The Research Edition, February 2024

No. 2 | February | 2024

News

FROM THE FOUNDATION WORKING TO END MELANOMA

THE RESEARCH EDITION

Articles

01 02 03

04 05

From the Desk of Alicia Rowell, Vice President AIM at Melanoma Foundation

Bias About Acral Melanoma May Lead to Missed Diagnoses

by Mandi Murph, Director of Medical Education for AIM at Melanoma

Notes from the Lab: Could Microbes Help the Fight Against Melanoma?

By Paul Bunk, Ph.D. candidate, Cold Springs Harbor Laboratory

Rising Melanoma Incidence Rates Much Higher Than Expected on Tribal Lands

by Mandi Murph, Director of Medical Education for AIM at Melanoma

In Plain English: Highlights of New Directions in Cutaneous Melanoma Therapy—a Brief Update on Recent Treatments and Future Directions

By Kim Margolin, M.D., FACP, FASCO

Our focus for this newsletter is research and treatment.

FROM THE DESK OF

Alicia Rowell VICE PRESIDENT | AIM AT MELANOMA FOUNDATION

A

belated Happy New Year to our AIM community! I hope your 2024 has started off well.

This year is a special and important one for AIM at Melanoma, as we are celebrating our 20th anniversary.

Our late founder, Valerie Guild, incorporated our nonprofit in February of 2004, almost 20 years ago today.

We are proud of two decades of providing education and resources to the melanoma community. And we’re equally proud of our contributions to global, collaborative research. We will be celebrating all year!

I am excited to share our first newsletter of the year with you, as it’s jam-packed with information on the latest research in melanoma. From our two continuing series In Plain English and Notes from the Lab, to articles about two surprising findings—melanoma rates in non-Hispanic American Indian/Alaska Natives and rates of acral lentiginous melanoma among different ethnic and racial groups—there is a lot of interesting information for you to peruse. As always, our goal is to present complex material in an accessible way. We hope we’ve succeeded.

I’d also like to share an update with you on our major research project, the International Melanoma Tissue Bank Consortium. As of December 31, 2023, we had collected 197 tissues, a huge increase since we last reported one year ago. Our tissue sites have pushed through the operational hurdles and COVID slow-downs of the past few years. We are excited to see collection rates increase even further in 2024!

As a reminder, here’s how the tissue bank typically works: A patient goes to see his or her dermatologist for a skin check at one of the tissue bank locations. The physician finds a lesion suspicious for melanoma and intends to biopsy it.

Before the excision begins, the physician asks for consent from the patient to use some of the tissue and the patient’s medical information—anonymized—for research. If granted, a portion of the tissue is removed for the biopsy, and a portion is frozen immediately, which, critically, preserves RNA. The doctor also asks the patient to fill out a special questionnaire and collects blood samples. Staff enter the patient’s medical record and questionnaire answers (again, all anonymized) into a special database, and the samples and tissue are coded and stored in refrigerators/freezers.

The bank, then, is made up of both fresh frozen tumor tissue and other samples such as blood, as well as data about each patient.

Once a critical mass of tissues and data are collected from a variety of patients across the US, the researchers can look at these fresh frozen primary melanomas and the accompanying data to find medical signs or indications, called biomarkers, that are shared by some or all of the tissues. These biomarkers will help reveal insights on diagnosis, prognosis, and treatment. We are nearing that critical mass number—and I’ll look forward to reporting again soon on progress.

Finally, as we begin this new year, I want to make sure to say thank you on behalf of everyone at AIM for all of your support in 2023. We are grateful for our community.

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Bias About Acral Melanoma May Lead to Missed Diagnoses

by Mandi Murph, Director of Medical Education for AIM at Melanoma Although

acral

lentiginous

melanoma

is

If you thought you were either immune or prone to this disease – you are not!

often

thought to be the most common type of melanoma among people with skin of color, recent data reported by the Centers for Disease Control and Prevention (CDC) invalidate that assumption.

The long-held belief that light skinned people were not at risk for acral melanoma and dark skinned people were prone to it is unsubstantiated by new data that assesses the number of cases diagnosed in ethnic and racial populations across a ten year period. The data reported by the CDC show that

Acral lentiginous melanoma occurs on the

acral lentiginous melanoma is not the most common

non-hair-baring surfaces of the body,

type of melanoma among people of color, nor is it

including the nail beds, palms of the

exclusive to people with skin of color. Overall, the

hands, and soles of the feet. The causes of

study showed the acral melanoma is rare and that it

acral lentiginous melanoma are unknown,

makes up a minority of melanoma cases across all

but research suggests it is unrelated to

ethnic groups.

ultraviolet (UV) exposure.

Which groups have the greatest number of diagnoses?

