One of the hallmarks of cancer appears to be the ability to persist in the face of an active immune system - see fig. 1. Newly cancerous cells and tumours are able to survive and proliferate without - or at least protecting themselves - against a full-blown immune attack. Our immune system is usually able to protect us from the development of cancer but in some cases something fails and the result is more often than not - cancer.
|Fig 1. Newly recognised cancer hallmarks - note avoiding immune destruction. (Hanahan and Weinberg 2011).|
Through the recognition of 'tumour antigens' (proteins expressed only on cancer cells) or 'tumour-associated antigens' (proteins expressed differently on cancer cells), our immune system is usually able to mount an effective response toward those cells. This is the system that tumours are able to suppress yet we may be able to boost the natural immunological nature of tumours in order to cure them. The discovery of these proteins - just like those found on the surface of virus particles or bacterial cells - may allow us to effectively vaccinate people against cancer, allowing their own immune system to remove the cancerous cells.
This is what we try and achieve through cancer vaccines and immunotherapies. Kotke et al set about trying to improve upon these current immunotherapy platforms, which - as they state - suffered from a number of problems including: lack of known tumour antigens and coverage of only a few such proteins. Most current immunotherapies rely upon the immunization with only a single antigen. Previous work by the group showed that if you kill normal cells from a patient in vivo - you may be able to elicit an effective anti-tumour immune response through the induction of tumour-associated antigen immunity (when cells die they either burst and release their insides).This work effectively showed that you could immunize with a wide range of tumour-associated antigens from normal cells and protect against cancer - both circumventing the above two problems.
|VSV particles - www.standford.edu|
|Fig.3. Cloning the cDNA library into the VSV genome in forward and reverse orientations = VSV-ASEL library|
In order to express hundreds of tumour-associated antigen genes, the group used reverse-transcriptase PCR to amplify all expressed genes from normal prostate tissue and inserted the entire normal prostate tissue cDNA library into VSV. They were then able to infect mice that suffered with prostate cancer and observe what happened to their tumours - specifcally, was an effective immune response generated and did the tumour shrink? VSV virus particles were injected into the mice, virus entered the cells of the mice and began to replicate and express their genes, including the newly inserted prostate cDNA. Essentially, thousands of virus particles were adminsired, each containing a slightly different gene from the prostate cDNA library. High levels of tumour associated antigens were therfore being expressed in mice allowing for the generation of an effective immune response.
|Survival of mice treated with the VSV viruses - GFP expressing negative control; and the VSV ASEL in mice with established 'TC2' prostate tumours.|
This approached effectively cured the mice who suffered from prostate cancer. Following this treatment a number of resistant tumours emerged which were again subjected to a further treatment using a cDNA library taken from the tumour itself this time and this readily treated the secondary resistant cancers. The clinical benefits of this approach can hardly go unnoticed. The ability to administer a broad tailored therapy that has the potential to cure an established tumour will be revolutionary, especially given the relative ease at which this can be developed 'at the bedside'. The ability to easily genetically manipulate viruses has - and will continue to - revolutionise the medical sciences. Look out for the eminent clinical trials.
Kottke, T., Errington, F., Pulido, J., Galivo, F., Thompson, J., Wongthida, P., Diaz, R., Chong, H., Ilett, E., Chester, J., Pandha, H., Harrington, K., Selby, P., Melcher, A., & Vile, R. (2011). Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors Nature Medicine DOI: 10.1038/nm.2390