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Immunotherapy for Melanoma

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  • Melanoma
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

How is Immunotherapy Changing the Outlook for Patients with Melanoma?

Reviewed By: Jedd D. Wolchok, M.D., Ph.D.
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Memorial Sloan Kettering Cancer Center and Ludwig Cancer Research, New York, NY
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Although melanoma comprises less than 5% of all skin cancers, it accounts for the vast majority of deaths caused by skin cancer. Melanoma is a cancer that most often arises in the pigment-producing melanocytes found in the skin, but there is also a form called uveal melanoma which can develop in the eye.

As with all skin cancers, the main risk factor for melanoma is exposure to UV light—both natural and artificial sunlight. According to the American Academy of Dermatology, more people develop skin cancer from tanning than develop lung cancer from smoking.

While melanoma is typically easier to detect in earlier stages than in many other types of cancer, it is also much more likely to metastasize, or spread to other organ systems of the body. For this reason, survival rates for localized (stage I and II) melanoma and metastasized melanoma vary greatly.

Unfortunately, instances of melanoma skin cancer are on the rise globally. Each year, the United States is expected to see approximately 178,000 new melanoma diagnoses, resulting in about 10,000 deaths. The 5-year survival rate for localized (stage I and II) melanoma is 98%; however, this drops to 17% in cases where cancer has metastasized to distant sites or organs. (These numbers are based on historical data collected up to 2011, and may change as immunotherapy is more widely used.)

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Melanoma Treatment Options

Current protocol for melanoma treatment depends on the prognosis at time of disease detection. When caught early, the melanoma tumor may be removed during surgery, but if a biopsy shows that the melanoma has spread to lymph nodes, the treatment strategy may include more intensive surgery, targeted therapy, radiation, immunotherapy, and/or clinical trials.

There are currently seven FDA-approved immunotherapy options for melanoma.

Immunomodulators

  • Ipilimumab (Yervoy®): a checkpoint inhibitor that targets the CTLA-4 pathway; approved for subsets of patients with advanced melanoma, including as a first-line therapy
  • Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced melanoma
  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced melanoma
  • The combination of nivolumab and ipilimumab, which target the PD-1/PD-L1 and the CTLA-4 pathways, respectively; approved for subsets of patients with advanced melanoma
  • Aldesleukin (Proleukin®):  a cytokine that targets the IL-2/IL-2R pathway; approved for patients with advanced melanoma
  • Interferon alfa-2b (Intron A®): a cytokine that targets the IFNAR1/2 pathway; approved for subsets of patients with melanoma
  • Peginterferon alfa-2b (Sylatron®/PEG-Intron®): a cytokine that targets the IFNAR1 pathway; approved for subsets of patients with melanoma

Oncolytic Virus Therapy

  • T-VEC (Imlygic®): a modified herpes simplex virus (HSV) that infects tumor cells and promotes their destruction; approved for subsets of patients with advanced melanoma

Despite the recent advancements in FDA-approved melanoma therapies, many advanced metastatic melanoma patients still face a significant mortality risk. The aggressive nature of this disease sustains an urgent need for more successful, effective melanoma immunotherapies.

Find a melanoma clinical trial

CRI's Impact in Melanoma

For more than three decades, CRI has funded laboratory and clinical research into the development of melanoma immunotherapies—granting nearly $38 million to the fight against this deadly skin cancer. This financial support has effectively funded more than 35 clinical trials enrolling roughly 750 melanoma patients, helping to advance the field of treatment through better insight and understanding of the disease.

Melanoma is a core focus of ongoing immunotherapy research done by CRI scientists. With the help of our donor community, our organization continues to supports innovative research in the field of melanoma immunotherapy—from lab to clinic to cures.

  • Padmanee Sharma, M.D., Ph.D., and colleagues discovered a cellular pathway called ICOS whose activation on T cells in response to ipilimumab treatment, and the sustained activation of this pathway, may explain why some patients respond better to therapy than others.
  • Through CRI’s venture philanthropy program, a phase I trial in melanoma and other cancers is testing the experimental antibody GITR (the first treatment of its kind to be tested in human cancer patients) to enhance the activity of T cells against cancer at Memorial Sloan Kettering Cancer Center under the direction of Jedd D. Wolchok, M.D., Ph.D.
  • CRI investigator Timothy N.J. Bullock, Ph.D., at the University of Virginia Health System, showed that a monoclonal antibody designed to activate the CD27 costimulatory molecule, which plays an important role in the activation, survival, and differentiation of T cells, significantly reduced the progression of metastases and primary tumors in a mouse model of melanoma.
  • Clinical trials investigator Hassane Zarour, M.D., and colleagues at the University of Pittsburgh Cancer Institute found that cells that express both the TIM-3 and PD-1 molecules constituted a highly dysfunctional subset of tumor-specific killer T cells in patients with advanced melanoma.
  • CRI postdoctoral fellow Li Tang, Ph.D., of MIT, Cambridge, MA, developed a novel technique using nanotechnology in melanoma and other cancers to deliver immune-stimulating chemicals called cytokines directly to the site of tumors.

