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Harnessing the Immune System to Treat Melanoma

Real World Health Care continues our series on melanoma with a discussion with Howard Kaufman, MD, FACS, surgical oncologist at Rutgers Cancer Institute of New Jersey. Dr. Kaufman’s clinical and research work focuses on using the immune system to fight cancer. He also runs a scientific laboratory focusing on oncolytic viruses and had his first agent approved in 2015. He authored The Melanoma Book as a resource for patients and family members dealing with the diagnosis of melanoma and currently serves as editor-in-chief for the Journal of Immunotherapy Applications.

Directions in Research & Treatment

Real World Health Care: How can the immune system be used to treat melanoma?

Dr. Howard Kaufman, Rutgers Cancer Institute of New Jersey

Howard Kaufman: We’ve known for many years that the immune system can recognize some cancer cells, and when this happens the immune system can eradicate the cancer cell. We’ve seen this most prominently in melanoma, where a small percentage of patients with advanced melanoma don’t even know they have the disease because their immune system eradicates it without treatment.

About two decades ago, interleukin-2 (IL-2) was approved to treat melanoma. IL-2 is a natural part of the immune system. It’s a messenger protein called a cytokine, which activates part of the immune system. IL-2 doesn’t kill tumor cells directly like chemotherapy. Instead, it activates and stimulates the growth of immune cells: T-cells and Natural Killer Cells, both of which are capable of destroying cancer cells directly.

I trained under IL-2’s developer, Dr. Steven Rosenberg, at the National Cancer Institute, and was one of the first oncologists in the country to start treating patients with the therapy. It worked well, and it even cured some patients. But only about 15-20 percent of patients responded, and the research community began to ask why more patients didn’t respond.

We subsequently found that melanoma cells express a protein, called PDL-1, that shuts off the T-cells in the immune system (by binding to PD-1, which is expressed by the T-cells) so the cancer can grow. Over the last five years or so, antibodies have been developed to block PDL-1 immune inhibitory receptors. We started to see dramatic results in patients, similar to that of IL-2. Even though large numbers of patients are not responding, when responses do occur, they are sometimes complete and often long-term.

Now, other researchers and I are starting to use oncolytic viruses, which are injected directly into tumor cells. The viruses replicate in cancer cells, but not in normal cells. This replication generates an immune response in the cancer cells and overcomes the immune inhibitory receptors. We’ve seen benefit of this therapy in clinical trials for about 25 percent of patients. Even for patients with metastatic melanoma, if the virus is injected in a melanoma cell in the arm or the leg, it will eradicate melanoma in the lung as well.

Our next step in terms of research is to look at putting immunotherapy together with oncolytic virus therapy to see if we can increase response rates among more patients.

Immunotherapy Challenges

RWHC: What are some of the biggest challenges in using immunotherapy to treat melanoma patients?

HK: Like every drug, there are side effects, but not the type of side effects typically associated with chemotherapy or radiation therapy. These side effects relate to over-active immune response. Typical side effects include inflammation of the colon, liver or even lungs. These side effects are manageable, if treated quickly with corticosteroids. Unfortunately, if they’re not treated quickly, immunotherapy needs to be stopped. I’m a member of the Society for Immunotherapy of Cancer (SITC), which is working with the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) to develop guidelines to teach the clinical community how to best recognize and treat side effects due to immunotherapy drugs.

Another challenge facing the clinical community is how long to treat patients with these newer drugs. There’s not a lot of consensus on whether treatments should last one year, or two years, or if therapies should be stopped as soon as the patient responds to avoid the risk of side effects. It’s possible that some patients are being over-treated. Ideally, we will be able to find biomarkers that indicate whether a patient will be cured or will need more treatment.

Melanoma is an interesting field. Ten years ago there were very few treatment options, and today we have many. We’re just beginning to understand how to sequence therapies so patients get the right treatment at the right time. We also need better therapies for patients with mucosal melanoma and ocular melanoma, because they don’t respond as well to immunotherapy.

Promise of Combination Therapies

RWHC: What are some of the most promising combination therapies on the horizon to treat melanoma patients?

HK: Right now, I’m excited about combining oncolytic viruses with anti-PD-1 and anti-PDL-1 agents. We’re seeing high response rates in clinical studies, without the increase in side effects common with other combinations. Other than a mild fever, chills and injection site reactions, the viruses have been very safe. This could be a powerful way to increase the number of patients who respond and cut down on side effects.

RWHC: How did you get interested in melanoma?

HK: I did a fellowship at the National Cancer Institute and became interested in how patients’ immune systems responded to IL-2. Melanoma seemed to be the most sensitive to immune system manipulation, and I’ve been honored to help develop what is today considered the paradigm in cancer care. During my fellowship, I became comfortable working with melanoma patients and was fortunate to build my practice quickly.

