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The Multiple Myeloma Landscape

Editor’s Note: This article originally appeared in Biotech Primer Weekly. For more of the science behind the headlines, please subscribe.

Emily Burke, BiotechPrimer.com

Multiple myeloma is a cancer formed by a type of white blood cell called a plasma cell. These cells are the antibody-producing cells of our immune system and play a critical role in our defense against infections. If they begin to grow and divide in an uncontrolled manner, however, they form a plasmacytoma – a mass of cells within the bone marrow that no longer function in our defense but instead simply take up space and interfere with the functions of healthy cells. Instead of producing normal disease-fighting antibodies, plasmacytoma cells produce abnormal antibodies called M proteins, which don’t provide any benefit to the body and crowd out normally functioning antibodies.

Easily Confused: Plasma Cells vs Blood Plasma

Plasma cells are specialized white blood cells that produce infection-fighting antibody proteins. Most plasma cells are found in the bone marrow. Blood plasma is the straw-colored liquid component of blood that holds blood cells in suspension, made up of water (95%), proteins, glucose, clotting factors, electrolytes, hormones, carbon dioxide, and oxygen.

Picking Apart Plasmacytoma

Plasmacytoma formation can lead to a host of problems with recognizable clinical symptoms. Because all blood cells are formed in the bone marrow, over-production of plasma cells can essentially “crowd out” normal blood-forming cells. This can lead to anemia, caused by a shortage of oxygen-carrying red blood cells; increased bruising and bleeding due to a reduction in clot-promoting platelets; and an increased risk of infections due to lower levels of healthy infection-fighting white blood cells.

Although multiple myeloma is classified as a blood cancer, it has a significant impact on bone health. As the plasmacytoma grows, bone-forming cells called osteoblasts are suppressed. At the same time, production of a substance that activates bone-reabsorbing cells, osteoclasts, is increased. The resultant damage to the bone structure results in soft spots or lesions which may extend from the inner bone marrow to the outside surface of the bone. Bone lesions result in significant pain and increase the risk of fracture. Bone destruction also releases excessive calcium into the bloodstream, which leads to a range of symptoms including changes in urination, restlessness, confusion, increased thirst, nausea, and loss of appetite. Excess blood calcium, combined with high levels of M protein, also contributes to the impaired kidney function seen in multiple myeloma patients.

Unmasking Multiple Myeloma

There is no one diagnostic test for multiple myeloma. Blood and urine tests to detect some of the symptoms listed above such as low blood cell counts, elevated blood calcium levels, and impaired kidney function may suggest multiple myeloma. These tests can be followed by a bone marrow biopsy for confirmation.

Most cases of multiple myeloma have no known cause, although some research suggests that regular exposure to herbicides, insecticides, petroleum products, heavy metals, and asbestos increases the risk of developing the disease. And although there is not a specific gene yet associated with multiple myeloma, abnormalities in chromosome structure or number are associated with the disease.

Multiple Myeloma Treatments

Once considered incurable, there are now a number of effective treatments for multiple myeloma, and several more are in the pipeline.

Currently, there are two FDA-approved monoclonal antibody therapeutics approved to treat multiple myeloma.  They work by recognizing and binding to proteins on the surface of multiple myeloma cells, activating the patient’s immune system to destroy those cells.

Another type of approved therapy for multiple myeloma is a small molecule proteasome inhibitor therapy. A proteasome is a specialized compartment within the cell that gets rid of damaged proteins by digesting them. If the proteasome is inhibited, damaged proteins build up within the cell. This triggers a process called apoptosis – essentially, cell suicide. In other words, the cancer cell kills itself.

Small molecule histone deacetylase (HDAC) inhibitors have also been shown to be safe and effective in treating multiple myeloma. HDACs are enzymes that modify chromosomes (strands of DNA that contain our genes) and influence how often specific genes are activated. Some cases of multiple myeloma are associated with changes in gene activation. By inhibiting HDACs, this faulty gene expression can be corrected.

In the Pipeline

Two novel drugs in the multiple myeloma pipeline are Mivebresib and Selinexor.

Mivebresib influences the activation of specific genes by inhibiting a group of proteins called Bromodomain and Extra Terminal motif (BET) proteins. In some types of cancer, genes are activated or deactivated inappropriately due to BET activity. By inhibiting BET, normal gene activity may be restored to these cells.

Selinexor helps to increase the number of tumor suppressor proteins present in the nucleus of cancer cells. These proteins help to protect against cancer by detecting DNA damage and promoting apoptosis in those cells that have high levels of DNA damage. In many types of cancer cells, tumor suppressor proteins are transported out of the nucleus, where they can no longer do their job of detecting DNA damage. Selinexor blocks this transport and enables tumor suppressor proteins to do their job of triggering apoptosis in cancer cells.

A number of CAR-T therapies are also in development for multiple myeloma, with several early stage clinical trials ongoing. 

Multiple myeloma is a complex type of cancer. In recent years, a better understanding of the disease has led to the approval of several new therapeutics. In the coming years, we can look forward to additional approvals as novel therapeutics move through the pipeline.