The study looked at data from 2010 – 2019, and during that time, the number of cases of acral lentiginous melanoma is the highest

among

individuals

at

non-Hispanic 6156.

This

White

number

is

followed by Hispanic White individuals at 872, non-Hispanic Black individuals at 636, non-Hispanic

Asian

or

Asian

Pacific

Islanders at 278, American Indian or Alaskan Natives at 52, and Hispanic nonWhite at 42. This cancer is, overall, very rare, with under 8000 cases diagnosed in a ten year period.

When looking at cases of acral melanoma in certain populations, it’s important to understand those numbers in the context of

all

melanoma

diagnosed

in

that

population.

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Similarly, the number of cases diagnosed in non-Hispanic Asian or Asian Pacific Islanders is 278, but that number is 11.9% of all melanomas diagnosed. In this population, it’s a little higher than a onein-ten chance that a melanoma diagnosis will be acral.

To obtain data for most of the U.S. population,

the

lead

author,

Dawn

Holman, and her colleagues combined recent data from the CDC’s National Program of Cancer Registries with the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program.

The results provided incidence rates of melanoma that covered 99% of the U.S. population from 2010-2019.

For example, while non-Hispanic Whites had 6156 cases of acral melanoma diagnosed over the ten year period, that number represented only 0.8% of all melanoma diagnosed in that group. Less than 1% of cases were acral, yet it was still over 6000 cases, because there is a lot of melanoma diagnosed in the non-Hispanic White population.

The results challenge previous beliefs that people with skin of color should be vigilant at recognizing acral lentiginous melanoma but not necessarily concerned about cutaneous melanoma or other subtypes. The reality, per the study, is that just under one-in-five are acral lentiginous melanoma.

By contrast, the 636 cases diagnosed in non-

Similarly, a common assumption is that

Hispanic Black individuals represented 17.6% of

non-Hispanic Whites are unaffected by

all melanomas diagnosed in that population. In

acral melanoma, but the results also

this group, if you have a melanoma diagnosis,

prove that non-Hispanic White individuals

there is a higher chance that it is acral melanoma

are not immune to this type of disease. In

than it is for non-Hispanic Whites, but it’s still

fact,

less than a one-in-five-chance and more likely

largest numbers of diagnoses.

non-Hispanic

Whites

have

the

that the diagnosis will be another type of melanoma.

This

study

suggests

that

messaging

about acral melanoma should be revised to reflect that while rare, it occurs in all populations, not just those with darker skin tones. The take-away for the public is to check your nail beds, palms, and soles during your monthly skin exam regardless of the tone of your skin.

Click here for information on how to perform a skin self-exam This article was based on the study by Homan DM, King JB, White A et al. Prev Med. 2023;175:107692.

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NOTES FROM THE LAB Could Microbes Help the Fight Against Melanoma?

By Paul Bunk, Ph.D. candidate, Cold Springs Harbor Laboratory Our bodies have a myriad of microscopically small organisms living on and inside of us. These microorganisms include bacteria, fungi and other single-celled organisms. When we talk about bacteria, we often think of pathogens that will make us sick, but bacteria and other microorganisms are actually very important for our body to stay healthy. Our natural community of microbes, which covers every inch of our body both outside and inside, helps us keep harmful pathogens away and aids in digestion of food as well as many other crucial processes.

There are as many bacteria in our body as human cells, highlighting the importance of these microscopic companions.

But what do microbes have to do with cancer and melanoma? Scientists are increasingly learning how important microbes, particularly the microorganisms in our intestines, are for our body to function properly.

Research has shown that the composition of bacteria living in cancer patients is significantly different than what can be found in a healthy human. But do these changes have any impact on the cancer?

Recent studies suggest they might.

This research has spawned a number of strategies to use microbes to help melanoma and other cancer patients.

Below, you can find a snippet of our current understanding of how microbes can affect melanoma and its treatment. This field of research is very active, and new studies are published frequently, but this article should give you a broad understanding of what we do and do not know about microbes and melanoma.

Microbes in and around your body shape health and disease Anyone who has ever dealt with a Salmonella infection can attest to the fact that bacteria can have a significant impact on your health. We are aware of several bacteria that can cause disease: Salmonella, certain types of E. coli, Vibrio choleri (the cause of cholera), and Staphylococcus aureus (the cause of Staph infections) are just a few examples. But we encounter bacteria every second of every day, most of which have no effect on our health, and some actually benefit us.

Our body acts as a home to about 38 trillion bacteria that live in our gut and all other surfaces of our body (compared to about 30 trillion human cells that make up the body of a ‘standard man’). The entirety of the microorganisms living in our body is referred to as the microbiome. The microbiome helps us digest food, produce nutrients, fight off infections and regulate our immune system.

