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Immunotherapy for Skin Cancer

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  • Skin Cancer
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

How is Immunotherapy Changing the Outlook for Patients with Skin Cancer?

Reviewed By: Jedd Wolchok, M.D., Ph.D.
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Memorial Sloan Kettering Cancer Center
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More people in the United States are diagnosed with skin cancer than all other cancers combined, with roughly 5.3 million new cases each year according to the most recent estimate, which projects one in five people in the U.S. likely to be diagnosed with skin cancer before age 70.

Fortunately, skin cancer is commonly diagnosed at an early stage when it can be dealt with more effectively. Only a small fraction—roughly 1 to 2 of every 500 cases—prove deadly.

The majority of skin cancers (90%) are linked with exposure to sunlight’s ultra violet rays, and as a result typically occur in sun-exposed areas such as the face, head, neck, arms, and legs, and are more common in those with lighter (less-pigmented) skin; however, skin cancers can occur in all people and can arise in areas that are rarely if ever exposed to the sun.

There are three main types of skin cancer, which arise in the three main types of skin cells:

  • Basal cell carcinoma (BCC), which arises in the basal cells that produce new skin cells, is the most common type of skin cancer, comprising roughly 80% of all cases. Basal cell carcinomas rarely spread, or metastasize, to distant tissues.
  • Squamous cell carcinoma (SCC), which arises in the squamous cells that form the skin’s inner lining, is the second most common type of skin cancer, comprising the vast majority of the remaining 20% of (non-basal cell) skin cancers. While metastasis occurs more frequently in SCC compared to BCC, it is still relatively uncommon but can occur if the disease is left untreated too long.
  • Melanoma, which arises in the pigment-producing melanocytes, is much less common in the United States than both BCC and SCC, but is responsible for the majority of skin cancer deaths.

There are also several other types of skin cancer that occur much less frequently, including:

  • Merkel cell carcinoma (MCC) is a very aggressive skin cancer that arises in Merkel cells and is often associated with the Merkel cell polyomavirus. MCC affects about 1,500 people each year in the United States.
  • Kaposi’s sarcoma (KS) is a skin cancer that arises in the blood vessels of the skin and occurs mainly in people with weakened immune systems, such as people with AIDS or those who have received organ transplants and take immune-suppressing drugs to prevent transplant rejection.

While immunotherapy has been successful in melanoma and cutaneous squamous cell carcinoma, new treatment options for these and other skin cancers are urgently needed.

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Skin Cancer Treatment Options

Early-stage skin cancers that remain localized are often successfully treated through a variety of surgical techniques as well as radiation therapy, photodynamic therapy, and topical chemotherapy. For advanced cases beyond surgery, there are several chemotherapies and immunotherapies available for patients. In addition to seven immunotherapies that have been approved by the FDA for melanoma, there are two FDA-approved immunotherapies for non-melanoma skin cancer.

Immunomodulators

  • Avelumab (Bavencio®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced Merkel cell carcinoma (MCC)
  • Cemiplimab (Libtayo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced cutaneous squamous cell carcinoma (CSCC). 

These checkpoint immunotherapy approvals were landmark events for the treatment of certain skin cancers. While the vast majority of cases of early-stage, non-melanoma skin cancer are successfully treated by dermatologists in an outpatient setting, those who have advanced disease that doesn’t respond to traditional treatment may want to consider clinical trials in which promising immunotherapy strategies are currently being evaluated. 

Find a skin cancer clinical trial

CRI's Impact in Skin Cancer

Since its founding, the Cancer Research Institute (CRI) has dedicated numerous grants and fellowships to the research of skin cancer immunotherapy, primarily melanoma. Fortunately, many of these breakthroughs in melanoma have since benefited patients with other types of skin cancer, too. Recent CRI-funded discoveries and breakthroughs include:

  • CRI CLIP Investigator John Carucci, M.D., Ph.D., discovered that blocking the activity of the JAK/STAT pathway reduces the growth of suppression-associated squamous cell carcinoma (SCC) tumors in mice, thus providing a potential strategy through which cancer patients who have also received organ transplants could be treated without compromising the tolerance of their transplants.
  • Drew Pardoll, M.D., Ph.D., and Suzanne Topalian, M.D., Ph.D., members of the CRI-SU2C Dream Team at the Johns Hopkins University School of Medicine, revealed the benefits of anti-PD-1 checkpoint immunotherapy prior to surgery in patients with resectable Merkel cell carcinoma (MCC).

Explore CRI’s current research into skin cancer in our funding directory.

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Featured Patient

I'm hopeful that one day this may be the norm instead of the unusual

Dale Biggs
Skin Cancer  |  Diagnosed 2015
Read My Story
Featured Scientist
Roland S. Liblau, M.D., Ph.D.
Delegation Regionale Inserm Midi-Pyrenees / Limousin (France)
CLIP Investigator  |  2015
View Funding Profile

Skin Cancer Statistics

5.3 Million estimated cases of skin cancer each year
>99% Cases are successfully treated
1 in 5 Americans will be diagnosed before age 70
>90% Cases linked to UV exposure

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Advanced Skin Cancer 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 Therapy

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 skin cancer clinical trials include: 

  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • 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 skin cancer clinical trials include:

  • CEA: a protein involved in cellular adhesion normally produced only before birth; often abnormally expressed in cancer and may contribute to metastasis
  • HER2: a pathway that controls cell growth; commonly overexpressed in cancer and associated with metastasis
  • MUC-1: a sugar-coated protein that’s commonly overexpressed in cancer
  • Personalized neoantigens: these abnormal proteins arise from mutations and are expressed exclusively by an individual’s tumor cells
  • Ras: a central signaling protein that is commonly mutated in cancer and has been linked to abnormal growth and cell division
  • WT1: a protein that is often mutated and abnormally expressed in patients with cancer

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.

There are currently no cell-based immunotherapy targets under evaluation in skin cancer clinical trials.

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 skin cancer 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
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • 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
  • 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
  • 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 skin cancer clinical trials include:

  • Herpes simplex virus: a virus that can cause the formation of sores on the mouth and genitals
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Sources: American Cancer Society Facts and Figures 2018. American Cancer Society Facts and Figures 2008. Stern et al. 2007 (PMID: 20231498); Rogers et al., 2015 (PMID: 20231499); Mohan et al., 2014 (PMID: 24587976); American Cancer Society “What are basal and squamous cell skin cancers?”; Mansouri et al., 2017 (PMID: 28975200); Lindelöf et al., 2000 (PMID: 10971322); CRI grantee progress reports and other CRI grantee documents

Updated November 2018

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

*Immunotherapy results may vary from patient to patient.

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