New Real World Health Care Series: Multiple Myeloma Research and Treatment

Krista Zodet, President, HealthWell Foundation

Susan, from Columbia, S.C., is among the millions of Americans struggling to manage a chronic and life-altering disease without the financial means to afford needed medication. Here at HealthWell, we’re honored to be able to help Susan and other patients like her. It always warms our hearts to receive letters like the one she sent:

“I have been a multiple myeloma patient since December 2007 and, unfortunately, there is presently no cure for this cancer. Thankfully, I am responding to treatment, but it is expensive. My oral maintenance medication costs over $11,000 per month and it gets more expensive every year. I am so very thankful for Medicare, but we have a $3,600 deductible that has to be met before insurance pays the claims. That’s a lot of money to come up with each year on a worship pastor’s salary. The charity I was receiving help from can no longer help multiple myeloma patients, but they referred me to HealthWell Foundation and it could not have been easier! The HealthWell representatives I have spoken with have been professional, caring, and efficient. I am thrilled with my experience. Thank you to the wonderful and generous donors who make this possible.” – Susan, Columbia, SC

Susan’s story is not unique. It is however, unfortunate, and one that we hear at the HealthWell Foundation all too often. Cancer is not easy and it’s not inexpensive. That’s why it’s important for us to continue to use this blog to highlight advances in current research, therapies, and what’s on the horizon for treating devastating diseases like Multiple Myeloma.

About Multiple Myeloma

Multiple myeloma is a type of blood cancer that affects the plasma cells found in bone marrow. It is the second most common blood cancer and is considered incurable. It is a treatable disease, however, thanks to recent advances in cancer research which are improving the life expectancy of multiple myeloma patients.

According to the American Cancer Society, more than 30,000 new cases of multiple myeloma are expected to be diagnosed in 2017 and more than 12,000 deaths are expected to occur. The disease is more prevalent among men than among women.

Promising New Therapies

Our new Real World Health Care series will shine a spotlight on the individuals and organizations driving research on new multiple myeloma therapies, including monoclonal antibodies, CAR-T cell therapy, checkpoint inhibitors and other immunotherapies. I share the hopes of these researchers that these new therapies, or others just coming to the drawing board, will allow multiple myeloma to be treated easily and effectively, and with the possibility of a cure.

Supporting Multiple Myeloma Patients

The HealthWell Foundation, sponsor of Real World Health Care, is proud to support the multiple myeloma patient community with copayment and premium assistance. We have helped more than 9,000 multiple myeloma patients afford their treatments since launching our Multiple Myeloma Medicare Access Fund in 2015 — thanks to the generous support of our donors. We invite corporations and individuals to help us by contributing to our Multiple Myeloma Medicare Access Fund, so no one goes without essential medications because they cannot afford them.

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

This is the last week of Real World Health Care’s brief hiatus, during which we are re-publishing some of our most popular interviews on oncology-related topics.

The editors of Real World Health Care, along with our sponsor, the HealthWell Foundation, understand that cancer takes a huge toll on patients, their families and loved ones. About 1.6 million new cases of cancer were diagnosed in the United States last year, and nearly 600,000 people died from the disease.

Real World Health Care is pleased to shine a spotlight again on the researchers, clinicians and organizations dedicated to the future of cancer care. We also are proud of the work being done by the HealthWell Foundation, which provides a financial lifeline to underinsured Americans through grants for cancer patients across a variety of funds, such as multiple myeloma, bone metastases, and chronic myeloid leukemia for Medicare patients, to help them afford the medical treatments they so desperately need.

In May, Real World Health Care continued our recognition of 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

Non-Small Cell Lung Cancer: EGFR Mutations and Targeted Therapies

For the next several weeks, Real World Health Care will take a brief hiatus as we re-publish some of our most popular interviews on oncology-related topics.

The editors of Real World Health Care, along with our sponsor, the HealthWell Foundation, understand that cancer takes a huge toll on patients, their families and loved ones. About 1.6 million new cases of cancer were diagnosed in the United States last year, and nearly 600,000 people died from the disease.

Real World Health Care is pleased to shine a spotlight again on the researchers, clinicians and organizations dedicated to the future of cancer care. We also are proud of the work being done by the HealthWell Foundation, which provides a financial lifeline to underinsured Americans through grants for cancer patients across a variety of funds, such as multiple myeloma, bone metastases, and chronic myeloid leukemia for Medicare patients, to help them afford the medical treatments they so desperately need.

Continuing our series on non-small cell lung cancer, this week Real World Health Care speaks with Lecia V. Sequist, MD, MPH, Associate Professor of Medicine at Harvard Medical School and the Mary B. Soltonstall endowed chair in oncology at Massachusetts General Hospital. Dr. Sequist’s research focuses on studying novel targets and targeted agents for lung cancer treatment, particularly those that target the epidermal growth factor receptor (EGFR) and in detecting and studying the significance of tumor cells circulating in the bloodstream.

Real World Health Care: Tell us about what you do at Massachusetts General Hospital, especially in relation to research and treatment of non-small cell lung cancer.