Melanoma knows no boundaries. It can affect people of all ages; I have personally treated patients as young as 5 years of age and up to 98 years of age. It’s such an evil type of cancer and it can spread anywhere. Offering hope to patients has been very rewarding, and I’ve enjoyed the opportunity to get students and residents interested in treating the disease and studying immunotherapies.

Profiling Melanoma to Predict Immune Therapy Success

May is Melanoma awareness month, and our series on melanoma continues with a discussion with Dr. Douglas B. Johnson of the Vanderbilt-Ingram Cancer Center. Dr. Johnson leads Vanderbilt’s melanoma clinical and research program, overseeing clinical trials, patient care and translational research. His research interests focus on developing new immune and targeted therapies for melanoma, and in using existing treatments in the most effective ways. Specifically, he is exploring ways to profile cancers to predict which patients will benefit from immune therapies.

Combination and Targeted Therapies Allow Long-Term Survival

Real World Health Care: You published a review of therapeutic advances and treatment options in metastatic melanoma. Can you summarize the review and discuss its implications for patients with the disease?

Dr. Douglas Johnson, Vanderbilt-Ingram Cancer Center

Douglas Johnson: Treatment options for advanced melanoma have been rapidly advancing. We now have multiple options for patients with this disease, when even 5-10 years ago very few existed. Immune therapies, which unleash the immune system against the cancer, result in long-lasting responses in a large fraction of patients. The number of patients who benefit from treatment increases when two immune therapy treatments are combined, although at the cost of increased side effects. Targeted therapies, which block the effects of particular genetic mutations, have also made a big difference, particularly for patients who have mutations in the gene BRAF, which represents about half of melanoma patients. These treatments have transformed a disease which was essentially uniformly fatal to one that is often associated with long-term survival.

RWHC: Are you currently working on any new studies or trials relating to melanoma?

DJ: We have a number of combination immunotherapy trials. These types of trials are attempting to use strategies that extend the benefits of immune therapy to more patients. We are also working on developing biomarkers for immune therapy responses. In particular, we are evaluating whether the number and types of mutations in melanoma, as well as the expression of particular immune proteins, can predict which patients will respond to immune therapy. We also are studying the side effects and toxicities of immune therapy, to understand why they occur, who is affected, and develop effective prevention and treatment strategies.

Melanoma Research and Treatment 

RWHC: What do you see as the most promising treatments on the horizon for melanoma?

DJ: A number of promising immune therapy combinations are being developed. It is very difficult to say which is the most promising, but likely some combination of anti-PD-1 therapy with other immune or targeted therapy agents.

RWHC: What are the biggest challenges facing melanoma researchers?

DJ: One of the biggest challenges is predicting who will respond to current immune and/or targeted therapies so we can assign the right treatment to the right patient. Researchers also are challenged to develop the most effective combination therapies and to prevent and manage toxicities. In some ways, the development of effective therapies has made it more difficult to enroll patients in clinical trials. This is a good problem to have, but it limits the speed of developing new effective therapies.

RWHC: What are the biggest challenges facing clinicians treating patients with melanoma?

DJ: From a clinical standpoint, the challenges are similar. Despite the current advances, there is still a large subset of patients who do not respond well to treatments. We need to understand who those patients are upfront, and develop more effective treatment strategies for them.

Toxicities are also a major consideration, particularly for patients with other medical problems or who have limited functional status. It is always a difficult balancing act deciding between single agent and combination immune therapy. On one side is the potential for a somewhat higher response rate, on the other side is the significant increase in side effects (which are typically manageable). Every clinician and patient has a different threshold regarding when to offer these therapies.

Improving the Lives of Melanoma Patients

RWHC: What initially interested you in studying and treating melanoma? What continues to inspire you?

DJ: I had a friend during my medical training who developed stage III melanoma and I was struck by the lack of treatment options at the time. When I joined Vanderbilt, my mentor Dr. Jeff Sosman was doing amazing research, and I become very excited about the prospect of doing groundbreaking research that would affect patient lives. That approach continues to drive and inspire me.

Accelerating Melanoma Research

It’s Melanoma Awareness Month and this week, Real World Health Care is pleased to shine a light on The Society for Melanoma Research. We spoke with the Society’s President, Keith Flaherty, MD. In addition to his role with SMR, Dr. Flaherty serves as director of the Henri & Belinda Termeer Center for Targeted Therapy and the Richard Saltonstall Chair in Oncology at the Massachusetts General Hospital Cancer Center.

Supporting a Diverse Melanoma Research Community

Real World Health Care: Please describe the mission of the Society for Melanoma Research.

Dr. Keith Flaherty, Society for Melanoma Research

Keith Flaherty: The Society for Melanoma Research was intended to be a scientific home for the melanoma research community. When it was created in 2003, there was no organization run by and for melanoma scientists that convened regular scientific meetings to provide a venue for publication of melanoma research. Our research community is quite diverse, spanning many medical specialties and numerous scientific disciplines. Simply bridging the divide between the clinical research community and laboratory-based investigators was central to the SMR mission.

