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?
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.
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.