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia Sequist: I’m a medical oncologist with a busy practice, seeing and treating patients with lung cancer. I also conduct clinical and translational research on new drugs, looking at the molecular aspects of tumors and biopsies as patients go through various forms of treatment. My focus is on personalizing treatment for each patient.

RWHC: Can you share some highlights of your recent research in non-small cell lung cancer?

LS: Most of my recent research has revolved around EGFR mutations. One of the biggest advances in lung cancer in recent years is that we’ve come to understand lung cancer is not one disease. It’s many diseases. We can now tell the difference between one cancer and another by looking at the tumor genetics. These are not the genes we inherit from our parents, rather they are genes that reside only in cancer cells. These genes are at the core of what causes cancer. By identifying these genes in a lung cancer patient’s tumor, we can be more successful with treatments that target those genes and the proteins they produce.

EGFR mutations were first discovered here at Mass General, right around the time I started in oncology. It was a very exciting time, and ushered in a new era of personalized treatment for cancer. Since those early days, we’ve done a tremendous amount of research with patients who have the EGFR mutation, and we’ve found treatments that work better than standard chemotherapy.

RWHC: What are some of the biggest challenges you face as a researcher studying non-small cell lung cancer?

LS: I think of the challenges in two categories: scientific and societal. From the scientific point of view, we can’t currently identify mutations in every lung cancer, though we’re constantly working to uncover more of them. The group of lung cancer patients who have no identifiable mutation, or who have a mutation with no matching drug therapies at this time, are effectively left out of the “molecular revolution.” For those groups, the challenge is to find alternative approaches. Luckily some of the newer immunotherapies may work particularly well in such patients. Then down the road, we know that targeted therapies eventually “wear off,” in the sense that cancer cells get smart and find ways to work around the roadblocks we put in their path. For example, we saw this with the first generation of tyrosine kinase inhibitors (TKIs) developed to target EGFR mutations. Most patients initially responded, but subsequently developed a resistance after about a year, because they developed a second mutation that prevents the TKIs from binding to the cancer cells. Last year, a new EGFR drug was FDA approved that is able to effectively target this second mutation. Now we’re racing trying to learn how the cancers may get around the newer drug and also looking at strategies to prevent resistance.

From a societal standpoint, one of our biggest challenges in the lung cancer research community is the stigma that still exists around lung cancer. In the United States, we were fortunate to have had a very successful public health campaign around the dangers of smoking over the last generation. Those dangers are important to understand, but one of the unexpected consequences of this was to popularize the opinion that lung cancer is a self-inflicted disease and therefore patients carry some degree of blame. Not only does this end up negatively affecting individual patients, it also cuts into research funding. The fact is, some smokers get lung cancer while others don’t. And more importantly, many lung cancer patients have never smoked. No one deserves lung cancer and research must push forward to stop this, the deadliest of all cancers.

RWHC: What are some of the biggest challenges you face as a clinician treating patients with non-small cell lung cancer?

LS: There are promising treatments being studied in clinical trials, but many patients don’t have access to those treatments because the trials are concentrated in academic centers. Even if patients have geographic access to research studies, clinical trials have fairly high thresholds for eligibility, so if a patient has other medical conditions — which many lung cancer patients have — or if their cancer has certain characteristics, they won’t be eligible for the trial. We need to keep pressure on the pharmaceutical industry to include broader groups of patients in trials so all patients can get access to promising new treatments.

RWHC: What do you think are some of the biggest opportunities for advancement in how we research non-small cell lung cancer and treat people with the disease?

LS: Immunotherapy has really changed the paradigm for non-small cell lung cancer. Years of failed vaccine studies led us to believe that it wasn’t possible to affect the human immune system in meaningful ways against lung cancer. Now that we’ve hit upon a different way to activate the immune system, new discoveries are tumbling out the door every day. Unlike past treatments, immunotherapy has true promise for long-term disease control. There are already three FDA-approved lung cancer immune therapy treatments over the last year and likely many more to come. I think someday we’ll look back on this time and say that this is when the needle really started to move.

RWHC: Why did you get into this field of research? What continues to inspire you?

LS: I was initially drawn to studying lung cancer when I was in training by the doctors who were mentoring me and the patients I met. At the time, there weren’t many treatments available for non-small cell lung cancer, so there was a lot of room for improvement. This was attractive to me as a clinician and a researcher and it has remained a vibrant and ever-changing field. I enjoy being involved in the exponentially increasing number of treatments available and how these new treatments can bring hope to patients. It has ended up being an intellectually stimulating and extremely fulfilling career and I continue to be inspired by the patients I meet every day.

Pain Management: Opioid Adherence in Cancer Patients

For the next several weeks, Real World Health Care will take a brief hiatus as we re-publish some of our most popular interviews on oncology-related topics.

The editors of Real World Health Care, along with our sponsor, the HealthWell Foundation, understand that cancer takes a huge toll on patients, their families and loved ones. About 1.6 million new cases of cancer were diagnosed in the United States last year, and nearly 600,000 people died from the disease.

