New Research in Skin Cancer: Melanoma, Merkel Cell Carcinoma and Basal Cell Carcinoma
Most of today’s immunotherapy breakthroughs are built upon research that began 20-30 years ago, when it was realized that the immune system can vigorously react to melanoma.
Immunotherapy is a broad term for treatments that stimulate a patient’s immune system to attack cancer cells. This treatment strategy should be part of the conversation for most patients with advanced skin cancers, although the strategy may not be appropriate for every patient.
Immune Checkpoint Blockers
Immune checkpoint blockers interfere with signals cancer cells use to hide from immune cells. Sometimes, cutting off the inhibitory signals transmitted from cancer cells to immune cells can unleash an immune attack against the cancer. Immune checkpoints can be thought of as stoplights for immune cells, preventing them from proceeding to attack cancer cells. Different checkpoint blockers control different stoplights. For some cancers, it may take just one checkpoint blocker to turn the stoplight green for immune cells. For other cancers, it may take two or three checkpoint blockers to clear the way for immune cells to attack cancer cells. In a groundbreaking advance in March 2022 led by Hopkins scientists and oncologists, the FDA approved the combination of anti-PD-1 with another checkpoint blocker, anti-LAG-3, as the first systemic treatment a patient might receive for advanced melanoma.
In other research, the adjuvant (post-surgical) use of anti-PD-1 drugs or BRAF/MEK inhibitors (for patients with BRAF-mutant melanomas) was recently shown to extend disease-free time after surgery for patients with Stage III or limited Stage IV melanomas. These findings led to several FDA approvals, bringing adjuvant treatments for melanoma into standard-of-care practice. Researchers at Hopkins are also leading the way in developing anti-PD-1 for even earlier stages of skin cancer, in a “neoadjuvant” (pre-surgical) approach. A trial led by our program showed the effectiveness of this early treatment strategy in Merkel cell carcinoma, a rare but aggressive form of skin cancer that can be particularly challenging to control.
Our unique collaboration between laboratory researchers and clinicians is key to our advances in immunotherapy—identifying treatments for each patient that will bring about long-lasting control of cancer. Our research in collaboration with investigators in the Bloomberg-Kimmel Institute for Cancer Immunotherapy has uncovered two signs that identify a cancer that is likely to respond to immunotherapy such as anti-PD-1 drugs: cancers with many mutations in their DNA and those that express a protein called PD-L1.
Generally, skin cancers have some of the highest numbers of DNA mutations among all cancers, because the mutations are caused by exposure to ultraviolet light (sunlight, or tanning beds), which damages DNA. Many of these cancers also express the PD-L1 protein. There are, however, skin cancers that have lots of DNA mutations and express the PD-L1 protein but do not respond to immunotherapy. A better understanding of these two biomarkers and uncovering new ones is a major focus of ongoing research in the Johns Hopkins Melanoma/Skin Cancer Program. This will help our experts figure out how to make immunotherapy work effectively in more patients.
Adoptive Cell Therapy
Adoptive cell therapy is another type of immunotherapy that can be a powerful treatment for patients with melanoma. In one type of adoptive cell therapy, the patient's own tumor is taken into the laboratory so that immune cells within the tumor, called tumor-infiltrating lymphocytes, can be isolated and modified to become better cancer-fighting cells. A few weeks later these cells are transfused back into the patient. Although this kind of immunotherapy is not yet FDA-approved for melanoma, it has been studied and tested for more than 30 years and is performed in specialized research centers.
Melanomas with BRAF Mutations
Melanomas that contain a specific type of mutation in a gene called BRAF may respond to other types of drugs, known as BRAF and MEK inhibitors. A recent Phase 3 randomized trial showed that immunotherapy should be recommended as the first treatment for most patients diagnosed with advanced melanoma, because remissions may be long-lasting. However, patients with BRAF-mutant melanomas and their doctors should discuss which type of treatment—PD-1 checkpoint blockers or BRAF/MEK inhibitors—might be best.
Advanced Basal Cell Carcinoma
Basal cell carcinoma is the most common type of skin cancer and is usually cured with a simple procedure performed in a dermatologist’s office. However, in a small number of patients, the cancer advances and/or spreads to other organs. Standard treatments (so-called Hedgehog inhibitors) for these advanced cases may have unpleasant side effects and generally don’t result in long-lasting responses. Our experts are now studying anti-PD-1 (nivolumab, Opdivo) for patients with advanced basal cell skin cancer as the first treatment, or for patients whose cancer comes back after treatment with standard therapy. In the same clinical trial, additional groups of patients may receive a combination of anti-PD-1 plus anti-LAG-3 (relatlimab), or anti-PD-1 plus anti-CTLA-4 (ipilimumab, Yervoy).
Merkel Cell Carcinoma
Our skin cancer experts co-led a national cooperative group trial and published the first study showing that anti-PD-1 (pembrolizumab, Keytruda) worked in many cases of advanced Merkel cell carcinoma (MCC), a rare but very aggressive form of skin cancer. Before this study, MCC was considered an orphan disease lacking good treatment options. In 2018, the FDA approved pembrolizumab to treat advanced MCC, creating a new standard of care. Our experts then built upon these initial findings, showing that giving anti-PD-1 (nivolumab, Opdivo) at an earlier stage, before definitive surgery for MCC, could lead to complete tumor regression in ~50% of patients with long-lasting results. This advance, combining immunotherapy with surgery, was published in the Journal of Clinical Oncology in 2020 and has influenced standard clinical practice. Scientists in our program are now examining surgical tissues from the patients on this trial, to discover markers that may be associated with treatment response or resistance. This may lead to the development of new tests that would guide individualized treatment plans for patients with MCC.
