RNA vaccines – will they treat cancer?
Author: Agata Młodzińska
The development of an RNA vaccine led to the successful treatment of the Zika virus. However, its production is a long and complicated process. Despite the obstacles, these preparations give us hope in the fight against cancer.
Vaccines are preparations that protect us from diseases caused by micro-organisms such as viruses, bacteria, parasites. They contain living or dead biological fragment that triggers our immune system to action. The presence of "foreign" biological material (an antigen) in an organism leads to production of specific antibodies, namely T-Lymphocytes. These cells recognize the antigen and destroy it. The produced antibodies protect us from diseases – in the case of another contact with the micro-organism, our immune system is prepared and knows how to neutralize it.
The first vaccines were developed as early as in the 18th century and a great many more have been developed since then. These include smallpox, tetanus, cholera, rabies, bubonic plague, anthrax, mumps, polio and flu vaccines. Unfortunately, the produced vaccines protect us only from the form of micro-organism they have been developed against. Thus, every modification (mutation) of a micro-organism may cause our organism to treat it as an entirely new threat that fighting against has to be “learned” from the scratch. Bacteria and viruses have great adaptability to various environmental conditions, becoming immune to current vaccine preparations. Researchers develop new vaccines to respond to the demand and occurrence of new and mutant forms of micro-organisms. The flu vaccine can serve as an example here, due to the fact that there are currently three subtypes of it – A, B and C. Additionally, the search for its new forms is a work in progress. The production of live or attenuated vaccines is very time-consuming and requires an individual approach to a disease entity. Due to numerous limitations, the researchers have developed innovative preparations – RNA vaccines. This type of vaccines, referred to as the "all-purpose vaccines", sparks the interest of the pharmaceutical industry. Its working principle, however, is entirely different.
RNA vaccines are preparations developed on the basis of messenger RNA (mRNA) instead of a live or attenuated micro-organism. Messenger RNA is used to produce any viral, bacterial or parasitic protein that consequently triggers the immune system to produce antibodies, similarly to classic vaccines. Whereas developing RNA vaccines is much simpler and less time-consuming.
Researchers from USA have used an RNA vaccine against the Zika virus. The virus is spread by mosquitoes, the infected people present basically no symptoms, and its main consequence is microcephaly among the children of the women infected by this micro-organism. The researchers used the LNP carrier that transferred the modified mRNA encoding wild-type and modified ZIKV structural genes typical for this type of virus. The preparation was injected into mice and the entire experiment has been closely monitored. “Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers that protected against ZIKV infection and conferred sterilizing immunity” – we can read in the publication of Cell (Source: Richner et al., 2017, Cell 168,1114–1125, March 9, 2017 a 2017 Elsevier Inc. http://dx.doi.org/10.1016/j.cell.2017.02.017). Positive test results in mice provided the opportunity to use the preparation for clinical trials on human subjects.
In the meantime, the researchers went one step further and began tests on using the mechanism of action of RNA vaccines in cancer prevention. Introduction of mRNA responsible for the production of proteins/particles typical of a given tumor type should enable its neutralization and the confernment of sterilizing immunity. Additionally, familiarity with proteins/particles typical of several types of tumors should pave the way for developing a universal RNA vaccine, containing comprehensive information about multiple types of cancer. In practice, the idea turned out to be much more complicated and developing such a universal vaccine became a challenge. Researchers at the CureVac pharmaceutical company developed the first prostate cancer RNA vaccine, which after the second phase of clinical trials on humans resulted in a failure. The researchers have observed no improvement in health condition of patients suffering from metastatic prostate cancer after standard therapies. Despite this failure, there has been an increasing number of reports on the use of RNA vaccines that prevent the incidence and progression of other types of cancer. Lately, researchers at the BioNTech company informed that they had had positive results in the tests of melanoma RNA vaccine. The vaccine was developed with the use of RNA-lipoplex carrier of RNA particles encoding 4 antigens typical of melanoma cancerous cells: NY-ESO-1, MAGE-A3, tyrosinase and transmembrane phosphatase. The researchers observed the immunological response against the mentioned antigens, as well as the additional presence of interferon-alpha responsible for the communication between cells to eliminate antigens and triggering the immune system to action.
There are over a dozen of RNA vaccines that are currently undergoing clinical research trials. According to Laura DeFrancesco (source: L. DeFrancesco, Nature Biotechnology, vol 35, no. 3, March 2017) the global leaders in the development of RNA vaccines are the forementioned CurVac and BioNTech companies, as well as Moderna, Argos and GSK - Vaccine Research Center. Vaccines have been developed against breast cancer, skin cancer, prostate cancer, lung cancer (NSCLC), kidney cancer (RCC), and viruses/viral diseases: rabies, chikungunya, HIV virus, RSV virus, H10 and H7 influenza viruses, HMV virus, Zika virus and HMPV virus. Some vaccines are in the pre-clinical phase, which focuses on determining the influence of the preparation on an organism in in vivo and in vitro conditions, and making an estimate of the appropriate concentration of the active substance. Skin cancer and prostate cancer RNA vaccines are in the first phase of clinical trials, where the first contact of a patient with the preparation is examined. Preparations developed against HIV or lung cancer are in the second stage of clinical trials. This phase involves administering – apart from the RNA vaccine – a placebo, in order to determine the effects of the preparation. Kidney cancer RNA vaccine, developed by Argos, is the closest to finishing the clinical trials – it is currently in the third phase. The last phase includes testing the preparation on a large group of patients (several thousand) in a period of time from several to over a dozen years.
If the clinical research trials are successfully concluded, we can be certain that RNA vaccines will become the cancer treatment breakthrough of the 21st century. Unfortunately, it may take well over ten years before an RNA vaccine is produced and released on the market.