, enjoy:
Click Here If The Embedded Video Doesn’t Load Automatically!
Want to learn more?
You might also like to read:
Enjoy Bitter Foods For Your Heart & Brain
Take care!
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