Study Could Change How Advanced Melanoma Patients Are Treated
- Researchers predict that mRNA vaccines may help prevent the progression of melanoma, and could change the landscape of treatment.
- mRNA vaccines use lab-created mRNA to train the cells inside our body to make proteins. These proteins activate our immune system, which then responds by making antibodies. Antibodies are key in fighting infections, and can also help protect us from disease in the future.
- Adding a personalized mRNA cancer vaccine to a type of immunotherapy (called Keytruda) may prolong recurrence-free survival (the time a patient lives without having their cancer return) in those with high-risk melanoma.
Patients who were treated with the combination of vaccine and Keytruda had better outcomes than those treated with just Keytruda which is big news for patients who have advanced disease.Read More
What Are mRNA Vaccines?
Messenger RNA vaccines (mRNA) differ from traditional vaccines in that they don’t contain dead or weakened viruses. Instead, they use pieces of genetic code to help the body produce an immune response against a specific virus or disease.
An example of mRNA vaccines currently in use is the Pfizer-BioNTech and Moderna COVID-19 vaccines. These vaccines protect against the COVID virus, which can cause potentially severe respiratory illness.
How Do mRNA Vaccines Work?
mRNA vaccines use laboratory-created mRNA to train the cells inside our body to make proteins. These proteins activate our immune system, which then responds by making antibodies. Antibodies are key in fighting infections, and can also help protect us from disease in the future.
When your body develops antibodies toward a specific virus or disease, it's better prepared to fight that infection if it comes in contact with it again. mRNA vaccines help our body create these antibodies before we're even infected, which could be a lifesaving measure against many serious illnesses including melanoma and other cancers.
How Might Vaccines Be Used to Treat Melanoma?
mRNA vaccines are still in development, so it’s difficult to say for certain how they might be used to treat melanoma. However, there are a few potential ways they may help:
- As a preventative measure: One possibility is that mRNA vaccines could be given as a preventative measure for people who are at a high risk of developing melanoma. This could include people with a family history of the disease.
- To help stop the progression of melanoma: Another possibility is that mRNA vaccines could help stop the progression of melanoma in patients who have already been diagnosed. This could include using the vaccine in combination with other treatments, such as chemotherapy or radiation therapy.
- To help prevent metastasis: Finally, mRNA vaccines may help prevent metastasis in patients who have already been treated for melanoma. Metastasis is the spread of cancer cells from the original site to other parts of the body.
Improving Recurrence-free Survival
Dr. Weber presented some very interesting new findings at the AACR Annual Meeting 2023, held April 14-19 in Orlando, Florida. He demonstrated that a personalized mRNA-based cancer vaccine, in combination with the immune checkpoint inhibitor Keytruda improved recurrence-free survival (RFS) compared with Keytruda alone in patients with high-risk melanoma. RFS means that patients were living longer without having their cancer return.
Pembrolizumab (brand name Keytruda) is the immunotherapy drug that was used in the study. It’s an FDA approved drug to treat melanoma and many other cancers. It belongs to a class of widely used immunotherapies known as checkpoint inhibitors, designed to disable the PD-1 (or programmed death 1) protein that helps cancer evade the immune system.
Adjuvant therapy ( which means treatment is given after an initial surgery/resection) with an immune checkpoint inhibitor, such as Keytruda, has become standard of care for patients with high-risk resectable melanoma.
Whether the benefits of immunotherapy could be enhanced by a personalized cancer vaccine was unclear before this study. The underlying premise of a personalized cancer vaccine is to target an individual patient’s unique tumor mutations. Vaccine production involves obtaining a specimen of a patient’s tumor and a sample of normal tissue, performing next-generation sequencing of tumor DNA and RNA, and determining the patient’s HLA type.
The Study – KEYNOTE-942 trial
The randomized KEYNOTE-942 trial assessed the efficacy of mRNA-4157/V940 in prolonging RFS in patients with resected, stages IIIB/IIIC/IIID and IV melanoma when given in combination with Keytruda, the standard-of-care adjuvant therapy for this type of patient.
The vaccine was administered every three weeks for a total of nine doses, and Keytruda was given every three weeks for up to 18 cycles.
According to the results of the primary trial analysis, after 18 months, the RFS was 78.6% in the population where patients received the combination and 62.2% in those who just got Keytruda, corresponding to a 44% reduction in the risk of recurrence or death in patients who received both mRNA vaccine and Keytruda compared to those who only received Keytruda.
The majority of treatment-related adverse events were mild, and the rates of serious adverse events were comparable between the two groups.
