An experimental vaccine delayed the recurrence of pancreatic cancer

Therapeutic mRNA vaccine technology has reached the point where some facilities can create and rapidly deliver individualized neoantigen vaccines.

The T lymphocyte is an important part of the immune system and has become a central focus in the fight against cancer.  Researchers at Sloan Kettering decided to see if a vaccine could help people with pancreatic cancer, the third leading cause of cancer deaths in this country. 

When someone’s pancreatic cancer is surgically removed, the tumor recurs 90% of the time at a median of 7–9 month.  But there are long term survivors, and their cancers produce proteins that are immunogenic neoantigens.  The long term survivors have 12-fold higher densities of activated CD8+ T cells..

On May 10 2023 the Sloan Kettering researchers published a study of 16 people with pancreatic cancer who were vaccinated with an individualized mRNA vaccine in an attempt to activate their T cells..  From December 2019 to August 2021 when surgeons at their institution removed pancreatic cancers, they shipped hunks of tissue to BioNTech’s research lab in Europe. In Germany researchers analyzed the tumor, identified proteins that were unique to each cancer (neo-antigens), and created individualized MRNA vaccines that targeted the distinctive proteins. The vaccines contained up to 20 neoantigens suspended in lipoplex nanoparticles, and they were given intravenously.

While the Europeans were developing the uridine mRNA–lipoplex nanoparticle vaccines, (and it usually took about 9 weeks) the people with pancreatic cancer received standard treatment.  About 6 weeks post-op, the 16 people in the study received a check point inhibitor drug.  As usual it didn’t seem to do much.  Pancreatic tumor cells have a low mutation rate and checkpoint inhibitor immunotherapy doesn’t usually help.  The subjects also received standard multi drug chemotherapy--FOLFIRINOX .  At about 9 weeks after their surgery the people in the study were vaccinated.  Then they were followed for two years. 

Using an IFNγ ELISpot assay the people at Sloan Kettering learned that  eight of the 16 patients who received the vaccine, mounted neoantigen-specific T cell responses against at least one vaccine neoantigen.  Four people targeted more than one neoantigen.

At the two year mark the treatment prevented recurrence of the tumor half the time, and it was ineffective half the time. 

On further analysis it seemed that the vaccine was less effective in people who, at the time of the pancreatic surgery, also lost their spleen.   That jives with mouse data.  When a vaccine based on uridine mRNA–lipoplex technology is given to splenectomized mice it only stimulates a weak T cell responses.

Of note, although the vaccine (cevumeran) is designed to activate both neoantigen-specific CD4+ and CD8+ T cells, it apparently activates high magnitude CD8+ T cells in pancreatic ductal adenocarcinoma.

The authors concluded:  “Our results imply that a high-magnitude T cell response may contribute to a favorable clinical outcome. Thus, strategies to ensure high-magnitude responses are being pursued."

https://www.nature.com/articles/s41586-023-06063-y

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