Through all these mechanisms, microbes can change our health not just in the case of pathogens causing food poisoning but also through affecting more chronic and potentially more serious diseases. One good example is H. pylori which is a bacterium that lives in the stomach of a large proportion of the human population. Certain strains of H. pylori can cause stomach ulcers which further progress to gastric cancer.

This Nobel Prize-winning discovery was made by Robin Warren and Barry Marshall and involved Marshall drinking a beaker of H. pylori and demonstrating that just 10 days after infection he had developed marked inflammation in his stomach. H. pylori is the only bacteria that is known to directly cause cancer (it is responsible for a significant proportion of gastric cancers) but research into the relationship between bacteria and cancer is ongoing.

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Patients with melanoma show changes in their microbiome With the importance of the microbiome becoming increasingly obvious to scientists, there have been many studies evaluating the microbiome of patients with melanoma and how it differs from healthy individuals. Indeed, certain bacteria seem to be reduced in cancer patients whereas others are overrepresented compared to healthy controls.

However, such studies can only show us correlations and do not tell us whether the change in bacteria is affecting the growth of cancer. To understand how the bacteria is affecting the cancer, scientists rely on animal models of human disease. In mice (and humans) there are various ways we can transfer the microbiome of one individual to another, one of which is called fecal microbiota transplantation, or FMT for short.

Without going into too much detail, feces from one individual are transferred into another individual, carrying all the microbes in the transfer which can then “colonize” the recipient’s gut. Mice that have melanoma also have microbiome changes similar to human patients. Notably, researchers found that when melanoma-bearing mice receive the microbiome of a different mouse via FMT, melanoma progresses more slowly. This discovery was the first evidence that the microbiome influences the progression of melanoma.

Transferring the whole “healthy” microbiome is based on the hypothesis that the “healthy” microbiome contains bacteria that can help the body fight against melanoma, but it is a rather untargeted approach, without knowing which components of the microbiome are helping the body and how the microbiome affects cancer growth. Looking at the differences between the microbiome of healthy individuals and those that have melanoma has given us some hints as to which bacteria are beneficial and which ones are not. This understanding might allow for more targeted approaches beyond FMT, such as using probiotics which are live microorganisms that can be taken as a dietary supplement. If we can identify individual bacteria species that impair tumor growth, they could theoretically be given as probiotics to patients to help their body fight against the cancer.

But it is unlikely such microorganisms would be given as a sole therapeutic agent, and therefore researchers have focused on how the microbiome shapes the response to other therapies in patients with melanoma. In other words, does the microbiome of a melanoma patient who responds to therapy (“responder”) differ from the microbiome of a melanoma patient who does not respond to therapy (“non-responder”). If yes, if you alter the non-responder’s microbiome to be more like the responder, will that patient then respond to treatment?

Microbes and immunotherapy The introduction of immunotherapies, namely checkpoint inhibitors, has revolutionized the treatment of melanoma and has significantly changed the survival chances of patients with metastatic melanoma, which used to be associated with a survival time of mere months. However, there remains a significant proportion of patients with melanoma who do not respond to immunotherapies or who become resistant after initial treatment success. Researchers are working hard to figure out what affects the response of patients to immunotherapy, and it seems like the microbiome may be playing a crucial role here as well.

Throughout the 2010s, studies were published showing that the microbiome of patients with melanoma who responded to immunotherapy showed distinct differences to those who did not. Again, such correlations do not necessarily show causation, meaning even though the microbiome is different between responders and non-responders, this difference does not automatically demonstrate that the microbiome affects the response to immunotherapy. So, three research groups investigated causality, and published their findings in the prestigious journal Science in 2018. They (and others after them) demonstrated that when they transferred the microbiome of responders, or even just certain bacteria that were more commonly found in responders, to mice that had melanoma (or other cancers), those mice were significantly better at fighting their tumors and had higher responses to immunotherapy.

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These studies showed that bacteria can play a causal role in the response of patients with melanoma to immunotherapies. Since then, two studies in humans showed that patients who had not responded to immunotherapy previously could overcome therapy resistance by receiving FMT. In one 2021 study, out of the 10 non-responders, three started to respond to immunotherapy after they had received a FMT from a responder. The MIMic trial, a phase I study with 20 melanoma patients, also showed that FMT before immunotherapy was safe for patients and improved the response rates among this small cohort.

Besides therapy efficacy, side effects are another major issue with immunotherapies. Immune-related adverse (negative) events can be caused by an overactive immune system that not only attacks the tumor but also the rest of the body. The severity can range from uncomfortable to life-threatening and a significant proportion of patients are forced to drop out of treatment because these side effects are too harsh. Colitis (inflammation of the colon) is a very common manifestation of immune-related side effects and seems to be closely intertwined with the composition of the gut microbiome. Unfortunately, these side effects usually become more severe the more potent an immunotherapy is (such as a combination of two different immune checkpoint inhibitors) and can therefore preclude patients from using these potentially life-saving therapies.