RWHC: What type of research programs do you support and how do you support them?

KF: Our primary supporting role is served by organizing and hosting an annual, international, scientific conference focused on melanoma research. We support travel to the meeting for trainees and young scientists. Plus, we maintain a web-based presence and newsletter to update our members on emerging discoveries. Additionally, we partnered with the International Federation of Pigment Cell Societies to transform a pre-existing Journal (Pigment Cell Research) into Pigment Cell and Melanoma Research in order to have a peer-reviewed journal supported by SMR with scientific leadership by melanoma researchers.

Combination Therapy Research

RWHC: Are there any studies your members are involved in that are particularly promising at this moment?

KF: As ours is the only international scientific society focused on melanoma research, our membership includes all of the clinical investigators from the major academic centers who have been conducting groundbreaking clinical trials in melanoma over the past eight years. Outcomes for patients with metastatic melanoma have been transformed by the development of molecularly targeted and immunotherapies. The most promising current trials have been investigating combinations of these two approaches at the same time. Preliminary results presented at the 2016 SMR Congress suggest that these combination approaches may further improve outcome significantly.

Multidisciplinary Collaboration

RWHC: Why are multidisciplinary collaborations so important in developing new therapies for melanoma? How is the SMR working to encourage or create such collaborations?

KF: Multidisciplinary collaborations can be defined by teams of clinical investigators, such as medical oncologists, surgical oncologists, pathologist, and radiologists. Or, they can encompass clinical and laboratory-based investigators partnering together. We have numerous examples of each kind within and across the major academic medical centers with a focus on melanoma research.

For years, the melanoma research community was characterized by empiric clinical trials in which therapies that had been successful in other cancer types were tried in melanoma, but with little scientific basis and focus on understanding whether those therapies were doing their molecular “job” or not. Since the late 2000s, the emergence of BRAF, MEK, CTLA-4 and PD-1 inhibitors has provided not only substantial benefit to patients, but it has transformed the research approach by bringing clinical and laboratory-based scientists together. Even for these FDA approved therapies, there remain questions regarding mechanisms of action and resistance which are critical to informing rational combination therapies that will be the focus of the next generation of clinical trials. This approach literally taught us how to define the limits of these partially effective therapies and will hopefully accelerate our pace of progress.

More Funding, More Time

RWHC: What are the biggest challenges melanoma researchers face today and how can they be overcome?

KF: Funding and time. For a decade, we have seen a decline in publicly funded research. The U.S. has always been the largest investor in biomedical research, and pairing that down has had global impact. New discoveries are made through publicly funded research before private sector research comes in to take those discoveries and reduce them to practice. This has made the melanoma research field increasingly dependent on philanthropic foundations and individuals.

Additionally, clinical researchers are constantly pulled between clinical duties and research activities. Many medical centers cannot afford to have their clinicians spending time on research. Therefore, research funding is needed to cover the portion of their time that is away from direct patient care. With the accelerated pace of technology development relevant to biomedical research and the inroads that we have made in the past eight years with regard to therapeutic approaches, there is more opportunity now than ever to accelerate the application of science to medicine for melanoma patients. But, these rate limiting factors are unquestionably slowing us down.

Industry’s Role

RWHC: What role do you think the biopharmaceutical industry should play in furthering research into new melanoma therapies?

KF: As always, advancing diagnostic and therapeutic approaches to widespread use requires risk-taking and investment by the biopharmaceutical industry.

In the cancer field overall and melanoma specifically, we have seen tighter integration between the public and private sectors that has come as a consequence of the initial successes with the now FDA-approved drugs. This has drawn in more interest from companies developing novel diagnostic technology that may allow us not only to find localized, advanced melanoma at an earlier point, but also allow us to deploy the optimal therapy for each patient in a personalized way. And, of course, the very costly process of drug development requires involvement of the biopharmaceutical industry from beginning to end.

Through close collaboration with the academic scientific community, we are able to discern very early in development whether a new therapy is accomplishing its biological task before investing massive additional resources in large-scale clinical trials to prove whether or not it has a clinical impact.

Dramatic Unmet Need

RWHC: What initially attracted you to the field of melanoma research?

KF: I was attracted to the melanoma field first and foremost by the dramatic unmet need. It is a cancer that has an awe-inspiring ability to metastasize from tiny primary tumors, making the challenge of early detection a key hurdle. And, when melanoma metastasizes, it is one of the most aggressive cancer types. Melanoma affects a far greater proportion of young adults than other more common cancers, making it one of the leading cancers with regard to aggregate years of life lost. At the time that I was entering the field, it seemed that the pace with which biologic insights into melanoma were being made was increasing. And, right at the end of my training, BRAF mutations were discovered and that drew my focus for all of the years since.