Skin Cancer After Kidney Transplant
Kidney transplants are the most common type of solid organ transplant in the United States, and cancer, most often resulting from the immune suppression required to prevent organ rejection, is the third most common cause of death among kidney transplant patients. Skin cancer is the most common cancer that kidney transplant patients develop. Typically, these cancers occur many years after transplant, are detected early and are easily treatable. However, some transplant recipients develop advanced skin cancers that are resistant to standard treatments.
To address this difficult problem, our experts have designed and are leading an innovative clinical trial of immunotherapy for kidney transplant recipients who develop advanced skin cancers (melanoma, basal cell, Merkel cell or squamous cell carcinomas). A combination of the anti-PD-1 immunotherapy nivolumab with immunosuppressant drugs used to prevent kidney rejection is being studied through a multicenter collaboration, supported by the National Institutes of Health Cancer Therapy Evaluation Program and Experimental Therapeutics Clinical Trials Network. The combined treatment is aimed at striking a balance that will help the body’s immune system identify and kill cancer cells but leave the transplanted organ intact.
Medical Therapy for Melanoma
The Johns Hopkins Melanoma Program offers a broad range of expertise in using medications to manage melanoma at all stages. In addition to offering standard therapies, our Melanoma Program specialists collaborate with other Johns Hopkins scientists, national cooperative groups and the National Cancer Institute in developing and conducting studies of experimental therapies. Read more about this work in our Research section and our Clinical Trials section.
William Sharfman, M.D.
Some patients who have had melanoma removed by surgery have no evidence of residual disease, but are at significant risk for relapse. For these patients, options include careful observation, or treatment with interferon or experimental therapies.
Interferon is an FDA-approved therapy for patients with melanoma whose tumors have been surgically removed. Johns Hopkins oncologists are experts in administering the approximately yearlong therapy, which requires careful monitoring, dose adjustments, and attention to therapy-associated symptoms.
Our melanoma specialists also lead and participate in clinical trials of experimental medications, such as vaccines and other investigational therapies. Please see our clinical trials section for more information.
Treatments for Advanced Melanoma
Patients with melanoma that cannot be removed by surgery (stage IV, some stage III) have a variety of treatment options available. These treatments fall into 3 broad categories: immunotherapy, targeted therapy and chemotherapy.
Immunotherapies are drugs that activate the body’s immune system to fight cancer. Each of the treatments listed below is administered by our team of experts to ensure safety and maximum efficacy.
Interleukin 2 (IL-2) activates the body’s immune cells to fight cancer. It is administered to patients as a five-day inpatient treatment, which may be repeated for several cycles depending on the tumor’s response. In a small percentage of patients treated with IL-2, tumors may stop growing or disappear completely for several years. Because IL-2 can cause side effects such as nausea, vomiting, rash, liver and kidney complications, high heart rate and low blood pressure, it is generally administered to younger patients without brain metastases who have good heart and lung function.
Johns Hopkins is among a select few Comprehensive Cancer Centers in the Mid-Atlantic region equipped to give IL-2 therapy. Johns Hopkins patients are treated in private rooms in our well-equipped Cancer Center, under the watchful eye of expert physicians and specially trained oncology nurses.
Ipilimumab (Yervoy) is administered intravenously once every three weeks for a total of four doses. In some cases, ipilimumab causes tumors to shrink and helps patients live longer. In some patients, the immune system is activated to attack normal parts of the body, which causes side effects such as diarrhea, rash and kidney or liver damage. The expert team at Johns Hopkins are highly experienced at managing the potential side effects of Yervoy, which is critical for the safe and effective use of the drug.
Investigators at Johns Hopkins have led the way in developing novel drugs to restore the immune system’s ability to spot and attack cancer cells. Clinical trials of the investigational medication nivolumab (anti-PD-1) have demonstrated reductions in tumor size in about 1/3 of patients, and, in some cases, long-lasting remissions.
The drug, now in Phase 3 clinical trials, has also shown activity in patients with advanced lung and kidney cancers.
Some melanomas contain genetic mutations that lead to tumor growth. The most common of these mutations – BRAF, cKIT and NRAS – can be targeted with specific medications. The Johns Hopkins team brings expertise in the comprehensive testing of melanoma tumors and the administration and management of appropriate therapies.
These drugs include vemurafenib (Zelboraf), dabrafenib (Taflinar), and trametinib (Mekinist) and are administered as pills.
Chemotherapy is offered to select patients at Johns Hopkins by our expert team of medical oncologists. These medications include:
- Dacarbazine (DTIC), an intravenous drug administered every three weeks in an outpatient clinic
- Temozolomide (Temodar), an oral chemotherapy taken daily for five days each month
- Carboplatin and Taxol, two intravenous drugs administered weekly in an outpatient clinic