How A Cancer Vaccine and Keytruda Work to Treat Patients With Melanoma

Among patients with advanced melanoma, long-term data have shown that a personalized mRNA cancer vaccine, when combined with the immunotherapy Keytruda (pembrolizumab), has been associated with a 49% reduction in the risk of recurrence or death for high-risk patients.

Dr. Andrew Pecora, Co-Division Chief Skin and Sarcoma Service Hackensack Meridian John Theurer Cancer Center in New Jersey, sat down for an interview with CURE to discuss how the treatment combination of intismeran autogene and Keytruda works to treat patients.

Transcript:

How does this combination of a personalized mRNA vaccine and immunotherapy work?

When you think about our immune systems, how do we come into existence and live 80, 90, 100 years when there are so many different pathogens out there that are capable of infecting us and killing us? The flu, COVID, whatever. And fundamentally, it works because T cells that we're born with are educated in our youth and augmented with vaccines to recognize foreign proteins, proteins that don't originate in our bodies, and go after the cells that are expressing those proteins and eliminate them. So, eliminate infection.

Well, it turns out cancer, even though it originates in our own cells, those cells, their DNA, has been mutated such that they're no longer our cells. They're foreigners living inside our body, and they express on their surface what are called neoantigens, new proteins that allow for the human immune system to recognize, identify and kill those cells expressing those neoantigens. Immunotherapy, in and of itself, has unleashed the immune system because cancer cells are capable of turning off an immune response through things called checkpoints and checkpoint inhibitors like [Keytruda], that's discussed in this trial, actually cover up the off switch on a T cell so that the cancer cell can't turn off the T cell once it recognizes and has been activated to kill the cancer.

That works in about half the patients with metastatic melanoma and a bit more in advanced stage 3 melanoma. Along comes the realization that if you could augment neoantigen recognition by pre-priming the immune system, no different than we do with measles, mumps, rubella vaccines or flu vaccines, you can strengthen and broaden the T cell response to these neoantigens. So, the brilliance of this approach is you take the technology that was perfected to make the COVID vaccine, and you take tumor from a patient, you extract the DNA from the tumor, you also extract DNA from a normal cell. You sequence and match the two strands of DNA, and you find where the differences are in the tumor. You then have those pieces amplified, and you messenger RNA from that mutated DNA, and that messenger RNA is then pre-loaded in little vacuoles that are sent back to me that I inject in you, no different than a vaccine. They go to the local lymph node, the mRNA goes into our cells that then make proteins, these neoproteins, and present them to T cells to say, “Hey, these proteins don't belong to us,” no different than if you do a flu vaccine or a measles vaccine, “and any cell expressing these proteins you want to get rid of.” And that augments the effectiveness of the standard immunotherapy, such that on this five-year follow up data, there was a 49% reduction at a median of five years in the risk of recurrence and death.

Transcript has been edited for clarity and conciseness.

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