The same relationships seem to hold true for a lot of bacterial species as well. For example, Bacteroidetes and Firmicutes species have been shown to enhance the efficacy of immune checkpoint blockade but at the same time they also increase the risk of patients developing colitis during treatment. However, there are studies that show that the microbiome may be manipulated to decrease side effects without affecting therapy efficacy.

Researchers found that in mice with melanoma that received immunotherapy, a reduced number of Lactobacillus bacteria was associated with increased colitis. Introduction of Lactobacillus into these mice reduced colitis symptoms without affecting the efficacy of the immunotherapy. This field is ripe for more research.

Paul Bunk is a Ph.D. Candidate at Cold Spring Harbor Laboratory, a New York-based research institute world-renowned in the fields of cancer biology, neuroscience, and plant biology. Paul works in the group of Semir Beyaz and focuses his research on the impact of metabolism on immune cells and their ability to fight cancer. With this research, the Beyaz Lab sits at the cutting edge of cancer immunology and hopes to help make better immunotherapies for the future.

Paul Bunk, Ph.D. Candidate Cold Springs Laboratory

The future of microbiome manipulation To summarize, research in animals as well as humans has established that the microbiome of patients with melanoma is different than in healthy individuals and that the presence or absence of certain bacteria can change the progression of tumors as well as the response to immunotherapies. However, translation of these findings into the clinic are still at an early stage.

While we have seen some preliminary studies demonstrating the potential of FMT in humans, other microbiome targeted approaches that may act in a more targeted fashion have not yet been widely tested in cancer patients. As mentioned previously, probiotics could be used to introduce specific microbes that are associated with better responses into the patient. This tactic has been successful in mice, but probiotic colonization is much more challenging in humans than in mice, since we have a more complex microbiome.

Furthermore, there are safety concerns of giving probiotics to critically ill patients, as bacteria could transfer into the bloodstream and cause disease. And most important: Preliminary results of human studies suggest that the use of over-the-counter probiotics may negatively affect the microbiome of patients with melanoma. Therefore, the off-trial use of probiotics in patients with melanoma is discouraged.

When talking about the microbiome, there are two additional major factors that may have an impact on the microbial composition within an individual: diet and antibiotic use. Studies have shown that high fiber diets are associated with increased therapy response in human patients with melanoma, potentially due to their beneficial effect on the microbiome. Conversely, the use of antibiotics may be detrimental to patients with melanoma. In mice, immunotherapy response is reduced when mice are treated with antibiotics, and clinical studies have highlighted that antibiotic use before or shortly after the initiation of immunotherapy in melanoma patients is associated with reduced survival.

Overall, while the microbiome clearly has a significant impact on the progression and treatment of melanoma, we have not yet identified clear strategies to manipulate these relationships for the benefit of patients. Nonetheless, this is an area of heavy research, and given the wealth of information researchers have generated over the last decade alone, we should be hopeful for future developments in this space.

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FROM THE CLINIC TO THE LIVING ROOM WEBINAR SERIES

THE ROLE OF THE MICROBIOME & THE IMPACT OF THE GUT MICROBIOME In a groundbreaking two-part webinar series, colleagues Melissa Wilson, PA-C, MPAS, Lead Physician Assistant of the Melanoma Program, and Diwakar Davar, MD, MS, Clinical Director for the Melanoma and Skin Cancer Program at UPMC Hillman Cancer Center, delve into the fascinating relationship between melanoma and the microbiome.

This series sheds light on a relatively unexplored aspect of cancer research and provides valuable insights into potential therapeutic avenues.

CLICK HERE TO VIEW

RISING MELANOMA INCIDENCE RATES MUCH HIGHER THAN EXPECTED ON TRIBAL LANDS

by Mandi Murph, Director of Medical Education for AIM at Melanoma

If you read this newsletter, you likely know already that non-Hispanic Whites have the highest rate of invasive melanoma in the U.S. That makes sense: The lighter our skin color, the more susceptible we are to ultraviolet (UV) damage. However, do you know which racial or ethnic group has the second highest rate? What about the third?

According to new analysis using cancer registry data by the Centers for Disease Control and Prevention, non-Hispanic American Indian/Alaska Natives have the second highest incidence rate for invasive melanoma in the US. The incidence rate revealed in this study was far higher than expected. It was also nearly three times the rate of Hispanics in the US, the third racial/ethnic group when ranking melanoma incidence. The new results suggest the previously reported rate for invasive melanoma among non-Hispanic American Indian/Alaska Natives were inaccurately low.

The reason why the incidence rate was previously lower lies in data misclassification. Melanoma incidence rates often categorize groups of people by age at diagnosis, sex, and race/ethnicity.

