New Research in Skin Cancer: Melanoma, Merkel Cell Carcinoma, and Basal Cell Carcinoma
Most of today’s immunotherapy breakthroughs are built upon melanoma research that began nearly 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 it 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. This may require treatment with a single checkpoint blocker or a combination of two or three different checkpoint blockers. Immune checkpoints can be thought of as traffic lights for immune cells, regulating when they stop and when they go. Different checkpoint blockers control different traffic lights. For some cancers, it may take just one checkpoint blocker to give the green light to immune cells. For other cancers, it may take two or three checkpoint blockers to clear the way for immune cells to attack cancer cells.
The neoadjuvant use of checkpoint blockade immunotherapy is showing promise in early clinical findings, opening up a potential new frontier for the game-changing modality to make an impact in earlier treatment settings in multiple solid tumor types. Suzanne L. Topalian, MD, a pioneer in the development of anti–PD-1/PD-L1 immunotherapy, discussed the potential for the checkpoint blocking drugs in the neoadjuvant setting recently during the Noreen O’Neill Melanoma Research Symposium at the Wistar Institute in Philadelphia, Pennsylvania. Read more from OncLive.com (August 20, 2018).
The drugs nivolumab (Opdivo) and pembrolizumab (Keytruda) block the PD-1 checkpoint expressed on immune cells trying to attack cancer cells. Much of the science behind these drugs was developed at Johns Hopkins and has revolutionized the treatment of melanoma and other aggressive skin cancers. The first FDA approvals were for patients with advanced melanoma, and the drugs have increased long-term survival for these patients from approximately 5 percent to about 50 percent. More recently, nivolumab was FDA-approved for treating patients with stage 3 melanoma after surgery, to prevent relapse.
Ongoing laboratory research and clinical trials are exploring combinations of anti-PD-1 with other checkpoint blockers that may make the treatment work better and in even more patients. Using one or more of these other checkpoint blockers with a PD-1 checkpoint blocker can interfere with additional signals and turn red lights to green lights. These signals include KIR, IL-8, and LAG-3, all of which are the focus of ongoing clinical studies. Much of the scientific development of anti-LAG-3 occurred in laboratories in the BKI. Preliminary results from a clinical trial suggest that some melanomas that did not respond to the PD-1 checkpoint blocker nivolumab alone, responded when a LAG-3 blocker was added. Ongoing multicenter trials are investigating anti-LAG-3 plus anti-PD-1 in a variety of cancer types.
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 given back to the patient through an IV. Although this kind of immunotherapy is not yet FDA-approved in 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. Although our experts believe that immunotherapy should be considered for most patients diagnosed with melanoma because remissions may be long-lasting, patients with BRAF-mutant melanomas and their doctors should discuss which type of treatment—PD-1 checkpoint blockers or BRAF/MEK inhibitors—should be tried first.
Advanced Basal Cell Carcinoma
As part of the Bloomberg~Kimmel Institute for Cancer Immunotherapy’s Skin Cancer Program, our experts plan to study nivolumab for patients with advanced basal cell skin cancer as a first treatment, or for patients whose cancer comes back after treatment with standard therapy (hedgehog inhibitors). 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, but in a small number of patients, the cancer advances and/or spreads to other organs. Standard treatments for these advanced cases may have unpleasant side effects and generally don’t result in long-lasting responses. The response of basal cell carcinoma to anti-PD-1 will be studied in a new clinical trial conducted at Johns Hopkins
Merkel Cell Cancer
Our skin cancer experts co-led a national trial and published the first study showing that a PD-1 checkpoint blocker worked in many cases of advanced Merkel cell cancer, a rare but very aggressive form of skin cancer. Before this study, it was considered an orphan disease lacking good treatment options. Our experts are building upon these initial findings, in a new study that combines nivolumab and the CTLA4 blocker ipilimumab (Yervoy) in an effort to get long-lasting responses for more patients. Research in other cancers found this combination worked well in some patients whose cancers did not respond to nivolumab alone.
Skin Cancer After Kidney Transplant
Our experts are leading a clinical trial of immunotherapy for kidney transplant recipients who develop advanced skin cancers. Kidney transplants are the most common type of solid organ transplant in the U.S., 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, the cancers occur many years after transplant, are detected early and easily treatable. However, some transplant recipients develop advanced skin cancers. A combination of the immunotherapy nivolumab and tacrolimus, an immunosuppressant used to prevent kidney rejection, will be studied through a Bloomberg~Kimmel Institute-led multi-institutional 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 alone.
Why melanoma and other advanced skin cancers respond to immunotherapy:
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 has uncovered two signs that identify a cancer that is likely to respond to immunotherapy:
- Cancer cells that contain many mutations in their DNA
- Cancer cells that express a protein called PD-L1
Generally, skin cancers have some of the highest number of DNA mutations among all cancers, which are caused by exposure to ultraviolet light (sunlight, or tanning beds). Many of these cancers express the PD-L1 protein. However, this is not the whole story. There are 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 BKI. This will help our experts figure out how to make immunotherapy work effectively in more patients.
Our experts are exploring whether cancers that start in the skin, a highly immune organ that is the first line of defense against foreign invaders, are more easily recognized by the immune system than other types of cancers.
Immunotherapy and Surgery
New research is also exploring if medical therapy given to patients with melanomas that have been removed by surgery could prevent cancers from coming back. Recent clinical trials have demonstrated that PD-1 checkpoint blockers and, in patients with BRAF-mutant melanomas, BRAF/MEK inhibitors can improve outcomes in these patients. Nivolumab and dabrafenib+trametinib were recently FDA-approved for this purpose.
Additionally, emerging research shows that anti-PD-1 immunotherapy given briefly before surgery, called neoadjuvant therapy, may also prevent cancer recurrence. Bloomberg~Kimmel Institute experts have demonstrated promising activity in a type of lung cancer called non-small cell lung cancer, and an ongoing clinical trial in Merkel cell carcinoma is also showing promise.