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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.

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