Yet broad generalizations for the assignment of race/ethnicity can misclassify people of color.

Having multiple ethnicities, being multiracial, or having a range of skin color may also complicate categorization.

8

Correcting

for

misclassification

racial

and

ethnic

among

non-Hispanic

American Indian/Alaska Natives began with data from the US cancer registry records.

Then,

the

cancer

records

were

cross-

referenced with the Indian Health Service administration database. Records used for the study required that patients had membership in a federally recognized tribe and received health care from Indian Health Services.

In addition, researchers restricted the data to health care records from counties on federally recognized tribal lands or counties adjacent to tribal lands. Results led to the current crosssectional study assessing records from 2151 people

confirmed

to

be

non-Hispanic

American Indian/Alaska Natives who were diagnosed with invasive melanoma, a far

This article was based on the study by Townsend JS,

higher number than expected.

Melkonian SC, Jim MA, et al. Melanoma Incidence Rates Among Non-Hispanic American Indian/Alaska

Perhaps expectedly, men 55 years and older were

highest

among

the

non-Hispanic

Native Individuals, 1999-2019. JAMA Dermatol.

2023;e235226. doi: 10.1001/jamadermatol.2023.5226.

American Indian/Alaska Native group. NonHispanic American Indian/Alaska Native men had a higher rate of regional/distant stage melanoma compared to women. The late stage of diagnosis is troubling because it complicates treatment, may jeopardize cure, and also unexpectedly highlights a substantial medical gap.

Similar to nationwide trends among many groups, from 1999 to 2016, the rates of melanoma

increased

American

Indian/Alaska

women.

In

addition,

in

non-Hispanic

Native

rates

of

men

and

late-stage

melanomas increased from 1999 to 2019 among this population.

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Geographically, the highest rates among the men were among those residing in the Southern Plains region, and the lowest incidence rates of invasive melanoma occurred among people living in Alaska.

Since ultraviolet levels are higher in the southern and western regions of the US than in Alaska, it’s likely that ultraviolet radiation is at least partially responsible for the melanoma in this population.

Click here for information on how to protect your skin from UV damage

Additionally, the locations of the melanomas in men suggest outdoor sun exposure. In men, melanomas were mainly located on the upper

Consistent with the theory that ultraviolet radiation is partially responsible for the melanoma in this population, there was a miniscule percentage of acral lentiginous melanomas diagnosed among the 2151 cases in this group of non-Hispanic American Indian/Alaska

Natives.

Acral

lentiginous

melanoma often occurs on body parts not sun-exposed. This type of melanoma is thought to have an association with injury, pressure, or trauma.

limb/shoulders,

face/ears,

and

scalp/neck. Women were more likely to have melanomas on their lower limbs and hips.

This

study

suggests

that

non-Hispanic

American Indian/Alaska Native populations may need more awareness of sun-safety practices. Nearly 80% of those living on a reservation reported having a sunburn and using sunscreen infrequently.

Other troubling data complicate this new information about the melanoma rate in this population.

Fewer

dermatologists

are

available in rural, nonmetropolitan areas, and reservations, and access to specialists for skin conditions may be limited for those relying

on

the

Indian

Health

Services,

suggesting a substantial gap in medical care.

Previous

studies

have

shown

American

Indian/Alaska Native people are more likely to receive a diagnosis for a skin condition in the emergency department. Overall, we know

that

multiple

interventions

and

improved access to care are needed to reverse the burden of melanoma in this population.

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Tips for Early Detection EARLY DETECTION MEANS IDENTIFYING MELANOMA AS EARLY AS POSSIBLE, WHEN THE DISEASE IS EASIEST TO TREAT AND MOST SURVIVABLE

1

Most melanomas that appear on the skin can be seen with the naked eye. The best way to find melanoma is to examine your skin.

2

See a physician for a comprehensive skin exam before you begin self-exams so that a baseline of “normal” can be established.

From that point on, you can watch for changes.

3

Give yourself a complete head-to-toe skin examination once a month.

4

When you check your skin, note your mole patterns, freckles, and other spots. Take photos, which will help you notice changes over time.

5

Since some parts of your body, such as your back and your scalp, are difficult to see, ask your spouse, partner, or friend to help.

Melanoma can develop anywhere on the skin, but it is important to be aware that it often occurs in different places in men and women: 6

In men, melanoma is most often found on the torso, head, and neck.

In women, melanoma is most often found on the lower legs and torso.

IN PLAIN ENGLISH

HIGHLIGHTS OF NEW DIRECTIONS IN CUTANEOUS MELANOMA THERAPY—A BRIEF UPDATE ON RECENT TREATMENTS AND FUTURE DIRECTIONS

T

raditional adjuvant therapy is defined as drug treatment that follows the surgical removal of a primary melanoma and biopsy of one or a few nearby lymph node(s).

