Cancer immunotherapy harnesses the power of the immune system to fight cancer. Anti-cancer immune responses are usually suppressed because immune cells are trained not to attack “self”, and all cancer cells derive from normal cells (“self”) that acquired genetic mutations. Now, researchers have discovered a clever way to get around this by tricking immune cells into reacting to cancer cells as if they were virus-infected.
Recent years have seen several major breakthroughs in the field of cancer immunotherapy, whose goal it is to turn the immune system into a highly targeted, cancer-killing machine. The immune system can be divided into two arms: the innate immune system, which acts as a rapid, first line of defence against unwanted invaders like viruses or bacteria, and the adaptive immune system, which provides a more gradual but very specific and potent response against the particular invader in question. Cells of the innate immune system are generally first to detect an infection and trigger an alarm that recruits cells of the adaptive immune system to come and fight it. It is therefore necessary to engage both arms of the immune system to target cancers effectively. An example of cancer immunotherapy already in the clinic is the use of immune checkpoint inhibitors (Antonia et al., 2016) that work by blocking immune suppression, enabling anti-cancer immune responses to swing into action.
Checkpoint inhibitors have already shown great success in treating several forms of cancer, particularly melanoma (Hamid et al., 2013), but have been less effective in treating cancers against which existing immune responses are weaker. A long-term goal in the field has been the development of therapeutic cancer vaccines, which would allow immune responses to be generated against any cancer-associated protein, called a cancer antigen. A key challenge is that most cancer antigens are also “self” antigens and our adaptive immune systems are taught early-on not to attack “self”. This could be overcome by targeting cancer antigens to innate immune cells, which would then trigger alarms to activate adaptive immune cells, essentially simulating invasion by a virus or bacterium. But this is trickier than it sounds. The difficulty has been in targeting the cancer antigens specifically to the innate immune cells in the body.
Now, researchers in Germany have discovered an exciting solution (Kranz et al., 2016). Cancer antigens, like all proteins, are encoded by DNA. In order to make proteins from DNA, our cells must first convert the DNA into its sister molecule, RNA. The RNA can then be used to make the protein. Lena Kranz and colleagues were able to deliver RNA encoding cancer antigens to innate immune cells using lipid nanoparticles. These innate immune cells reacted to the cancer antigen as if it were a viral infection, producing all the characteristic alarm signals including a key anti-viral molecule called IFNα. The alarm triggered the activation of highly specific anti-cancer immune cells, which destroyed tumours in mice with cancer. An initial test of the treatment on three clinical trial patients demonstrated the same anti-viral signalling and specific anti-cancer immunity.
Lipid nanoparticles deliver RNA encoding cancer antigen to innate immune cells, which then trigger anti-viral type immune responses against cancer cells.
Other research groups (Perche et al., 2011; Zhou et al., 1999) had previously tried to use lipid nanoparticles to deliver RNA to immune cells by adding complex targeting molecules to the surface of these particles. However, Kranz et al were able to achieve efficient targeting by simply altering the lipid ratio of the particle. More negatively charged particles were better targeted to immunological organs in the body and specifically to the innate immune cells of interest. The fact that the anti-cancer immune responses generated were anti-viral in nature is an important observation and suggests that a better understanding of anti-viral immunity will be relevant in cancer.
In the article describing their findings (Kranz et al., 2016), the researchers noted that these RNA-LPX vaccines, as they are called, are very cheap and easy to make. Further to this, this type of cancer vaccine could be deployed against a wide range of cancers given that RNA can be used to encode almost any cancer antigen.
Antonia, S. J., López-Martin, J. A., et al. (2016). Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. The Lancet Oncology. http://doi.org/10.1016/S1470-2045(16)30098-5
Hamid, O., Robert, C., et al. (2013). Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. N Engl J Med. 369(2), 134–144.
Kranz, L. M., Diken, M., et al. (2016). Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. http://doi.org/10.1038/nature18300
Perche, F., Benvegnu, T., et al. (2011). Enhancement of dendritic cells transfection in vivo and of vaccination against B16F10 melanoma with mannosylated histidylated lipopolyplexes loaded with tumor antigen messenger RNA. Nanomedicine: Nanotechnology, Biology and Medicine, 7(4), 445–453.
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