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New Research

Dr Topalian and other researchers in a lab

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.
 

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