Traditional Adjuvant Therapy Traditional adjuvant therapy currently consists of treatment with one year of either immunotherapy—a single-agent intravenous PD-1 antibody—or, less often, targeted therapy—two oral medicines that block sequential steps of the overactivated biochemical pathways in melanoma cells that possess a BRAF v600 mutation.

Similar results (about a 30% absolute reduction of relapse) have been achieved with both immunotherapy and targeted therapy, but we now have treatments with two immunotherapy drugs that are more effective and not much more toxic than one (tested in patients with metastatic melanoma).

In this issue of IPE, we will highlight new studies that seek to improve the outcomes of patients with melanoma. We’ll look at information from studies in traditional adjuvant therapy, in neoadjuvant therapy, and in adjuvant therapy incorporating mRNA vaccines personalized to the patient’s tumor. We’ll also look at novel engineered drugs and what is on the horizon for treatment of metastatic melanoma.

BY KIM MARGOLIN, M.D., FACP, FASCO

These combinations consist of an antibody against the immune checkpoint called LAG-3 added to one of the PD-1 antibodies, such as nivolumab (Opdivo) or pembrolizumab (Keytruda). LAG-3 and PD-1 both inhibit T cells from doing their job of killing cancerous or infected cells, and antibodies against LAG-3 and PD-1 can help T cells to kill melanoma. The question is, which combinations work best? Several studies are ongoing to compare standard pembrolizumab with the combination of cemiplimab (Libtayo), another PD-1 antibody, so far approved for several other cancers but not yet for melanoma, and an investigational antibody against LAG-3 called fianlimab. Another study is comparing nivolumab alone with a drug called Opdualag, which is a combination of nivolumab and relatlimab (a LAGblocking antibody).

Because many of the side effects of these drugs are events that can also occur in daily life (such as fatigue, itching, diarrhea, thyroid problems), the patients and doctors are “blinded” to the treatment, which means they do not know which treatment the patient is assigned to.

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When these trials have completed, we will know whether these two classes of drug together are better than one alone and, importantly, whether they are more toxic. This form of assessing risk versus benefit is critical for any new therapy because even if a treatment proves to be more effective than another treatment, if it’s more toxic—so much so that some or many patients cannot tolerate the treatment—it’s not a “better” treatment.

Neoadjuvant Therapy Neoadjuvant therapy is drug treatment that is given before surgical removal of the cancer. Until recent years neoadjuvant therapy was limited to certain cancers and primarily given to people whose tumors were inadequately controlled with surgery alone. But neoadjuvant therapy has recently demonstrated dramatic benefits in some patients with melanoma. Such patients generally have a single large mass of melanoma, usually in lymph nodes, and show other indicators that immunotherapy or, less often, targeted therapy may work well for them. A recent randomized study compared patients receiving three cycles of pembrolizumab prior to surgical removal of their large mass of melanoma followed by 15 additional cycles of pembrolizumab versus patients whose 18 cycles of the identical treatment were all given after surgery. The group who received neoadjuvant therapy—three cycles before surgery—showed a much lower relapse rate than those who received traditional adjuvant treatment. Longer follow-up may show that neoadjuvant therapy also leads to longer lifespan for melanoma patients.

Several other neoadjuvant regimens have been tested and compared in smaller trials, and in every case, neoadjuvant therapy has shown a high level of anti-tumor activity demonstrated by a marked reduction in size of most patients’ tumors when they are finally surgically removed.

These studies have initiated a major shift in thinking about how to treat melanoma that is not about which drug or combination of drugs to give but when to give the treatment—before or after surgery, or both, but possibly for shorter durations of treatment than we use now.

But that’s not all: Similar to the above-detailed study of double versus single-agent immunotherapy in the postoperative adjuvant setting, combinations of two drugs are now being evaluated and compared with a single drug in the neoadjuvant setting in order to see if the benefits can be pushed even higher without excessive toxicity. If the two-drug regimens prove to be superior to single PD-1 blocking antibody, it will be critical to figure out (by immunologic and genetic testing) which patients benefit most and least from each regimen so that treatment can be customized, thus improving outcomes while limiting toxicity and expense as much as possible.

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Adjuvant Therapy Plus mRNA Vaccines A wide variety of cancer vaccines have been developed across tumor types, but all of these strategies have so far been disappointing in melanoma, save one: an oncolytic (cancerdestroying) viral product that delivers a mild immunostimulant into tumor cells when administered by injection directly into the tumor.