A MESSAGE FROM OUR SPONSOR:

The HealthWell Foundation, sponsor of Real World Health Care, is proud to have supported the melanoma patient community in recent years with copayment and premium assistance. We have helped more than 2,230 melanoma patients afford their treatments since approving our first Melanoma grant in 2011 — thanks to the generous support of our corporate partners. Due to high patient volume, our melanoma fund is temporarily closed until we receive additional funding. We invite corporations and individuals to help us meet this demand by contributing to our Melanoma-Medicare Access Fund, so nobody goes without essential medications because they cannot afford them.

Categories: General, Melanoma

Skin Cancer Awareness and Prevention Efforts in Focus at American Academy of Dermatology

This week, Real World Health Care continues our recognition of May’s Melanoma and Skin Cancer Awareness Month by highlighting the work of the American Academy of Dermatology. We spoke with the AAD’s new President, Henry W. Lim, MD, about the organization’s mission and some of the challenges and opportunities associated with preventing and treating melanoma and other skin diseases.

Real World Health Care: Please tell our readers about the overall mission of the American Academy of Dermatology.

Henry W. Lim, MD, American Academy of Dermatology

Henry Lim: The American Academy of Dermatology promotes leadership in dermatology and excellence in patient care through education, research and advocacy.

As the largest, most influential and representative dermatology group in the United States, and the largest such organization in the world, the AAD works to make sure its values reflect this mission. The AAD’s values include putting patients first, encouraging its members to adhere to an uncompromising code of clinical and ethical standards, fostering an interest in our members to pursue lifelong learning, encouraging collaboration and working within our communities and embracing diversity.

Public Education: Sun Safety

RWHC: How does the AAD’s mission address melanoma?

HL: It is estimated that 161,790 new cases of melanoma will be diagnosed in the U.S. in 2017.  That is a staggering number that could be reduced if people incorporated skin cancer detection and prevention behaviors into their lives.

The AAD works to increase public awareness of skin cancer and its risks through its SPOT Skin Cancer campaign, which is designed to create a world without skin cancer through public awareness, community outreach programs and services, and advocacy that promote the prevention, detection and care of skin cancer.

The first step toward a world without skin cancer is educating the public about prevention. The Academy has long communicated sun-safety messages to the public about the importance of skin cancer prevention and detection.

In addition, dermatologists have led the medical community in finding and treating skin cancer. For more than 30 years, dermatologists across the country have hosted 2.5 million free SPOTme® skin cancer screenings that have detected 28,822 suspected melanomas and 256,329 suspected skin cancer lesions.

To assist the public with learning more about skin cancer prevention and detection, the AAD offers a variety of free, online videos, downloadable handouts and skin self-exam resources, including a body mole map, as well directories to find a dermatologist and skin cancer screenings.

Melanoma & Skin Cancer Awareness

RWHC: What is the AAD doing in 2017 to recognize Skin Cancer Awareness Month?

HL: The AAD’s 2017 SPOT Skin Cancer campaign, Check Your Partner. Check Yourself, encourages the public to be aware of changes on their skin that could be signs of skin cancer. Research has shown that women are more likely to detect suspicious spots on others.  Men over the age of 50 have a higher risk of developing melanoma, than the general population, so the campaign encourages women – often the health care decision makers of a household – to check their partner’s skin regularly, check their own skin, and to visit the AAD’s SpotSkinCancer website to find a free SPOTme® screening in their area.

RWHC: Do you have additional initiatives you’d like to highlight?

HL: In addition to the activities for Skin Cancer Awareness Month in May and the SpotSkinCancer™ website, the AAD works with state dermatology societies and state legislatures to introduce and support laws and regulations that protect consumers and promote awareness about skin cancer prevention and the dangers of indoor tanning. As a result, 42 states have enacted tanning bed restrictions to potentially reduce the risk of melanoma and other forms of skin cancer.

The AAD’s Shade Structure Program awards shade structure grants to schools and non-profit organizations across the country in order to protect children and adolescents from the sun’s harmful rays.  Since its launch in 2000, the AAD’s Shade Structure Program has awarded 350 shade structure grants, which provide shade for more than 600,000 individuals each day.

The AAD also has a strategic social media presence on Facebook, Twitter, YouTube and Pinterest, designed to raise awareness about skin cancer detection and prevention.  Social media, including paid, promoted posts, reach our targeted audiences – the public, our members and the media – with links to AAD resources.  We encourage our followers to like, share and re-tweet our skin cancer awareness videos and tips.

Melanoma Research

RWHC: Does the AAD underwrite or otherwise support research into melanoma detection and/or treatment?

HL: While AAD is not a research funding organization, the AAD does provide annual awards for Young Investigators in Dermatology.  These awards recognize outstanding basic and clinical/translational research by young dermatology investigators and some of the projects are related to melanoma.