See what melanoma-specific research we’re currently funding. With your help, we can fund more research and revolutionize the way melanoma is treated—saving more lives.

Donate to melanoma research

Featured Patient

When I was in the hospital, I made a vow that when I was through with “this,” I would make a difference in the lives of others.

TJ Sharpe
Melanoma  |  Diagnosed 2012
Read My Story
Featured Scientist
Nicholas David Huntington, Ph.D. and Sandra Nicholson, Ph.D.
Walter and Eliza Hall Institute of Medical Research (Australia)
CLIP Investigator  |  2016
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Melanoma Statistics

#1 Deadliest form of skin cancer
<5% Of all skin cancers are melanoma
2011 Year FDA approved CTLA-4 checkpoint inhibitor treatment

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Melanoma Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new cancer treatments. Use this information to consider your clinical trial options.

Therapies
  • Targeted Antibodies
  • Cancer Vaccines
  • Adoptive Cell Therapy
  • Immunomodulators
  • Oncolytic Virus Therapies

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers on cancer cells, in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. Bi-specific T cell-engaging antibodies (BiTEs) bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. Antibody targets under evaluation in melanoma clinical trials include:

  • Angiopoietin: this pathway can promote the growth of blood vessels in tumors
  • CD52: a protein found on the surface of mature immune cells as well as other cell types
  • DLL/Notch: a pathway that can promote cell growth
  • FGF/FGF-R: a pathway that controls cell growth, death, and migration
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and associated with metastasis
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Cancer vaccine targets under evaluation in melanoma clinical trials include:

  • NY-ESO-1: a protein that’s normally produced only before birth, but is often abnormally expressed in cancer
  • P53: a tumor suppressor protein that is often mutated, nonfunctional, and overexpressed in cancer
  • Personalized neoantigens: these abnormal proteins arise from mutations and are expressed exclusively by an individual patient’s tumor cells
  • Survivin: a protein that can prevent cellular death and is overexpressed by a number of cancer cell types
  • Telomerase: an enzyme that helps maintain the health of cellular DNA; exploited by cancer cells to achieve immortality
  • Tumor-associated antigens (TAAs): proteins often expressed at abnormally high levels on tumor cells that can be used to target them; also found on normal cells at lower levels
  • WT1: a protein that is often mutated and abnormally expressed in patients with cancer, especially Wilms’ tumor (WT)

Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in melanoma clinical trials include:

  • GD2: a pathway that controls cell growth, adhesion, and migration, and is often abnormally overexpressed in cancer cells
  • MAGE antigens: the genes that produce these proteins are normally turned off in adult cells, but de-regulated cancer cells often re-activate their expression
  • NY-ESO-1: a protein that’s normally produced only before birth, but is often abnormally expressed in cancer

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in melanoma clinical trials include:

  • CD40: activating this co-stimulatory pathway can kickstart adaptive immune responses
  • CD47: this surface protein acts as a “don’t eat me!” signal that protects cancer from being consumed by certain immune cells; blocking CD47 can improve their cancer-eating activity
  • CD73 or A2AR: blocking these pathways can help prevent the production of immunosuppressive adenosine
  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CSF1/CSF1R: blocking this pathway can help reprogram cancer-supporting macrophages              
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • CXCR4: blocking this pathway can promote the migration and recruitment of immune cells
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • ICOS: activating this co-stimulatory pathway on T cells can help enhance immune responses against cancer
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
  • LAG3: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
  • STING: activating this protein in the DNA-sensing pathway can help stimulate immune responses against threats such as viruses and cancer
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors

Oncolytic virus therapy uses modified viruses that can infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body. Viral platforms under evaluation in melanoma clinical trials include:

  • Coxsackie Virus: a virus that belongs to the same group as the polio virus; commonly infects young children and causes flu-like symptoms
  • Herpes simplex virus: a virus that can cause the formation of sores on the mouth and genitals
  • Measles virus: a highly contagious virus that infects the respiratory tract and can cause measles
  • Vaccinia virus: the virus that was used to help vaccinate against and eliminate smallpox; rarely causes illness in humans and is associated with a rash covering the body
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Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2016; GLOBOCAN 2012; NCI Surveillance Epidemiology and End Results (SEER); National Comprehensive Cancer Network (NCCN) Guidelines for Patients; ClinicalTrials.gov; Melanoma Research Foundation; CRI grantee progress reports and other CRI grantee documents

Updated October 2018

*Immunotherapy results may vary from patient to patient. Consult a healthcare professional about your treatment options.

*Immunotherapy results may vary from patient to patient.

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