Real World Health Care is pleased to shine a spotlight again on the researchers, clinicians and organizations dedicated to the future of cancer care. We also are proud of the work being done by the HealthWell Foundation, which provides a financial lifeline to underinsured Americans through grants for cancer patients across a variety of funds, such as multiple myeloma, bone metastases, and chronic myeloid leukemia for Medicare patients, to help them afford the medical treatments they so desperately need.

This week, Real World Health Care speaks with Salimah H. Meghani, PhD, MBE, RN, FAAN. Dr. Meghani is an associate professor and term chair in Palliative Care at the University of Pennsylvania School of Nursing. She is also associate director, NewCourtland Center for Transitions and Health. Her main research interest involves palliative care, specifically understanding and addressing sources of disparities in symptom management and outcomes among vulnerable patients.

We asked her about her study on analgesic adherence and health care utilization in outpatients with cancer pain, recently published in Patient Preference and Adherence. We also discussed the role of non-pharmacological approaches in treating cancer pain.

Opioid Adherence Patterns

Real World Health Care: Last year, you published an article: Patterns of analgesic adherence predict health care utilization among outpatients with cancer pain. Can you provide a brief summary of the article and talk about the study’s implications for cancer patients with pain management issues?

Salimah H. Meghani, University of Pennsylvania School of Nursing

Salimah Meghani: This is the first study to understand how opioid adherence patterns, over time among cancer patients, relate to health care utilization outcomes. We used objective measures of adherence (Medication Event Monitoring System – MEMS) and novel adaptive methods recently validated by the co-author, Dr. George Knafl from UNC-Chapel Hill. We found that inconsistent adherence patterns of analgesics over time was significantly associated with hospitalization over a 3-month observation period. The interaction of inconsistent adherence and strong opioids (WHO step 3 opioids) was one of the strongest predictors of health care use. It should be noted that this was a serendipitous finding. We did not plan to study adherence patterns and health care utilization. It therefore needs validation in hypothesis-driven study.

RWHC: Are you currently involved in any new research programs studying pain management in cancer patients? If yes, can you briefly describe?

SM: Yes, I am studying outcomes of opioid adherence and adherence patterns among cancer outpatients. This is an important topic as few recent U.S. based studies exist on the topic despite all the recent guideline contentions (e.g., CDC guidelines for managing chronic pain including chronic cancer pain and ASCO response) and national policy debates on opioids.

How Patients Manage Cancer Pain

RWHC: What do you think are the biggest challenges facing researchers studying pain management in cancer patients? How can those challenges be addressed?

SM: One of the biggest challenges is that we know very little about how patients manage their cancer pain. We know that opioids are widely prescribed, but we also know that there is poor adherence to prescribed opioids. Other treatments such as acupuncture are not consistently covered by health insurance or lack data on clinical effectiveness. There is a need to understand how patients are managing their cancer pain and what health care systems can do better to address the great burden on unrelieved cancer pain. Future work should also include improving access to effective non-opioid treatments for cancer patients. My previous research has also documented racial and ethnic disparities in cancer pain treatment for African Americans, which requires continued attention.

Safe Opioid Use

RWHC: What do you think are the biggest challenges facing clinicians treating pain in cancer patients? How can those challenges be addressed?

SM: There is a lot of confusion among clinicians about the role of opioids and the safe and rational use of opioids among cancer patients. Unfortunately, there is little empirical evidence base about the outcomes of opioid treatment among cancer patients. A look at the recent CDC guidelines on managing chronic pain would indicate that cancer patients frequently, if not invariably, have been excluded from the studies of the outcomes of chronic opioid therapy. More empirical evidence is needed to help clinicians develop comfort in opioid prescriptions.

Non-Opioid Treatments

RWHC: What do you think is the role of non-pharmaceutical pain management therapies for cancer patients? How can clinicians integrate both pharmaceutical and non-pharma therapies for cancer patients?

SM: I think access to non-pharmacological treatments is the biggest problem. While the NCCN guidelines for cancer pain identify a number of non-pharmacological modalities, they are not readily accessible to cancer patients. I have argued this in a recent letter to JAMA Oncology about the CDC opioid guideline that recommends that non-opioid treatments should be the first line therapy for chronic pain. This paradigm assumes easy and consistent access to non-opioid treatments. Also, access to effective non-pharmacological treatments are very different among poor, minorities, those with limited literacy.

Global Disparities

RWHC: What initially attracted you to this field? What continues to inspire you about it?

SM: My original research interest was global disparities in opioid availability for cancer pain management and the role of the International Narcotics Control Board. After migrating to the United States, I became familiar with racial and ethnic disparities in pain care and the toll it has for patients and families. This work continues to inspire me.

American Lung Association: Research Focused on Improving Patient Care and Saving Lives

For the next several weeks, Real World Health Care will take a brief hiatus as we re-publish some of our most popular interviews on oncology-related topics.

The editors of Real World Health Care, along with our sponsor, the HealthWell Foundation, understand that cancer takes a huge toll on patients, their families and loved ones. About 1.6 million new cases of cancer were diagnosed in the United States last year, and nearly 600,000 people died from the disease.