The purpose of the award is to acknowledge research contributions by individuals at the start of promising research careers that further the improvement of diagnosis and therapeutics in the practice and science of dermatology.

RWHC: What do you see as the biggest challenges facing researchers studying melanoma treatments and clinicians treating melanoma?

HL: The rapidly changing health care environment presents major challenges to researchers and clinicians in all aspects of dermatologic care, not just those studying and treating melanoma. 

A significant challenge is the inadequate funding for research, together with the pressure to increase clinical revenue generated by clinician researchers.  For many years, the American Academy of Dermatology Association (AADA) has been active in advocating increased research funding by NIH to dermatology research, including through our support of the 21st Century Cures Act.

The current health care system also presents barriers that impede patient access to the best possible care from a qualified physician.  To combat this, the AADA is working with all dermatology care providers and other physicians to confront these challenges.

In particular, the AAD recently launched a new specialty positioning campaign, SkinSerious, to raise awareness of the serious impact of skin disease. Our goal is also to improve access to dermatologists’ expertise and increase collaboration with our physician peers to ensure high-quality patient care. We know that when dermatologists work with other physicians as part of the health care team, everyone can benefit from improved patient outcomes and lowered health care costs.

Other concerns within the health care environment that the AADA is closely monitoring include the rise of big data and the growth of teledermatology.  We closely follow developments at the federal and state levels and, when appropriate, the AADA will take action on issues that can be influenced positively for dermatology and pursue opportunities to impact health care policy. 

Promising Melanoma Treatments

RWHC: What do you see as the most promising or breakthrough melanoma treatments on the horizon?

HL: This is an exciting era in melanoma research.  In-depth understanding of the molecular pathways of melanoma development has led to the availability of immune checkpoint inhibitors; combinations of these medications are being looked at in clinical trials.  Metabolic manipulation of the peri-tumoral environment to inhibit the growth of melanoma is being actively investigated.  Understanding of the genes responsible for melanoma resulted in the availability of gene expression profile (GEP) test that can be used to determine biologic behavior of melanoma.

Melanoma Prevention

RWHC: What are the biggest challenges facing the medical community in terms of increasing awareness of and adherence to melanoma prevention efforts among the general public?

HL: The challenges facing the medical community around melanoma prevention are two-fold.

One is the misconception that a tan is a sign of health.  Tanning is a protective physiologic response of our skin to damage caused by ultraviolet radiation.  There is no such thing as a healthy tan, yet people continue to seek the sun or use indoor tanning, thereby increasing their risk of skin cancer.  This is a particularly challenging message to get across to young women and men, who feel peer and societal pressure to be tan.

The AADA was instrumental, along with several other organizations, in having the FDA re-classify tanning lamps from the Class I to Class II medical device category, which requires more supervision and restriction in their purchase and use.  For the past several years, the AAD has released a new public service advertisement that focuses on the dangers of tanning, particularly targeting young women.  We know that melanoma is the second most common cancer in young women, and this may be due in part to their tanning habits.

The 2016/2017 public service advertisement is called “Arms,” and features two young women comparing their tans at various stages in their lives. The emotional ad concludes with the two friends clasping hands in the hospital as one of them reveals she has advanced stage melanoma.  This PSA, and our previous ones, have resonated strongly with young women, especially on social media, where they have liked and shared the video with their friends.

The second challenging misconception is that many people believe that sun exposure is the best source of vitamin D.

While our bodies need vitamin D to build and maintain strong, healthy bodies, the AAD does not recommend getting vitamin D from sun exposure or indoor tanning because of the increased risk of skin cancer.  In fact, it has been demonstrated that sun exposure that results in increased vitamin D levels is directly correlated with DNA damage.

Vitamin D from food and dietary supplements offers the same benefits — without the danger of skin cancer — as vitamin D obtained from UV light.  Vitamin D cannot be used by the body until it is processed by the liver and the kidneys. The usable form of vitamin D created by this process is the same, regardless of how it enters the body.

The AAD recommends dietary sources (foods naturally rich in vitamin D, fortified foods and beverages) and vitamin supplements as sources of vitamin D that are available year-round and can easily be incorporated into a healthy lifestyle. Good sources include fortified milk, cheeses and yogurt, fortified cereal, and oily fish like salmon and tuna. Research shows that vitamin D supplements are well tolerated, safe, and effective when taken as directed by a physician.

The fact is these myths are harmful because the consequences of this misinformation could be potentially fatal.

RWHC: What personally inspires you to build awareness of the importance of preventing melanoma?

HL: Having been in dermatology practice for 40 years, I see on a regular basis the devastating effects that melanoma has on patients and their family.  The risk of developing melanoma can be significantly decreased by sensible photoprotection, and avoidance of tanning beds.  The exciting new developments in the treatment and genetic profiling of melanoma reflect the value of investment in scientists and research projects, and I look forward to additional treatments in the future that will benefit patients.

