Gastric cancer is one of the leading causes of cancer-related mortality worldwide, and peritoneal metastasis, wherein the cancer spreads to the peritoneum or the lining of the abdominal cavity, represents the most common form of recurrence after gastric cancer surgery. This form of metastasis is particularly associated with poor survival outcomes, as current first-line treatment options, including anti-PD-1 therapy combined with chemotherapy, have proven ineffective against peritoneal dissemination.
Immunotherapy presents an attractive option for tackling this challenging condition—more specifically, vaccines that target tumor-specific antigens called neoantigens (neoAgs) are being explored as an option to generate durable antitumor responses in patients, with fewer off-target effects. Now, in a study published online in the journal Gastric Cancer on July 31, 2025, a team of researchers led by Professor Kazuhiro Kakimi, Department of Immunology, Kindai University, Faculty of Medicine, Japan, including Dr. Koji Nagaoka, from the same university; Dr. Hidetaka Akita, Graduate School of Pharmaceutical Sciences, Tohoku University; Dr. Keiji Itaka, Center for Infectious Disease Education and Research, Osaka University; and Dr. Tatsuhiko Kodama, Research Center for Advanced Science and Technology, The University of Tokyo, developed a neoAg mRNA (messenger RNA)-based vaccine that shows potent antitumor efficacy against gastric cancer cells, especially in combination with the standard anti-PD-1 therapy.
This vaccine consists of mRNA encapsulated within lipid nanoparticles (LNPs)—this mRNA is synthesized by in vitro transcription and comprises three linked minigenes, which code for three neoAgs that they previously identified from the mouse gastric cancer cell line YTN16. Once the vaccine was synthesized, they proceeded to test it, both alone and in combination with anti-PD-1 therapy, in various mouse models. The results were very promising—firstly, the vaccine induced a higher frequency of neoAg-specific cytotoxic T cells in mice than a similar neoAg-dendritic cell-based vaccine. On testing in a therapeutic setting, mRNA-based vaccination led to tumor regression and eradication in all treated mice, and this effect was enhanced in combination with anti-PD-1 therapy.
How can we explain the increased antitumor efficacy of this combined treatment? The key lies in how tumor-reactive T cells undergo differentiation within the tumor environment—Prof. Kakimi elaborates that they "progress from a progenitor exhausted state (Texprog), through an intermediate exhausted state (Texint) with strong effector function, and ultimately into a terminally exhausted state (Texterm)." While treatment with only anti-PD-1 therapy led to an increase in effector (Texint) cells, there was no corresponding increase in the production of the progenitor (Texprog) cells required to sustain these effector cells. In contrast, by combining anti-PD-1 therapy with the vaccine that expands Texprog cells, both populations were increased, resulting in a sustained antitumor effect.
Most promisingly, the vaccine shows impressive antitumor efficacy against peritoneal metastasis, which has historically been very challenging to treat. The vaccine on its own showed a protective effect in mice that were inoculated intraperitoneally with YTN16 cells. In combination with anti-PD-1 therapy, it was shown to reduce tumor growth even in mice with already established peritoneal metastases.
These results are especially exciting in the context of the push towards next-generation, 'personalized' cancer treatment. As Prof. Kakimi explains, "NeoAgs, derived from individual genetic alterations in each cancer patient, serve as unique immunological targets on tumor cells and represent the key to personalized immunotherapy."
However, there are some challenges that remain. Prof. Kakimi states that "Although we observed that these vaccines had remarkable therapeutic efficacy, the greatest challenge lies in identifying the true neoAgs that are recognized and attacked by T cells in vivo." Researchers worldwide, including Prof. Kakimi, are currently striving to improve the process of predicting and identifying these neoantigens. Nevertheless, multiple pharmaceutical companies are betting on the therapeutic potential of these vaccines—for instance, Moderna and BioNTech are conducting clinical trials that utilize various neoAg-based mRNA vaccines in combination with immune checkpoint inhibitors.
This study demonstrates the immense therapeutic potential presented by personalized cancer vaccines that use mRNA technology, paving the way for the next generation of genome-informed cancer immunotherapy!
