Cancer Vaccine Research Shows Promise as Melanoma Treatment : Oncology Times

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Cancer Vaccine Research Shows Promise as Melanoma Treatment

Froelich, Warren

Oncology Times 45(10):p 25,30, May 20, 2023. | DOI: 10.1097/01.COT.0000936848.57108.59
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Vaccine, Melanoma:
Vaccine, Melanoma

An experimental mRNA vaccine tailored to a patient's tumor, when combined with immunotherapy pembrolizumab, reduced the likelihood of death or recurrence by 44 percent in patients with surgically resected, high-risk melanoma compared to standard-of-care pembrolizumab alone, according to results of a randomized Phase IIb clinical trial.

The findings, presented during the 2023 American Association for Cancer Research (AACR) annual meeting, represented the first hint that a personalized vaccine, based on a patient's own specific tumor mutation or neoantigen, might one day become part of the cancer-fighting arsenal.

Jeffrey Weber, MD, PhD, Deputy Director of the NYU Langone Perlmutter Cancer Center—who admitted to being a “cancer vaccine skeptic”—was quoted as saying the mRNA-4157 cancer vaccine has “absolutely breathed new life” into this field.

“mRNA-4157 or KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival (RFS) in melanoma, or any cancer in my point of view, with an individualized neoantigen vaccine approach,” said Weber, who presented the study's findings at the AACR meeting.

Also adding thoughts on the study, Ryan Sullivan, MD, Associate Professor of Hematology/Oncology at Massachusetts General Hospital and study participant noted, “The relevance of this study is the impact it could have not just for melanoma patients, but for other cancers as well. From a general cancer therapeutic standpoint, this is a potential major breakthrough.”

In February 2023, the cancer vaccine in combination with pembrolizumab received Breakthrough Therapy Designation and subsequently a PRIME designation from the European Medicines Agency, both designed to speed the development of innovative treatments. A Phase III clinical trial is slated to begin this summer for melanoma.

Weber said that immunotherapies such as pembrolizumab have prolonged survival among patients with numerous types of cancers, including melanoma, and have emerged as the standard of care for many of these tumors. Also known as checkpoint inhibitors, several of these drugs are designed to disable a protein called PD-1, or programmed death 1, which helps cancer cells evade the body's immune system. In effect, once these checkpoints are blocked, cancer cells become more “visible” and vulnerable to the immune system's T cells.

One recent clinical trial, Weber noted, demonstrated that melanoma patients treated with pembrolizumab following surgery experienced a 55 percent recurrence-free survival some 5 years later compared to 38 percent for placebo. Other studies are reporting similar results.

“So, these are effective therapies,” Weber said. “The problem is if half the patients are going to relapse at 5 years; there's a major unmet clinical need due to these high relapse rates—even with frankly effective therapies—so there's plenty of room for improvement.”

To help fill this unmet need, scientists turned once again to the potential of cancer vaccines, even though the history of such efforts has been described by some as a “roller coaster ride,” filled with exhilarating highs followed by gut-wrenching lows.

“Despite hundreds of vaccine formulations and dozens of large studies, cancer vaccines have been disappointing so far and have largely failed to have a meaningful impact on oncology,” said Margaret Callahan, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, who was asked by AACR to provide commentary on this study.

Nevertheless, some members of the scientific community believed that a personalized cancer vaccine designed to incorporate molecular signatures harbored in a patient's own tumors might yet work.

“Neoantigen-based strategies may overcome the limitations that I think most of us would agree had been previous failed vaccine approaches,” Weber stated.

Like the vaccine designed to combat COVID-19, the cancer vaccine–dubbed mRNA-4157—is based on messenger RNA (mRNA), a chemical cousin of DNA that provides a blueprint to build proteins in the cell. Essentially, the vaccine is custom-built based on an analysis of the patient's own tumor neoantigens following their surgical removal. The vaccine is personalized to combat cancer mutations or neoantigens unique to the patient. As a result, T cells are produced specific to the neoantigen proteins encoded by the mRNA, which then attack any melanoma cells trying to grow or spread. The vaccine takes between 6-7 weeks to produce.