A MESSAGE FROM OUR SPONSOR:

The HealthWell Foundation, sponsor of Real World Health Care, is proud to have supported the melanoma patient community in recent years with copayment and premium assistance. We have helped more than 2,230 melanoma patients afford their treatments since approving our first Melanoma grant in 2011 — thanks to the generous support of our corporate partners. Due to high patient volume, our melanoma fund is temporarily closed until we receive additional funding. We invite corporations and individuals to help us meet this demand by contributing to our Melanoma-Medicare Access Fund, so nobody goes without essential medications because they cannot afford them.

 

Categories: General, Melanoma

The Mechanics of Melanoma

May is Melanoma Awareness Month. This article originally appeared in the Biotech Primer WEEKLY. For more on the science behind the headlines, subscribe. 

Melanoma 101 

Emily Burke, BiotechPrimer.com

Melanoma accounts for less than one percent of skin cancer cases, yet accounts for the vast majority of skin cancer deaths (skincancer.org). If detected early enough, melanoma is almost always curable. If it is not detected early, it is likely to spread to other parts of the body, where it is more difficult to treat. It’s estimated that in 2017, there will be 87,110 new cases of melanoma in the U.S., and 9,730 melanoma-related deaths (Aim at Melanoma Foundation). Melanoma is one of the types of cancers most common in young adults, with 25 percent of new cases occurring in people under age 45. Its prevalence is growing – the number of new cases/year relative to the total population has doubled since 1973.

In this column, we’ll review the basics of melanoma, and discuss the latest new therapies recently approved and in development.

Melanoma’s Method

Melanoma is the uncontrolled growth of the pigment-producing cells known as melanocytes, which are located in the bottom layer of the skin’s top layer (the epidermis). Like other types of cancers, melanoma arises from gene mutations in these cells that impact cell growth and division. In the case of melanoma and other skin cancers, the DNA damage is usually caused by ultraviolet (UV) radiation, resulting in a tumor that initially grows in the skin, spreading along the epidermis. If the melanoma is detected at this stage, it can often be surgically removed. If the out of control cell growth is not caught in these early stages, it penetrates deeper layers of the skin, eventually coming into contact with lymph and blood vessels which enable it to spread to other parts of the body. When the melanoma reaches this stage, it is called metastatic melanoma.

Although anyone can get melanoma, fair-skinned people are at higher risk for all types of skin cancer, since increased skin pigmentation helps to block the damaging UV rays from penetrating and damaging skin cell DNA. However, darker-skinned people can and do get skin cancer, and thus should also be vigilant about sun protection.

Atypical moles have also been linked to an increased risk of melanoma. Moles are clusters of melanocytes, and there is a slightly increased risk of melanoma arising within these clusters. Of course, most moles are harmless and do not lead to melanoma. However, any sudden changes in the color, shape, or size of a mole should be evaluated by a doctor.

Genetic Factors: p53 & BRAF 

Although most cases of all types of skin cancer are traceable to excessive sun exposure, about 10% are likely due to genetic factors. The gene most commonly mutated in familial melanoma is p53. p53 is a “tumor suppressor,” which means that it detects DNA damage in cells, and triggers either DNA repair pathways or activates cell death if the DNA damage cannot be repaired. Another gene, known as the BRAF gene, regulates cell growth and is mutated in inherited forms of melanoma. About half of all genetically-based melanomas have the BRAF mutation.

Let’s take a closer look at BRAF. BRAF codes for a protein required for the transmission of a growth signal from a cell surface receptor to the cell nucleus (growth signal transduction). Growth signaling is initiated by a growth factor binding to its receptor. This binding transmits a signal through the membrane, causing the internal portion of the receptor to interact with and activate a protein inside of the cell. This activation is then transferred to the next protein in the pathway, and so on until the signal reaches the last protein in the pathway. When this protein is activated, it enters the nucleus, where it turns on specific genes that make proteins which initiate cell division. BRAF is one of the proteins in this pathway. In BRAF-associated melanoma, the mutated BRAF is always turned on even when no growth factor is present.

Small molecule drugs that inhibit overactive BRAF have been developed and approved for the treatment of late-stage melanoma.

Immunotherapies in the Fight 

A few different checkpoint inhibitor therapies have been approved to treat metastatic melanoma. These are drugs that enable killer T-cells – immune system cells that recognize and kill threats such as cancer cells – to become fully active against a tumor cell target. These drugs target inhibitory proteins on the surface of T-cells such us CTLA-4 and PD-1. These proteins act as “off switches” for killer T-cells. By inhibiting these off switches, the killer T-cells become fully activated, and able to target and kill melanoma cells.

