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Melanoma management forges a new path


Experts discuss how personalized vaccines may reshape the future of cancer treatment.

Feature

By Emily Margosian, Assistant Editor, December 1, 2023

Banner for melanoma management forges a new path

Melanoma is among the most common cancer types and has one of the most rapidly increasing incidences around the world, studies say. However, over the last decade, new therapies for melanoma have been developed, with impressive effects on survival.

Among these therapies, a new model for melanoma treatment in the form of a personalized vaccine has emerged, with promising results. “This is an exciting, groundbreaking time,” said Elizabeth Berry, MD, FAAD, associate professor of dermatology at Oregon Health & Science University School of Medicine. “We’ve known for decades that melanoma is immunogenic, and the Holy Grail has been to develop some sort of vaccine against melanoma. Researchers have been trying to do this for decades, and it has not been successful until now.”

Proponents of personalized medicine say these new advances may allow for earlier intervention in the future, as well as the option to choose more efficient therapies tailored to a specific patient. DermWorld speaks with oncology researchers and melanoma experts to discuss what possibilities lie ahead.


Short on time?

Key takeaways from this article:

  • A new model for melanoma treatment has emerged, with promising results.

  • A recent study found that the use of a personalized neoantigen vaccine in combination with immunotherapy reduced the risk of melanoma recurrence by roughly half — marking the first time a cancer vaccine has shown such a level of benefit.

  • While further research is underway, the public may have to wait up to three years for FDA approval for use in patients.

  • While this new technology has promising implications for the treatment of melanomaand other cancers, questions about cost and access remain.

New milestones

Within the cancer vaccine field, melanoma management has become one of the most developed for personalized medicine — with exciting recent advancements.

In 2019, a small clinical trial involving 157 participants investigated the use of a personalized vaccine utilizing mRNA technology to target mutations unique to a patient’s cancer. All participants received immunotherapy (pembrolizumab), while two-thirds also received the vaccine.

In April 2023, results from the phase 2 trial were presented at the annual meeting of the American Association for Cancer Research (AACR), indicating that the combination of the vaccine with immunotherapy reduced the risk of melanoma recurrence by roughly half (44%) — marking the first time a cancer vaccine has shown such a level of benefit.

“The trial showed that there was an increase in recurrence-free survival and distant metastasis-free survival in the combination arm, compared to the control in patients with resected high-risk stage IIIc/IV melanoma. The hazard ratios were 0.56 and 0.34, respectively, with 24 months of follow-up in this modest-sized randomized phase II trial,” said Jeffrey Weber, MD, PhD, deputy director of NYU Langone’s Perlmutter Cancer Center and principal investigator of the study. “This was the first trial in which there were randomized data demonstrating the benefit of a neoantigen vaccine approach.”

“This is certainly a starting point for a whole franchise of trials in resected high-risk cancers and will hopefully decrease the proportion of melanoma patients that ever relapse, increasing the rate of cure in this disease.”

According to Dr. Berry, findings from the phase 2 trial forecast an exciting future for the development of personalized cancer vaccines. “We’re in the era of immunotherapy where we have access to drugs that will stimulate the immune system to function. However, it’s the personalized element that really makes a difference,” she explained.

The technology used to develop the personalized vaccines used in the study involved samples of patients’ tumors and germline DNA. “They sequence both and then pluck out up to 34 different neoantigens from their germline DNA that are specific to the tumor. It’s that personalized piece — where we’re stimulating the immune system to recognize the tumor — that is really promising. This study took place before COVID, so I like to say we knew Moderna before they were cool,” quipped Dr. Berry. “It’s neat to see the same technology that was harnessed for cancer therapy also be applicable to a big public health emergency like COVID.”

Exploring the technology

While attempts to create a cancer vaccine have been in the pipeline for decades, researchers have not previously seen success. According to Dr. Berry, recent advances in science have helped pave the way. “It’s twofold. We now have immunotherapy to turn on people’s immune systems, but also the technology to tailor it to the specific person’s tumor. Vaccines in the past have been all sorts of different immunogenic products, even BCG (Bacillus Calmette–Guérin), which was a vaccine for tuberculosis.”

However, immunotherapy alone isn’t always enough. That’s where the personalized mRNA vaccine comes in, according to Dr. Weber. “This was a personalized neoantigen vaccine that was based on mutated sequences specific to an individual patient’s tumor.” This combined approach helps direct a patient’s immune response against their unique cancer and prevent recurrence.

“Without tumors present, it’s hard for the immune system to understand what it’s being stimulated against when we administer immunotherapy,” said Dr. Berry. “A neoantigen approach to treating melanoma gives us something to train the immune system on.”


Therapeutic vs. preventative vaccines

Most patients are familiar with the concept of a preventative vaccine — one that is administered as a precautionary measure to avoid an infection or disease. However, therapeutic vaccines differ in that they are administered after an individual is already affected by a disease.

“This is a question I get from my patients all the time,” said Dr. Berry. “My very well-read patients with early-stage melanoma will send a huge flurry of messages and questions, one being, ‘Can you vaccinate me against my melanoma?’ Currently, what’s being investigated is not a preventative vaccine. It’s a therapeutic vaccine paired with immunotherapy to help one’s own immune system understand how to fight a cancer that’s at high risk of coming back. There are all sorts of different prevention strategies for melanoma, but currently the only one that’s truly effective for preventing melanoma is blanket UV protection. Right now, there’s no silver bullet or vaccine available that will truly protect against the development of melanoma or early-stage disease progression.”

Future implications and access

While a phase 3 trial is already underway, the public may have to wait several years before a melanoma vaccine is approved by the FDA for use in patients. “The phase 3 trial on a similar design but with stages IIB/IIC/IIIA/IIIB/IIIC/IIID/IV resected melanoma has already started,” said Dr. Weber. “The trial will take at least a year to accrue, at least 18 months of follow up beyond that are needed, then another year for preparation of the BLA package and review by the FDA.”

In the meantime, the development of a new therapy raises age-old questions about cost and access. “You always worry about patients who are either uninsured or underinsured not being able to access the technology,” said Dr. Berry. “Traditionally, companies have tried to bridge that gap, but we just don’t know what that will look like. Currently, it takes about six weeks to turn the vaccine around. I think the goal is going to be about 30 days, but you do worry about something happening to the patient while they’re waiting on their vaccine to get processed. I think the time involved with turnaround also really speaks to the complexity of the technology as well. That will probably add to the expense, and we know that immunotherapy is already very expensive. How much is this going to add? I don’t know.”

“I’m excited about the technology, but also cautious as we await more published data. It’s only been a little more than a decade where we’ve had therapies for people with advanced melanoma. This is forging the next step.”

Despite these potential hurdles, Dr. Weber estimates that approximately 90% of melanoma patients would be viable candidates for having a vaccine made. “This is certainly a starting point for a whole franchise of trials in resected high-risk cancers and will hopefully decrease the proportion of melanoma patients that ever relapse, increasing the rate of cure in this disease,” he said.

Such an approach may also serve as a potential treatment in the future for patients with earlier stages of melanoma and different types of cancer. “If successful in stages IIB-IV resected disease it may be tested in a biomarker chosen population of stage IB/IIA patients. It will also be tested in a variety of cancers including lung cancer, head and neck, and other malignancies like bladder and renal cell cancer,” said Dr. Weber.

While the preliminary results are cause for optimism, more research is ultimately needed, said Dr. Berry. “’I’m excited about the technology, but also cautious as we await more published data. It’s only been a little more than a decade where we’ve had therapies for people with advanced melanoma. This is forging the next step.”

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