"This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit," added Dr. Weber.
According to Dr. Weber, one limitation of the KEYNOTE-942 trial is that, although randomized, it is a phase IIb study with modest statistical power. "Overall, it is a small number of patients, and one has to be cautious with the interpretation of the results. A larger, phase III randomized study to confirm our findings will begin soon."
Additional limitations include relatively short follow-up time and some setbacks, including cancer vaccine shortage, during the COVID-19 pandemic.
Another technical limitation of the neoantigen vaccine approach is that it is based on DNA and RNA sequencing of tumor tissue, therefore it may not be applicable to patients with earlier-stage disease, whose tumors may be smaller and not provide enough tissue.
A Possible Treatment for Everyone?
During a discussion that followed the presentation, Dr. Weber suggested that the melanoma trial is just the beginning of what could be a therapeutic development not only in melanoma but for cancer in general.
“This approach is absolutely applicable to any solid tumor that expresses neoantigens, and that’s almost every solid tumor,” he said. “The number of neoantigens and tumor mutations varies hugely among solid tumors.
“I think breast cancer has an average of maybe 40 single nucleotide variants. Melanoma is the champion with between 600 and 800 per tumor. It only takes one. There is no reason why this strategy would not work in the adjuvant mode in any solid tumor that was sensitive to PD-1 blockade (such as Keytruda),” he added.
Melanoma: The Basics
Melanoma is known mostly as a cancer of the skin. Melanocytes are the cells of the skin that produce the pigment melanin that colors the skin, hair, and eyes. They can also form moles, which are typically the origin of a melanoma diagnosis. Melanomas are the fifth most diagnosed cancer in the United States annually and the rates have increased over the prior decade, according to estimates by the American Cancer Society.
Melanoma is staged based on how deep the cancer has infiltrated the skin.
- Stage 1: less than 1 mm in depth and easily removed by a dermatologist
- Stage 2: greater than 1mm in depth and removed by a surgical oncologist
- Stage 3: greater than 2 mm or 3 mm in depth and has spread into the lymph nodes
- Stage 4: the most advanced stage representing cancer that has spread to other parts of the body
Treatment for melanoma, like all cancers, is dependent on the tumor stage, location, and patient's specific factors, but often involves a combination of surgery, immunotherapy, targeted agents, and radiotherapy. One question that has been the subject of ongoing research and debate is how to sequence these therapies to better kill melanoma cells, reduce rates of melanoma recurrence, and improve patient quality of life.
What is Immunotherapy?
Immunotherapy is a drug that works to activate immune cells against cancer by harvesting the body's own ability to fight off the cells. Pembrolizumab, the drug used in the study (also called Keytruda), is a form of immunotherapy called a checkpoint inhibitor. Checkpoint inhibitors work by interfering with signaling pathways between T cells and cancer cells and prevent cancer cells from hiding from the body's T cells.
When pembrolizumab or other similar immunotherapies are given it is essentially taking the brakes off the immune system and allowing the body's T-cells to do what they were designed to do fight off invaders or abnormal cells such as bacteria, viruses, and cancer cells.
"We have known for a while now that immunotherapy is a very important weapon in the fight against melanoma," Dr. Janice Mehnert, associate director of clinical research at NYU Langone's Perlmutter Cancer Center, told SurvivorNet in a previous conversation.
Immunotherapy has been used in many cancers including melanoma and has been a game changer for oncology. Immunotherapy was initially used in the metastatic setting for various cancers but studies have shown it to be beneficial when given at various times in earlier stages of the disease.
Potential Side Effects From Immunotherapy
"The side effects of immunotherapy are not, quote, forever," said Dr. Anna Pavlick, a medical oncologist at Weill Cornell Medicine and a Professor of Medicine and Dermatology at the NYU Perlmutter Cancer Center.
The negative effects of immunotherapy can be quite severe, so it's important to inform your physician as soon as you experience any abnormal symptoms. Those who are taking more than one immunotherapy drug, referred to as combination therapy, are at an increased risk of experiencing side effects.
Common Immunotherapy side effects include:
- Nausea or stomach discomfort
- Joint pain
- Diarrhea or constipation (colon inflammation, such as colitis)
- Loss of appetite
- Changes in blood cell counts
Questions to Ask Your Doctor
- Could adding an mRNA vaccine to my treatment plan improve my chances of living without a cancer recurrence?
- Should I consider enrolling in a clinical trial?
- If I’m given immunotherapy for melanoma, what potential side effects should I be aware of?
- Will some sort of vaccine be part of my future treatment plans?