This drug, called TVEC (talimogene laherparepvec, brand name Imlygic), causes reduction of injected tumors in many patients and sometimes leads to regression of uninjected tumor masses in other parts of the body due to immune cells migrating out of the injected tumor into other sites of tumor in the body. However, the overall benefit of TVEC on lifespan is not proven, and it is likely that stronger forms of similar vaccines (termed oncolytic virotherapy) will be required.

But there is a lot of progress in studies of adjuvant therapy incorporating mRNA vaccines personalized to the patient’s tumor.

Major advances in the understanding of anti-tumor immune response, the types of antigens used, and the best strategies for maximum stimulation of killer cells have led to the possibility of making highly patient-specific and tumor-specific vaccine preparations. These vaccines are composed of the mRNA of each patient’s own tumor. Messenger RNA is the genetic material that encodes the proteins containing the tiny fragments recognized by killer cells—if tumor cells are displaying these protein fragments in a very specific pattern on their surface. The abnormal proteins contain alterations resulting from unrepaired damage to DNA from the ultraviolet rays of the sun and are unique to each patient.

Thus, the vaccine is a form of patient-specific, tumor-directed, DNA-damage-derived vaccine that has shown remarkable activity in the adjuvant treatment of surgically resected melanoma at high risk of relapse when added to pembrolizumab. A large, randomized trial is now underway to confirm the added benefit of this vaccine, called V940, plus pembrolizumab versus pembrolizumab alone. If the benefit of this V490 plus pembrolizumab is confirmed, it would become one of several standard adjuvant therapies and the first highlyactive vaccine for melanoma, a success that has eluded melanoma experts for several decades since the beginnings of cancer vaccine research.

Novel Engineered Drugs Novel engineered drugs to stimulate the immune system in melanoma have been modeled on similar products already tested and, in some cases, approved for other malignancies. Success has finally been achieved with the design of drugs with two functionalities on a single molecule—a targeting function and an activating function. These drugs are called BiTE, for “bispecific T cell engager.” The goal of such bifunctional agents is to direct a drug into a tumor using the component on one end of the molecule that attaches to something on the tumor with a tight affinity and a high specificity (not binding to other tissues or cells)—this is the targeting function. On the other end is the activating function—usually an antibody that stimulates the activity of a T cell and enhances its activity against the tumor cell. Thus, one end of the bispecific molecule provides a high killer effect, and the other end directs that killer effect specifically toward tumor cells. There is already one drug approved for uveal melanoma (melanoma arising in the eye) that works in this fashion, and several other such BiTE drugs for cutaneous melanoma are under evaluation.

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Other drugs are in testing that contain two different agents attached to each other and are able to act very specifically in the same part of the body. The functions of these molecules when delivered in this fashion are synergistic—that is, they work much more effectively when attached than if the two drugs had simply been given separately but at the same time. Examples of these structures are those that contain two different immunotherapies, like the BiTEs detailed above; drugs with a tumor-seeking component on one end and a chemotherapy drug on the other; and drugs that have a chemical “mask,” a portion that has to be cut off to be activated only when it reaches the tumor and only when acted upon by cutting proteins that are only found in the tumor.

New Directions in Treatment for Metastatic Melanoma Major advances in the treatment of metastatic melanoma have historically been difficult to achieve, and many of the breakthroughs reported in other cancers have not touched melanoma, which is almost completely resistant to traditional chemotherapies and appears to have very few targetable mutations and pathways. So when melanoma experienced the huge breakthroughs in the last decade, when multiple immunotherapies and three pairs of targeted drugs led to marked improvements in median survivals (time point at which half of the patients are still alive), there was reason to celebrate. But the celebration has tempered a bit in the last few years, because the unfortunate reality is that a substantial percentage of patients with melanoma do not benefit from either immunotherapies or targeted therapies. Further, the improvements in outcome in the last decade were primarily for patients with cutaneous melanoma and were not applicable to patients with mucosal melanoma or metastatic uveal melanoma. While modest benefit for the latter group of patients led to the FDA approval of the BiTE mentioned in the preceding paragraph, other bifunctional drugs (including ones with a chemotherapy agent attached to a tumor-targeting component) have shown greater promise in other malignancies. Nevertheless, many different bifunctional and other engineered molecules (see below for novel cytokines) are being evaluated for melanoma in studies likely to report out over the next few years.

The advances over the last several years for metastatic cutaneous melanoma have been incremental (small advances) rather than transformational (entirely new approaches)—for example, a definitive answer to the optimal sequence of types of drug for patients whose melanoma carries a BRAF mutation recently emerged from important randomized trials. When patients have advanced (Stage IV) melanoma with a BRAF mutation, they should receive immunotherapy before considering targeted therapy and switch only if it is clear that they are not benefiting from immunotherapy—also keeping in mind that sometimes it appears that tumors are growing but patients are stable or improving (pseudoprogression). Continuing immunotherapy for a while longer sometimes shows that the apparent tumor growth turns around, and switching to targeted therapy drugs is unnecessary or can be postponed (treating beyond progression).

