A major mRNA cancer vaccine breakthrough eliminates tumors in mice
Scientists around the world have been working hard to find a vaccine for various cancer types. It is, however, not an easy thing to achieve for several reasons such as cancer cells' resemblance to healthy cells. Another example would be that, unlike viruses and bacteria, cancer cells are not foreign to our immune system and each individual’s tumor has its own distinguishing antigens.
The range of cancer vaccines is not extensive. There are some vaccines that are used in the treatment of viral cancers such as Hepatitis B and HPV vaccines, both of which cause various cancers. However, researchers are working on developing more vaccines for many types of cancer, including melanoma, leukemia, brain tumor, lung cancer, and more.
But now, researchers from Tufts School of Engineering have developed a new and potent vaccine for targeting cancer in mice, according to a press release published by the institution.
The vaccine works quite similarly to Pfizer and Moderna's COVID-19 vaccines, which deliver mRNA in tiny lipid bubbles that eventually fuse with body cells, enabling the cells to "read" the mRNA and produce viral antigens, which are tiny fragments of the virus that trigger the immune system.
The mRNA codes for antigens present in cancer cells, and the bubbles, also known as lipid nanoparticles, may specifically target the lymphatic system, where immune cells are "trained," making the response far more effective.
“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,” said Qiaobing Xu, one of the authors of the study and a professor of biomedical engineering. “Targeting the lymphatic system helped us to overcome many of the challenges that have faced others in developing a cancer vaccine.”
There have been more than 20 mRNA cancer vaccine trials so far, but it's also been observed that much of the mRNA ends up in the liver, so there remains a risk of liver inflammation and damage.
Reaching the best target
The researchers achieved the target via modifying the chemical structure of the lipids that form the bubbles until they end up with a combination that goes to the targeted organ.
After subcutaneously injecting them into mice, the researchers discovered an LNP that accumulated in the lymph nodes. They also suggest that LNPs gather blood-stream molecules on their surface, and those chosen molecules attach to certain receptors in the target organ.
It was discovered that the present LNPs utilized in the Pfizer COVID-19 vaccine favored liver delivery over lymphatic system distribution by a four-to-one ratio. The researchers reversed that selectivity with their new LNP to prefer lymphatic delivery over liver by a three-to-one ratio.
The research has shown that mice with metastatic melanoma, who were treated with the lymph-targeted vaccine showed significant inhibition of tumors. Furthermore, when paired with another already available medication that aids in preventing cancer cells from suppressing an immune response, the vaccine achieved a 40% probability of complete response with no recurrence in the long term.
“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,” said Jinjin Chen, a postdoctoral research fellow at Tufts University who is part of Xu’s research team.
“This cancer vaccine evokes a much stronger response and is capable of carrying mRNA for both large and small antigens,” Chen said. “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.”
The results of the study were published in the journal Proceedings of the National Academy of Sciences.
The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8+ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen–bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180–188)–encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti–programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.