With the help of mRNA vaccines, researchers have succeeded in activating the immune system of mice in such a way that it specifically attacks and destroys cancer cells caused by the human papilloma virus (HPV). After a single, low dose of the tested mRNA vaccines, even advanced-stage tumors regressed completely in 80 percent of the mice. The results provide a basis for testing mRNA vaccines against cancer in human clinical trials in the future.
Cervical cancer is one of the leading causes of cancer-related death in women. The cause is almost always a previous infection with the so-called human papilloma virus (HPV). Vaccines have been available since 2006 against the most common types of HPV viruses, including HPV-16 and HPV-18, which are responsible for about 70 percent of cervical cancer cases worldwide. The vaccines reduce the risk of HPV infection and thus the risk of cervical cancer, but are only effective preventively. On the other hand, once a tumor has developed, only cancer treatments such as surgical removal of the tumour, chemotherapy and radiation therapy can help.
Vaccination against cancer
Since mRNA vaccines proved successful in the Covid-19 pandemic, numerous research teams around the world have been working to use the technology against other diseases, including not only viral diseases but also cancer. A team led by Jamile Ramos da Silva from the University of São Paulo in Brazil has now tested three mRNA vaccines designed to fight HPV tumors on mice. They focused on tumors associated with HPV-16 infection.
For the vaccine tests, the researchers first ensured that the mice developed the appropriate tumors. To do this, they inject the animals with cancer cells either under the skin, under the tongue or in the vagina. As a result, cancerous growths developed in the respective places. Ramos da Silva and her team grew these to different stages before giving the animals one of three mRNA vaccine candidates.
Immune system infiltrates and eliminates tumors
On the one hand, a vaccine with so-called self-amplifying mRNA, which multiplies in the cell and thus ensures increased production of the antigen, was used, on the other hand two non-replicating mRNAs, including one unmodified and one that is more stable thanks to a modification is and can be read more effectively. All three variants were protected by lipid nanoparticles and encoded the same antigen, a chimeric protein called gDE7. On the one hand, this contains the structure of the E7 protein that is typical for HPV-16 tumors and, on the other hand, the structure of the gD protein that occurs in the herpes simplex virus.
The result: “After a single vaccination, all three mRNA vaccines ensured that specific CD8+ T cells against the E7 protein infiltrated the tumor,” reports the research team. A relatively small dose of five micrograms of vaccine was sufficient for this. The immune cells ensured that the tumor cells died. Depending on the test line, a large proportion of the mice were tumor-free around three weeks after vaccination. Even advanced tumors regressed in 80 percent of the animals. The researchers also demonstrated that the vaccinations also have a protective effect: if they inject tumor cells into vaccinated animals, they did not develop any tumors.
Basis for clinical studies?
For comparison, the research team vaccinated some mice with a conventional protein vaccine or a DNA vaccine instead, both of which also targeted the gDE7 protein. However, these caused a weaker activation of the immune system, which was not sufficient to eliminate the tumors. To check whether the CD8+ T cell response is actually the key in the anti-tumor response, the researchers also tested the mRNA vaccines on mice in which the CD8+ T cells were switched off. In these mice, vaccination showed no therapeutic or protective effect. “This confirms that the CD8+ T cells play a crucial role in the anti-tumor immune response,” the team said.
A limitation of the study is that the tumors artificially induced in the mice are not fully comparable with HPV tumors in humans. So whether human cervical cancer would respond similarly well to appropriate vaccines is unclear. In addition, the vaccines now being tested are only directed against tumors associated with HPV-16. While this is the most cancer-causing variant, according to the World Health Organization, other variants can also cause cervical cancer.
Despite these limitations, the study shows that mRNA vaccines may in principle be able to actually have a therapeutic effect against tumors. “Our data support further evaluation of these mRNA vaccines in clinical trials,” write Ramos da Silva and her team.
Source: Jamile Ramos da Silva (University of São Paulo, Brazil) et al., Science Translational Medicine, doi: 10.1126/scitranslmed.abn3464