Real World Health Care is pleased to shine a spotlight again on the researchers, clinicians and organizations dedicated to the future of cancer care. We also are proud of the work being done by the HealthWell Foundation, which provides a financial lifeline to underinsured Americans through grants for cancer patients across a variety of funds, such as multiple myeloma, bone metastases, and chronic myeloid leukemia for Medicare patients, to help them afford the medical treatments they so desperately need.

As part of our series on non-small cell lung cancer (NSCLC), Real World Health Care spoke with Susan J. Rappaport, MPH, vice president for research and scientific affairs, American Lung Association. Rappaport provides leadership and direction in the development and implementation of the American Lung Association public health education and research programs. She works with leading scientists to develop research and scientific policies relevant to lung disease.

Here, Rappaport shares insights on how the American Lung Association supports research for NSCLC and other types of lung cancer.

Real World Health Care: How does the American Lung Association fund, or acquire funding, for the research it supports?

Susan J. Rappaport, MPH, American Lung Association

Susan Rappaport: The American Lung Association has been funding research for more than 100 years. We receive our support through public donations, including our annual Christmas Seals® campaign, Fight for Air Climbs and LUNG FORCE Walks. We have a long history of connecting with people and communities in support of lung health.

Our organization was founded in response to tuberculosis — the most feared disease at that time. Now, with tuberculosis largely controlled in the United States, we have turned our sights toward defeating lung cancer and working toward a world free of lung disease.

Research is a critical part of our LUNG FORCE initiative, which focuses on lung cancer in women, to raise awareness and more lung cancer research funds. Through LUNG FORCE, we have already invested an additional $1 million in lung cancer research. The Lung Association’s Awards and Grants Program supports a rich array of studies in lung cancer to help improve methods of early detection and develop better treatment options for patients. In the past four years, we have funded more than $4 million in lung cancer research grants and have doubled our investment in lung cancer since 2015. This year, the Lung Association is funding more than $6.5 million in lung disease research.

RWHC: How does the Lung Association determine what research it supports, either through direct funding or through its advocacy work?

SR: It is important to the Lung Association that we fund the best projects available on a host of lung disease issues. We solicit grant applications each year, and successful applicants are identified through a scientific peer review committee system modeled on the one used by the National Institutes of Health (NIH). These peer review committees are comprised of accomplished and diverse researchers with the necessary expertise to review and assess each proposal. Proposals are funded based on the results of this process, ensuring that we only fund those applications considered of the highest quality, and with the best chance to advance our understanding of diseases, improving patient care and ultimately saving lives.

We know our chances of significant improvement in patient lives and of finding a cure increase when we work together. That’s why we collaborate with other organizations and advocate for increased research funding at NIH.

RWHC: What is the Lung Association currently doing to promote and/or fund research into NSLC? What are your priorities in this area?

SR: Our overall priority is to fund the best research that has the greatest chance of a scientific breakthrough and making a difference in patient care and quality of life. With increased funds available to lung cancer researchers, we attract and retain brilliant, motivated investigators to the field.

As NSCLC accounts for 85 percent of all lung cancer cases, many of the proposed projects do focus on this specific issue. However, the nature of scientific discovery has shown us that answers from one area of research can also work more broadly. Areas that drive our lung cancer research — all of which can address NSCLC — include:

  • Development of new and combination therapies
  • Biomarker discovery and validation
  • Targeted therapies and resistance
  • Screening implementation and novel screening for the non-high-risk population
  • Lung cancer initiation and growth

RWHC: What are the biggest challenges in NSCLC research and how is the Lung Association working to overcome them?

SR: Among our biggest challenges is to be able to fund all the qualified research applications we receive. Each year, we turn away qualified researchers and projects due to the limited availability of funds. LUNG FORCE seeks to raise additional funds for lung cancer research and raise awareness about lung cancer as the leading cause of cancer deaths. Again, we strive to overcome gaps in funding by leveraging our resources, collaborating with other organizations and advocating for increased federal funding for lung cancer research.

RWHC: What would you say have been the most important advances in NSCLC treatment over the past 10 years?

SR: Scientists have discovered somatic mutations — called “driver mutations” — that drive the development of lung cancer. These discoveries, made over the past decade, have transformed how to identify and treat the disease. Now, lung and other tumors can be tested for these mutations.

There are now specific therapies that can address those genetic changes that keep the cancer cell growing. These therapies target the mutations in different ways, are more specific and have fewer side effects. These advances in precision medicine have led to lifesaving discoveries and treatments.

Another sea change in lung cancer treatment is immunotherapy. Cancer cells have found ways to keep the immune system from identifying and destroying them, as they do for infectious invaders. Immunotherapy medicines work to activate a person’s own immune system to recognize and kill cancer cells. So far, immunotherapy has only been approved to treat some forms of NSCLC. Currently, only a minority of patients respond to immunotherapy. However, a large proportion of those who do respond have improved survival.

RWHC: What do you think will be the next biggest advance in NSCLC treatment in the near future?

