This transcript has been edited for clarity.
Hello. I'm David Kerr, professor of cancer medicine at University of Oxford. I'd like to talk to you today about a study that's been published recently in The Lancet that is science fiction becoming science fact.
The title of the paper is "Individualised Neoantigen Therapy mRNA-4157 (V940) Plus Pembrolizumab Versus Pembrolizumab Monotherapy in Resected Melanoma (KEYNOTE-942): A Randomised, Phase 2b Study." I'll talk more about the design in a moment.
We know that neoantigens are immunogenic molecules that usually arise from nonsynonymous cancer-specific mutations. These are then translated into proteins, which are processed and presented through major histocompatibility complex and can stimulate really strong T-cell responses, part of the whole sense of activating the body's own immune system to recognize and destroy tumor cells.
In this adjuvant setting after resection of melanoma, we know that checkpoint inhibitors are fairly effective; but still, a very large number of patients relapse despite monotherapy with drugs like pembrolizumab. Here, they made a personalized mRNA vaccine. This is a remarkable technology.
The way that they went about it was that the transcriptome was established by RNA sequencing using patient-specific data from whole-exome sequencing, RNA sequencing and then human leukocyte antigen typing. They take all of those data points from individual patients and feed them into a bioinformatics system, which then establishes the amino acid sequences of up to 34 selected neoantigens. They're ranked from top to bottom.
The top amino acid candidates are then incorporated into an optimized concatenated mRNA sequence. It's a long continuous mRNA molecule, which is then manufactured as a patient-specific individual mRNA vaccine. This is fantastic. If we talk about personalized medicine, this is at the very cutting edge of it.
What sort of results were there? It was a 2:1 randomization. The study was led by an excellent bunch of US and Australian investigators. Conventional doses of pembrolizumab were given. The vaccine was given toward a maximum of nine doses intramuscularly in combination with conventional-dose pembrolizumab.
They randomly assigned 157 patients, including 107 to the combination therapy and 50 to pembrolizumab monotherapy. The median follow-up was around 2 years. They demonstrated that recurrence-free survival was significantly longer with combination vs monotherapy. The 18-month recurrence-free survival — choosing that as a categorical cut off — was 79% for combination therapy vs 62% for monotherapy.
Most of the treatment-related adverse events were relatively straightforward. Grade 3 or grade 4 adverse events were seen in about 25% of patients in the combination group and 18% of patients in the monotherapy group.
What they've demonstrated, I think convincingly, with some very solid statistics, hazard ratios, and so on, is that you can significantly prolong recurrence-free survival with this combination of an immune checkpoint inhibitor and this remarkable personalized mRNA vaccine.
Think of all the different elements of science that have come together, including our understanding of immunology, neoantigens, and the various elements of antigen expression; how we can get immune spreading; how the T cells in particular respond; and at the very cutting edge of sequencing technology, whole-exome RNA transcriptomics and those coming together by an artificial intelligence–driven bioinformatic model that selects the best personalized vaccine for you.
I stand in awe of this science, and it's the future. There's more yet to come. There's a ton of work going on in Oxford looking at how we can find other neoantigens, how we might be able to persuade various elements of the dark genome to yield new peptide targets, and so on. This is an incredibly hot, competitive area. What a promising study and a staggering piece of clinical translational science.
Have a look at it.
"My name is Ozymandias, King of Kings; / Look on my Works, ye Mighty, and despair!"
Just for once, this might be true.
Have a look and see what you think. For the time being, Medscapers, over and out. Ahoy. Thanks for listening.
Cite this: David J. Kerr. Science Fiction Becomes Fact: Neoantigen Therapy in Melanoma - Medscape - Apr 05, 2024.
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