A second type of immunotherapy that has been approved for melanoma is an oncolytic virus therapy. An oncolytic virus is a virus that infects and kills cancer cells. The cancer cells are killed through cell lysis – as the virus multiplies inside of the cells, it causes them to burst open. This in turn releases new infectious particles that can target remaining tumor cells. In addition to direct killing of cancer cells via lysis, the presence of an actively replicating virus helps to activate the patient’s immune response to target the area.

In the Pipeline 

A new type of immunotherapy drug is in Phase 3 clinical development. The drug is a small molecule inhibitor of the enzyme IDO1. IDO1 helps regulatory T-cells to develop and become activated. Regulatory T-cells suppress the immune response, and therefore help cancer cells to escape immune surveillance. Inhibiting IDO1 should suppress the development of regulatory T-cells, bolstering the immune response against melanoma.

Implications of microRNA 

Last year, researchers at Tel Aviv University published a report describing how melanoma metastasizes. Their work suggests that melanoma cells release tiny vesicles that contain microRNA, a type of regulatory RNA produced by all cells. These micro-RNA filled vesicles induce changes in the dermis – the layer of skin just below the epidermis where the melanoma begins. The dermis contains blood vessels, and thus a pathway for metastasis. The changes in the dermis induced by the small vesicles released from the melanoma cells makes the cancer cells able to access those blood vessels. The Tel Aviv team is identifying drug candidates that may interfere with this process, preventing the metastasis that makes melanoma so deadly.

The best strategy for melanoma remains prevention and proactive monitoring – limiting sun exposure and monitoring the skin for any unusual growths or changes in moles. Increased understanding of the molecular pathways that contribute to melanoma’s development and spread will provide physicians with additional tools to fight those cases of metastatic melanoma that inevitably will continue to arise.

Categories: General, Melanoma

New Real World Health Care Series: Melanoma Research and Treatment

“Have you heard from mom and dad recently?” My sister’s question caught me off-guard.  Without realizing it, I hadn’t actually heard from my parents in a while.  She had already asked my brother the same question and he reported not hearing from them lately either.  With no imminent trips back to Michigan from our respective homes in Colorado, Maryland, and North Carolina, all three of us started calling and emailing our parents with some urgency to make sure things were well.

Krista Zodet, President, HealthWell Foundation

My mom’s email came back quickly, bringing us up to speed: “Dad went to the dermatologist about a troublesome spot on his cheek and the doctor did a full body check too.  He found a spot on the back of his thigh and did a biopsy.  Diagnosis: melanoma.  Treatment: surgery.” They removed a patch of skin from my dad’s leg – an area he couldn’t see and for the most part was covered by shorts or pants year-round.  It had been malignant and they got all of it.

That was early 2001, and my dad had just retired (talk about timing).  Because of early detection and annual check-ups since, he has been melanoma-free for 16 years.  We learned a lot about melanoma back then: It is the most dangerous form of skin cancer; and we also understand – thankfully – if it is recognized and treated early, it is almost always curable.

May is Melanoma Awareness Month

Since HealthWell opened its melanoma fund, I have learned even more about this devastating disease: Without early detection, the cancer can advance and spread to other parts of the body, where it becomes hard to treat and can be fatal. According to the Skin Cancer Foundation, melanoma kills an estimated 10,130 people in the U.S. annually.

Treatment typically begins by surgically removing the melanoma. Surgical treatments have advanced over the past decade, and most can be done in the doctor’s office or as an outpatient procedure under local anesthesia. In recent years, Mohs Micrographic Surgery has become popular as an alternative to standard surgery for certain melanomas. This procedure spares as much of the normal tissue (known as the margins) as possible while allowing the surgeon to pinpoint the cancer’s location when it is invisible to the naked eye.

When melanoma cells spread to the lymph nodes (stage III) or more distant parts of the body (stage IV), the disease is considered advanced and additional therapy usually follows surgical removal of the original skin tumor. Thanks to an array of treatment options, patients with metastatic melanoma can extend their lives by months or years. A rising number of patients go into long-term remission.

The HealthWell Foundation, sponsor of Real World Health Care, is proud to have supported the melanoma patient community in recent years with copayment and premium assistance. We have helped more than 2,230 melanoma patients afford their treatments since approving our first Melanoma grant in 2011 — thanks to the generous support of our corporate partners. Due to high patient volume, our melanoma fund is temporarily closed until we receive additional funding. We invite corporations and individuals to help us meet this demand by contributing to our Melanoma-Medicare Access Fund, so nobody goes without essential medications because they cannot afford them.

 

 

Categories: General, Melanoma

UV Safety Month: Shedding Light on Melanoma Treatment and Prevention

In 2014, an approximate 77,000 Americans will be diagnosed with melanoma, culminating in nearly 10,000 deaths. Every eight minutes, an American is diagnosed with melanoma, and every hour, an American dies from it. Despite accounting for only four percent of all skin cancer cases, melanoma results in 80 percent of all skin cancer-related deaths. In observance of UV Safety Month, Real World Health Care is examining what’s working and what’s new in the prevention and treatment of melanoma.