SR: Our scientific advisors believe that the Lung Association should invest in the following areas, which they identified as having the potential for the most important breakthroughs — all of which can apply to NSCLC:

  • Additional precision medicine in treatment of early-stage lung cancer
  • Precision medicine to identify patients who would benefit from newly developed lung cancer screening, irrespective of smoking history
  • Non-invasive biopsy strategies
  • Comparative effectiveness studies to improve clinical outcomes and cost-effectiveness after treatment

RWHC: Does the Lung Association’s LUNG FORCE research innovation project address NSCLC?

SR: This award will address all types of lung cancer. To better understand the impact of lung cancer in women, the American Lung Association has created a new research award to examine gender differences in lung cancer. Sharad Goyal, M.D., is the first-ever recipient of the LUNG FORCE Research Innovation Project: Lung Cancer in Women Award.

Dr. Goyal’s project focuses on ionized radiation exposure during common cardiology procedures and how that affects the risk of developing lung cancer for women. The project leverages two large population-based data sets that include both cancer and cardiac information. Through analyses of these data sets, Dr. Goyal will evaluate the factors influencing the relative risk of developing lung cancer in a diverse group of people after this type of radiation exposure. This has not been previously studied, and it will take two to three years to complete the analysis.

Advancing Melanoma Research & Supporting Patients

Our series on melanoma concludes as we shine the spotlight on the Melanoma Research Foundation (MRF). We spoke with the MRF’s Director of Education, Shelby Moneer, MS, CHES and MRF’s Scientific Advisory Committee Co-Chair, Michael B. Atkins, MD, PhD, Deputy Director of the Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University.

The MRF is the largest independent organization devoted to melanoma. Its mission is three-fold. It supports medical research that leads to more effective treatments and eventually a cure for melanoma. It educates patients, physicians and the public about the prevention, diagnosis and treatment of melanoma. And it serves as an advocate for the melanoma community to raise awareness of melanoma and the need for a cure.

Research & Patient Support Priorities

Real World Health Care: What type of research programs does the MRF support?

Shelby Moneer, Melanoma Research Foundation

Shelby Moneer: The Melanoma Research Foundation is committed to advancing a broad scientific agenda across the disciplines of prevention, diagnosis and treatment. As part of the MRF’s mission to support medical research to find effective treatments and a cure for melanoma, we are proud to collaborate with internationally recognized research institutions, investigators, government entities and leading melanoma organizations. The MRF currently offers research awards for medical students, junior investigators and senior investigators in both clinical and translational science. We fund research related to cutaneous, mucosal and ocular melanoma.

RWHC: How does the MRF support the patient community?

SM: The MRF provides a broad range of patient support programs offering access to peer-to-peer educational information, as well as professionally moderated support networks, financial and treatment assistance and more. These are continually updated and expanded as new resources become available because we believe that educated and informed patients with a strong support network live longer, better lives.

The MRF advocates for the melanoma community on the local, state and federal level on issues that promote melanoma awareness, prevention and treatment. Current priorities include increased federal funding for melanoma research, restrictions on the use of indoor tanning devices and expanded access to sunscreen in schools. The MRF trains and supports a nationwide network of dedicated volunteers who serve as advocates everywhere from their local communities to the halls of Congress.

RWHC: What are some of the biggest challenges facing researchers studying melanoma?

Dr. Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center

Michael Atkins: The MRF feels that the biggest challenge is helping to launch the careers of young investigators who are interested in doing research into the biology and treatment of patients with melanoma. The MRF is addressing this challenge by offering an expanded number of Career Development grants in the coming year targeted toward young investigators.

Treating Melanoma Patients

RWHC: How are clinicians addressing the challenges of treating patients with melanoma?

MA: For clinicians, the big challenges are learning how to optimally use new treatment options for patients with melanoma. For example, identifying how to integrate targeted therapy with immune therapy, when to stop immune therapy, how to treat patients with variant melanoma presentations (acral, mucosal, uveal) and patients with CNS metastases, how to treat patients with resistance to immunotherapy, determining the best adjuvant therapy for patients with resected high and intermediate risk melanoma, identifying predictive biomarkers for particular treatment approaches, identifying safe and effective combination regimens, and learning how to manage the novel toxicities of immunotherapies.

These questions can only be answered through continued clinical research. The MRF is addressing these challenges through the Melanoma Research Foundation Breakthrough Consortium (MRFBC), which brings together clinical investigators from 20 leading academic melanoma centers to design and conduct clinical trials addressing these types of questions.

RWHC: How can patients work with clinicians to optimize their treatment?

MA: Melanoma patients face the challenge of getting the best treatments for their disease in a setting that is convenient for them and will get them back to their normal lives as quickly and as functionally intact as possible. Patients can work with clinicians by participating in clinical trials aimed at both providing tomorrow’s treatments today and addressing the important unanswered questions facing researchers. Patients can also go to organizations like the MRF to gather information about optimal management of their disease, unanswered questions and available clinical trials. Their support community can work with and contribute to MRF to foster the clinical and basic research that will lead to even further advances in the treatment of patients with melanoma.

RWHC: What does the MRF see as the most promising treatments on the horizon for melanoma?

MA: The MRF sees many promising new treatment opportunities including novel combination immunotherapies, triple combination of BRAF/MEK and anti-PD1 regimens and moving effective treatments for advanced disease into the adjuvant high risk setting.