“The revelation over the past 5-10 years is that, for better or worse, virtually all neoantigens are unique to an individual patient,” Weber said. “There are very, very few true universal neoantigens that at least could have clinical utility.”

Briefly, the process begins with biopsied tumor and normal tissue removed from the patient and sequenced, then screened, for any single nucleotide variants found in the tumor but not in normal tissue. A novel computer algorithm then selects potential tumor mutations that would bind to the patient's specific HLA-type—markers that recognize which cells belong in your body and which do not. Once selected, these neoantigens are engineered into a single synthetic strand mRNA vaccine that's packaged with nanoparticles into a capsule.

In the past, similar experimental cancer vaccines only were capable of targeting a single neoantigen. The structure and size of the cancer mRNA-4157/V940 vaccine was designed to accommodate as many as 34 neoantigens based on the unique mutational signature of the patient's tumor. So instead of a weapon capable of shooting just a single bullet at a time, the new vaccine allows for a “shotgun” approach.

“The large number of antigens they're able to include in their vaccine may get around the problem that we don't really know which of these neoantigens are most relevant clinically,” Callahan said.

As outlined, the KEYNOTE-942 trial sought to assess the efficacy of the mRNA-4157/V940 vaccine in prolonging RFS in patients with resected Stages IIIB/IIIC/IIID and IV melanoma when given in combination with pembrolizumab, the standard of care for this population. Patients were randomly assigned (2:1) to receive mRNA-4157/V940 in combination with pembrolizumab patients (107) or pembrolizumab alone (50 patients). The vaccine was administered every 3 weeks for a total of nine doses, and pembrolizumab was given every 3 weeks for up to 18 cycles.

According to the results, some 78.6 percent of patients in the combination arm were cancer-free at 18 months compared to 62.2 percent of those in the pembrolizumab arm. That's a 44 percent reduced risk of recurrence or death in patients who received both the cancer vaccine and pembrolizumab compared to those who only received the PD-1 inhibitor.

The majority of treatment-related adverse events were mild, and the rates of serious adverse events were comparable between the two arms, Weber noted.

“In my view, without exaggeration, I think you'll see what is a typical COVID vaccine response—fevers, chills, fatigue, myalgia, malaise lasting anywhere between 24 to 48 hours,” Weber said. “All our patients were pre-treated with Motrin and Tylenol, which helped significantly to attenuate these side effects.”

He noted that the interpretation of results from this Phase II should be viewed with a note of caution. “It was 157 patients with 50 patients on the control arm,” he said. “And the follow-up is not 5 years; the follow-up is 2 years, which is modest. Nonetheless, I don't think these caveats detract from the significance of the data.”

When asked if the vaccine-immunotherapy combination would work in patients who had metastatic melanoma, Weber said he was “a little skeptical” that there would be enough time—given the vaccine production time of 6-7 weeks—to counter a rapidly growing disease.

“I would bet you any amount of money as a trained scientist [that] it's going to take multiple vaccinations to generate enough of an immune response to have any clinical benefit,” he said. “That's 3-4 months...The patient is going to relapse or progress.”

Callahan noted that the bottom line is “there's reason for cautious optimism” that the vaccine-immunotherapy combination would be “clinically meaningful” in the future.

“Today, the authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy endpoint,” she said. “And this is a trial that incorporates many of the lessons that we have learned over the past few years. This is the first positive randomized vaccine in melanoma.”

However, she noted the history of cancer vaccine development has been filled with multiple challenges and there still are a lot of unknowns with this cancer vaccine.

“We don't know which antigens are clinically relevant and don't know which, if any, immune correlates are clinically relevant,” Callahan said. “So, we're flying blind a little bit. But this is also a great opportunity for research and development in a place where I expect the field to move forward.”

Warren Froelich is a contributing writer.

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