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Nathan Sheon

If detected early, melanoma is easily treated with surgery. If a tumor in the epidermis – the upper-most layer of skin – is removed before it deepens into the skin or spreads to other parts of the body, the likelihood of completely curing melanoma is high. When melanoma spreads, other treatment options include chemo- and radiation therapy.

Once melanoma has progressed to its later stages, however, treatment of the disease becomes much more difficult. For these patients, treatment options usually focus on extending life expectancy and improving quality of life.

Within the last few years, developments in melanoma research have provided promising leads on how to increase a patient’s lifespan beyond the capabilities of existing treatments. Certain activation immunotherapies – drugs that activate the immune system’s ability to fight disease – are showing potential in their ability to combat the spread of melanoma by killing tumors. Though these treatments do not work in all melanoma patients, in some cases they have been associated with unprecedented increases in lifespan.

“All of these trials involve late stage cancer patients. Suddenly we’re seeing those same patients getting two years or more survival time,” said Ashani Weeraratna of the Wistar Institute, the nation’s first independent institution devoted to medical research and training. “Enhancing the immune system such that it can effectively target and destroy your tumor has been a goal for many years. That’s [the field’s] big advance.”

Melanoma is almost always curable when detected and treated early on. Monthly self-examinations and yearly visits to the dermatologist are highly advised, even for those not predisposed to skin cancers. More information on how to perform a self-examination can be found online in guides from the Skin Cancer Foundation and the Melanoma Research Foundation.

Among other important measures like self-examinations and avoiding tanning booths, the American Academy of Dermatology (AAD) advises that wearing sunscreen when spending time outdoors is vital, especially during peak daylight hours between 10 AM to 2 PM. The AAD suggests using sunscreen with a sun protection factor (SPF) of 30 or above. With a range of sunscreen products on the market, choosing the right one can be difficult. Different products are more effective for different people depending on skin type. Visit the Skin Cancer Foundation’s guide for more information on choosing the right sunscreen product for you. For more information and tips on preventing and detecting melanoma, visit the AAD’s online guide.

How do you stay safe in the sun? Let us know in the comments section.

*Jamie Elizabeth Rosen, editor of Real World Health Care, contributed to this piece.

Companion Diagnostics Target Therapy to the Patients Most Likely to Respond

What cancer patient would want to use trial and error with various chemotherapies when he or she could know first from a diagnostic that one agent in particular would result in the most successful outcome?

David Sheon

David Sheon

A new field has emerged, companion diagnostics, to help predict a patient’s compatibility with chemotherapy or other cancer treatments.  This is a game changer to help ensure drugs are given only to the patients most likely to respond to them. 

According to the Food and Drug Administration (FDA), companion diagnostics already play an important role in determining which therapies are the safest and most effective for a particular patient.  By identifying treatments that work best for specific patients, less money is spent on those that do not work because patients no longer have to endure multiple treatments to find the one that is right for their case. Companion diagnostics, usually created in combination with targeted therapy, not only reduce cost and waste, but also reduce side effects for the patient.

Over the past several years, the FDA has approved the following five companion diagnostics: 

  • Zelboraf and the Cobas Test: The drug Zelboraf specifically treats the melanoma of patients whose tumors express a gene mutation called BRAF V600E. Alberto Gutierrez, Ph.D., Director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health, said that approval “is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner.”
  • Vysis ALK Break Apart FISH Probe Kit: Developed along with the targeted therapy drug Xalkori for patients with late stage, non-small lung cancer who express the abnormal anaplatic lymphoma kinase gene. The test determines if a patient possesses that gene to ensure that the correct treatment is applied.
  • therascreen KRAS RGQ PCR Kit: For those with colorectal cancer who are determining whether the drug Erbitux is right for them. This provides information about the KRAS gene mutation in patients whose colorectal cancer has spread to other parts of the body. If the test shows that the patient does not have the gene mutation, this demonstrates that Erbitux is the correct choice, but not the right one for those with the gene mutation.
  • EGFR Mutation Test: Administered in conjunction with the targeted therapy drug Tarceva, which detects the epidermal growth factor receptor gene mutation in patients with lung cancer. If the patient has the genetic mutation that Tarveca targets, then they are “candidates for receiving Tarceva as first line therapy,” Dr. Gutierrez says. Because this gene is present in approximately 10 percent of patients who have non-small lung cancer, it would go far to help improve the treatment and success rate among these patients.
  • THxID BRAF: Approved alongside two drugs (Tafinlar and Mekinist) – which treat the most dangerous type of skin cancer – this detects the BRAF V600E or V600K gene mutations associated with the disease. If the tumor of the patient contains either of these genes, both drugs are effective. 

Have you – or someone you know – ever been treated with one or more companion diagnostics? What was the experience like and would you recommend it for someone else?

Categories: Cost-Savings