Categories: General, Melanoma

Cutting-Edge Melanoma Treatment at Rutgers Cancer Institute of New Jersey

This week, Real World Health Care continues our series on melanoma by interviewing two colleagues from the Rutgers Cancer Institute of New Jersey, a National Cancer Institute-designated Comprehensive Cancer Center.

Sharad Goyal, MD, is Associate Professor and Director of Clinical and Translational Research in the department of Radiation Oncology. He treats patients with brain tumors, melanoma and skin cancers, providing comprehensive cancer evaluation and the latest treatment planning technology to “map” tumors. He designs radiation treatments with pinpoint accuracy, ensuring that tumors get the most effective dose while healthy tissues and organs are spared.

Ann W. Silk, MD, is a medical oncologist who cares for patients with melanoma, and other skin cancers. She also leads clinical trials focused on combination treatment with immunotherapy and viral therapy for melanoma and other cancers.

Drs. Goyal and Silk discuss their work as part of a multidisciplinary team that translates research of investigational treatments and directly applies them to patient therapies.

Managing Multiple Melanoma Brain Metastases

Real World Health Care: How is treatment advancing for patients with multiple brain metastases (MBM) from melanoma?

Sharad Goyal; Faculty and Staff, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ. 05/01/2014 Photo by Steve Hockstein/HarvardStudio.com

Sharad Goyal: The treatment of brain metastases from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS) and whole brain radiation (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing for subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving.

As patients are living longer due to more effective systemic therapy, surveillance and management of intracranial disease is increasingly important. At this time, the standard of management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both.

In addition, emerging data supports the notion that SRS, in combination with targeted therapies or immune therapy, may reduce the need for whole brain radiation. Prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Given the advances in systemic therapy of melanoma, it is critical that oncologists treating these patients be aware of new treatment paradigms to optimize the outcomes for all patients with metastatic melanoma.

RWHC: Are there ways to treat melanoma in order to avoid or lessen the chances of brain metastases? Does early initial detection of melanoma help?

SG: Early detection of melanoma will always help reduce the chance a patient develops brain metastases. There is usually a fairly lengthy period when the tumor expands beneath the top layer of skin but doesn’t go any deeper. This allows time for screening, early detection, treatment, and a full recovery if the tumor is discovered before it spreads.

After a patient is diagnosed with melanoma, the use of certain anticancer treatments that are given after a cancer is surgically removed, such as interferon alfa and ipilimumab, will allow for an improvement in overall survival in patients with stage III or IV melanoma. In addition, the use of anti-PD-1 checkpoint inhibitors prolongs overall survival in patients with stage IV melanoma. Currently, many studies are underway investigating the optimal anticancer treatment in patients with Stage III melanoma.

Promising Therapies

RWHC: What are the most promising therapies on the horizon for metastatic melanoma?

Ann W. Silk, MD, Rutgers Cancer Institute of New Jersey

Ann Silk: Melanoma is the “posterchild” for breakthrough immunotherapies. At Rutgers CINJ, we are testing novel combinations of new agents coupled with immunotherapies. Those novel agents help to “prime” tumors so immunotherapies work better. One example of this is combining an immune checkpoint inhibitor pembrolizumab with intra-tumoral injections of talimogene laherperepvec, which is a live herpesvirus that infects cancer cells, replicates within them, and lyses the cancer cell, thus killing the cell. We’re also seeing promising early results in trials that combine intra-tumoral injections of coxsackievirus with injections of pembrolizumab, with response rate of 60%, which we reported at this year’s American Association of Cancer Research Annual Meeting. We have just recently opened a study in which we will combine IL-2 cytokine therapy with pembrolizumab, a combination of two drugs that have already demonstrated good activity in metastatic melanoma.  They are each FDA-approved as single-agents, but we are studying them as a combination therapy. The goal of these studies is to build on the success of immunotherapies to increase response rates, particularly complete response rates.

Access to Clinical Trials

RWHC: What are some of the biggest challenges facing researchers studying metastatic melanoma?

AS: Access to clinical trials is a challenge, from a patient or participant status. Running clinical trials requires vast resources and numerous support personnel, so they tend to be concentrated at large medical centers. As a result, only about five percent of the patient population has access to these trials. I think that number should be closer to 80 percent. Trials aren’t only important for the patients receiving the treatment; the knowledge we gain also helps future patients.

Treating Melanoma

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

SG: One of the most challenging types of cancer to treat is melanoma and the most challenging area it can spread to is the brain. With the advancements being made in cancer treatment, the odds of survival for many of these patients are changing dramatically.

In recent years, our understanding of cancer biology has progressed substantially and this has led to the development of targeted therapies and immunotherapies. These novel therapies have prolonged survival in a disease which previously had a dismal outcome. As patients are living longer due to more effective systemic therapy, surveillance and management of intracranial disease is of increasing importance.