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There are some exceptions and modifications to this rule that require careful judgment on the part of the treating oncologist—for example, occasionally patients have a large amount of rapidly growing melanoma and sometimes a lot of symptoms such as pain or mass effect. These patients are best treated initially with targeted drugs because in most patients they will shrink tumors quickly. However, it is best to switch treatment from the targeted drug regimen to an accepted immunotherapy regimen as soon as the patient’s advanced melanoma has been stabilized or reduced, rather than waiting for a relapse from targeted therapy before switching to immunotherapy.

Combining targeted therapy with immunotherapy has been difficult due to toxicities and has failed to provide the improvements in outcome—particularly to move the needle on overall survival—that were originally expected. Nevertheless, there is continuing research focused on understanding the deep biology of melanoma cells in order to come up with new combinations of existing drugs or applications of new agents that will overcome melanoma’s intrinsic resistance to most therapies. Many of these trials still include the immune checkpoint blocking antibodies (such as pembrolizumab and nivolumab) as the framework drugs and add one of the new agents under investigation.

The following are examples of some of the novel strategies and agents being explored to improve the remission rates: Interference with blood vessel development. Some drugs have been developed that interrupt the pathways by which cancer cells can promote the growth of nearby blood vessels, which result in increasing the delivery of oxygen and nutrients to the tumor cell.

Some of these drugs are antibodies and are given intravenously—they also enhance immune cell functions. Other drugs are taken orally and inhibit both blood vessel formation as well as other growth factor processes that help tumors grow. We have learned from sophisticated studies of melanoma that certain subtypes such as mucosal melanoma and acral melanoma may be responsive to drug combinations containing these blood vesselblockers. These subtypes represent rare but important unmet needs in melanoma research that need new treatment approaches.

Altering the patterns of expression of melanoma genes. If we can manipulate the genes of melanoma cells by treating with drugs that change their expression (i.e., turn on or off the production of an important protein in the cell), we may be able to inhibit melanoma growth.

Many approaches are available, some of which have already been successful in other malignancies, but as yet they have not proven effective in melanoma. However, other drugs are always under development, and the advent of permanent gene alteration using CRISPR technology is likely to reach melanoma treatment protocols before long.

Engineered cytokines and other ways to get T cells to grow and function safely and effectively. If we can get T cells to grow and function as they should (to find disease and kill it), tumors can be targeted. Engineered cytokines are one way to get T cells to grow and function as they should. Old engineered cytokines such as interleukin-2 (IL-2) and very new engineered cytokines are being used in adoptive T cell therapy, a treatment which is expected to be approved in early 2024. (Read about adoptive T cell therapy, also called TILs, in a previous issue of In Plain English.) One of the important aspects of this form of treatment is the use of IL-2, which is given for two days in high doses that can be very toxic to the patient and requires specialized expertise by the treating physicians and nurses.

Since these toxicities are quickly reversible, and the procedure is performed only once, the overall danger is felt to be low, but there remains a need to find ways to enhance and expand the antitumor T cells as much as possible. For this reason, and for many other immunotherapy strategies, there has been a resurgence of interest in IL-2 and several other cytokines. The new strategies involve testing cytokines that were not available before as well as traditional ones like IL-2 that have been chemically altered to make them safer and more effective.

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CONCLUSION While advances have occurred in the therapies of melanoma at all stages and in all manifestations, including several not covered here (such as management of brain metastases), there is still room for major improvement. The topics chosen for this episode are among the most important in today’s state-of-the-art and anticipated near-future advances and are worth keeping an eye on. Anything that turns out to be a real breakthrough will, of course, be covered in its own issue of IPE.

Dr. Margolin is a Medical Director of the SJCI Melanoma Program, St. John’s Cancer Institute. She worked at City of Hope for 30 years and also held faculty positions at the Seattle Cancer Care Alliance/University of Washington and at Stanford University.

Among her academic achievements were long-term leadership of the Cytokine Working Group, leadership involvement in the Cancer Immunotherapy Trials Network, participation in the Southwest Oncology Group’s Melanoma Committee, and many positions in the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer. Dr. Margolin has reviewed grants for many cancer-related nonprofit organizations and governmental agencies. She has also served as a member of the Oncology Drugs Advisory Committee to the FDA, the American Board of Internal Medicine’s Medical Oncology certification committee, and the Scientific Advisory Committee of the European Organization for the Research and Treatment of Cancer.

Dr. Margolin collaborates with AIM at Melanoma to write our In Plain English articles to provide timely updates on new developments for patients, caregivers, and other individuals with an interest in medical advances in melanoma.

KIM MARGOLIN, M.D., FACP, FASCO 17