With the significant success of COVID-19 messenger RNA (mRNA) vaccines, they continue to garner increasing attention for therapeutic strategies due to advantages such as rapid production, high immune response, and safety. Scientists around the world continue to work diligently to apply mRNA technology vaccines for various cancer types. To date, there are more than 20 mRNA cancer vaccines that are enrolled in clinical trials, however none are approved yet for clinical use.
Optimizing mRNA production and its delivery system are the two key factors to consider when designing an mRNA vaccine. The targeted delivery of mRNA to desired organs remains a considerable barrier for in vivo applications of mRNA technology. For example, a challenge to mRNA vaccines is that a significant portion of the mRNA ends up in the liver. This increases the risk of side effects in the liver, such as reversible hepatic damages and T cell-dominant immune-mediated hepatitis, which might be caused by the undesired expression of antigens in the liver.
The response of cancer vaccines is forecasted to be more efficacious and long-lasting if more of the mRNA is directed to the lymph node (LN) to lessen side effects and increase the immune response. The lymphatic system-where B cells, T cells, and other immune system cells are concentrated-is a vital target for vaccines because this is where immunity against a foreign antigen, or in this case, a cancer antigen, is acquired.
Now, an innovation from researchers at Tufts School of Engineering could provide a promising strategy for developing next-generation mRNA cancer vaccines. The development of a new and potent lymphoid-organ-specific mRNA vaccine for targeting cancer in mice was published in the journal Proceedings of the National Academy of Sciences (2022; https://doi.org/10.1073/pnas.2207841119).
The mechanism of the cancer vaccine in this study, like mRNA COVID vaccines, also delivers mRNA in tiny lipid nanoparticles that eventually fuse with cells in the body, allowing the cells to "read" the mRNA and produce viral antigens that activate the immune system. The current LN-targeting lipid nanoparticles (LNPs) used in the Pfizer COVID-19 vaccine were found to favor delivery to the liver versus the lymphatic system by a 4-to-1 ratio. Here, the scientists reversed that selectivity with their new LNP to prefer lymphatic delivery over liver by a 3-to-1 ratio.
"What we are doing now is developing the next generation of mRNA vaccines using lipid nanoparticle delivery technology, with the ability to target specific organs and tissues," stated Qiaobing Xu, PhD, Professor of Biomedical Engineering at Tufts School of Engineering. "Targeting the lymphatic system helped us to overcome many of the challenges that have faced others in developing a cancer vaccine."
The researchers investigated an endogenous LNP, named 113-O12B, without the modification of any active targeting ligands as a delivery vehicle in the therapeutic mRNA cancer vaccine. As a standard for comparison, the researchers used an LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. They discovered that LNP 113-O12B demonstrated enhanced and specific expression in the LN compared with the LNP formulated with ALC-0315, indicating the LN-specific targeting ability.
The targeted delivery of full-length ovalbumin (OVA)-encoding mRNA vaccine demonstrated enhanced CD8+ T-cell response. This resulted in improved protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model. Remarkably, 113-O12B can effectively deliver both a full-length protein and a short-peptide-based, antigens-encoded mRNA, therefore offering a universal platform for mRNA vaccines.
When treating the mice with metastatic melanoma,113-O12B encapsulated with TRP-2 peptide (TRP2180-188)-encoding mRNA also exhibited excellent tumor inhibition. Furthermore, when paired with anti-programmed death-1 (PD-1) therapy, the vaccine achieved a 40 percent probability of complete response-no tumors-with no recurrence in the long-term in the regular B16F10 tumor model. This indicates broad application of 113-O12B from protein to peptide antigens. Finally, all the mice that were in complete remission were prevented from forming any new tumors when injected later with metastatic tumor cells, demonstrating that the mRNA cancer vaccine led to excellent immune memory and provides long-term antitumor efficacy.
"Cancer vaccines have always been a challenge because tumor antigens don't always look so 'foreign' like antigens on viruses and bacteria, and the tumors can actively inhibit the immune response," concluded Jinjin Chen, PhD, a postdoctoral research fellow in Xu's lab. "This cancer vaccine evokes a much stronger response and is capable of carrying mRNA for both large and small antigens. We are hoping that it could become a universal platform not only for cancer vaccines, but also for more effective vaccines against viruses and other pathogens."
Dibash Kumar Das is a contributing writer.