AS: There are many standard therapies approved to treat melanoma, and as indicated earlier, there’s lots of research activity in this area as well. Patients benefit from the wealth of approved therapies on the market. But while about 30-40 percent of patients will respond very well to these therapies, the majority still struggle and succumb to their disease. Patients who don’t respond to the first line of treatment must move on to a second line of treatment. Once those treatment options are exhausted, the only course of action is to try and get the patient enrolled in an investigational therapy trial. In many cases, the patient would benefit from earlier involvement in clinical trials.

Early and Current Inspirations

RWHC: What initially interested you in researching melanoma and treating people with the disease? What continues to inspire you?

AS: I became interested in the interplay between cancer and the immune system in my first job as a data manager at the Dana-Farber Cancer Institute, where I managed one of the first clinical trials of ipilumumab, which was later FDA approved with the distinction of being the first drug that prolonged survival in melanoma. I was inspired by researchers who were on the forefront of personalizing medicine by using the immune system to attack cancer cells. Ever since then, in both my research and clinical practice, I haven’t found any better ally in the fight against cancer than retraining the immune system to attack cancer cells.

SG: Throughout my career, I have been inspired by the cancer patients I treat.  The relationships that I have developed with patients and their families are unlike those in almost any other medical specialty. Once a patient has a diagnosis of cancer, I am able to see the patient and his or her family members on a regular basis and develop a long-lasting relationship with them.

Fighting Melanoma with Immunotherapy

For this week’s post in our series on melanoma melanoma, Real World Health Care interviewed Kelly M. McMasters, MD, PhD. Dr. McMasters serves as the director of the Multidisciplinary Melanoma Clinic at the University of Louisville’s James Graham Brown Cancer Center. Here, he works with colleagues to identify the most effective combination of therapeutic modalities including surgery, immunotherapies, and targeted therapies for stage I-IV melanoma patients.

Dr. McMasters also directs a basic and translational science laboratory studying adenovirus-mediated cancer gene therapy and melanoma biomarkers, which has been funded by the National Institutes of Health, the American Cancer Society, the Melanoma Research Foundation and other agencies.

Sunbelt Melanoma Trial

Real World Health Care: You are the author and principal investigator of the Sunbelt Melanoma Trial. Can you briefly summarize the focus of this trial and its results?

Dr. Kelly McMasters, James Graham Brown Cancer Center, University of Louisville

Kelly McMasters: This was a multi-institutional study involving 3,500 patients from 79 institutions across North America. We studied whether interferon should be used for patients with minimal spread of melanoma to their lymph nodes. We found that this toxic, expensive treatment — which is like having the flu, but worse, for a whole year — was not necessary and did not result in survival benefits. This is important because many patients have been spared unnecessary treatment.

While interferon is still approved for adjuvant therapy for high-risk melanoma, other options now in the pipeline, and further research into the molecular basis of melanoma metastasis and immune system evasion will result in improvements in adjuvant therapy for patients at high risk of recurrence.

We also evaluated molecular tests to find patients at high risk of recurrence, but these tests turned out to not be clinically useful.

Immunotherapy Studies

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

KM: We currently are conducting and participating in several studies of immunotherapy for melanoma. Immunotherapy has revolutionized the treatment of melanoma in the past few years. Five years ago, there were essentially no treatments that were effective for patients with advanced melanoma. Now, we frequently can use immunotherapy that results in durable, complete remissions and even cure in such patients.

Former President Jimmy Carter is an example. He had metastatic melanoma in his brain and elsewhere, with a life expectancy of a few months. He got an immune checkpoint inhibitor and his cancer went away.

Immunotherapy Combinations and Resistance

RWHC: What are some of the biggest challenges facing researchers studying melanoma?

KM: Right now, the challenge is to figure out the best combination of immune therapies to get the greatest benefit for patients with the least side effects. We need to better understand the immune system and how it fights cancer.

Newer studies of melanoma adjuvant therapy using immune checkpoint agents, such as PD-1 inhibitors, show much promise. More work needs to be performed to understand the significance of molecular detection of melanoma cells in the lymph nodes and in the circulating bloodstream. We now suspect that melanoma, like other cancers, routinely sheds cancer cells into the lymphatic system and bloodstream. A small minority of these cells that have the ability to evade the immune system, attach, invade, develop their own blood supply and grow, becoming metastatic tumors.

RWHC: What are some of the biggest challenges facing clinicians studying melanoma?

KM: We need to find out why some patients have miraculous responses to immunotherapy and why some are resistant. Finding out how these mechanisms of resistance work will help us design treatments that are more effective for most people.

Clinicians also need to pay attention to side effects, which are variable, from very mild or virtually none, to potentially life-threatening. Early recognition and treatment — often immediately with corticosteroids — can be lifesaving, especially for autoimmune colitis, which can lead to bowel perforation and serious infection.

Beyond Surgery

RWHC: What interests you in studying melanoma, and treating patients with the disease?

KM: After so many years in which surgery was about the only truly effective treatment for melanoma, it is encouraging to see the development of other effective therapies. I find it gratifying when I now refer patients with advanced melanoma to my medical oncology colleagues for immunotherapy with realistic hope of remission or even cure, rather than engage in desperate attempts to surgically resect all of the cancer. Surgery still has a very important role, but we now have a lot of other possibilities.

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.