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Novel cancer vaccines with virus based cDNA libraries and monitoring for resistant tumour cell populations in prostate cancer

Final Report Summary - ONCOVIRVAX (Novel cancer vaccines with virus based cDNA libraries and monitoring for resistant tumour cell populations in prostate cancer)

There has been considerable clinical progress with immunological approaches to cancer treatment but great challenges remain. Progress depends on increasing knowledge of the epitopes on cancers and our ability to manipulate the immune response to these in model systems and in the clinic. We have previously shown in model systems that the expression of a cDNA library derived from a tumour (or modified from normal tissues) in an oncolytic virus, Vesicular Stomatitis Virus (VSV), is capable of generating a highly effective immune response to tumours. In our ERC Advanced Award we set out to translate this finding for prostate cancer patients into the clinic using a clinically relatively safe adenovirus, with cDNA prepared from prostate cancers in mouse and man. We also sought to understand the mechanisms of the immune response to cancers generated by the cDNA library vaccines to underpin further work of translational relevance. We envisaged using this vaccine in combination with the non-specific factors that can enhance an immune response in patients such as checkpoint inhibitors. In parallel with the development of the vaccine we developed proteomic and genomic approaches to identify relevant markers of the content and activity of our novel vaccines.

We successfully created an adenoviral based cDNA library vaccine for prostate cancer which had a modest impact on tumour growth in mice. We were able to identify with the VSV vaccine the key antigenic determinants of the anti-cancer immune response at different sites within the host and the diversity in these determinants between different sites. We identified the importance of antigen truncation in the formation of the cDNAs within the library. We identified mechanisms of the emergence of resistance to viral cDNA library vaccines and showed that with the VSV vaccine immune checkpoint blockade increased the anti-cancer effect in the mouse model systems. We successfully developed innovative proteomic approaches and pathway analysis to identify changes in the tumour proteome associated with the use of the cDNA viral vaccines in both Vesicular Stomatitis Virus and adenovirus. We designed and developed a Next Generation Sequencing approach to characterise viral cDNA library vaccines in order to be able to support future clinical applications.

Our work was associated with the submission of applications for Patents in the USA and Europe. We have been granted 11 Patents the whole library approach to vaccine development, as well as specific epitope portfolios in the vaccine.

Unfortunately the efficacy of the adenoviral cDNA prostate cancer vaccines was considerably less than the VSV cDNA vaccines and considerably less than checkpoint inhibitors used alone in our model systems. We have therefore not achieved our primary goal of producing a vaccine that is yet sufficiently effective for the clinic.

We have continued to explore related alternative approaches to enhance the efficacy of this anti-cancer viral vaccine strategy. We explored creating cDNA libraries in Maraba virus, which is closely related to VSV but maybe safer for clinical practice. We made some technical progress in the creation of those library vaccines. We explored generating a portfolio of neoantigens based upon the efficacy of APOBEC associated mutagenesis and this will be explored further. We have carried out preliminary experiments to evaluate the potential of the addition of immune adjuvant constructs to the cDNA virus libraries and these approaches will be pursued in future.

The ERC Advanced Award proved a key component in sustaining an excellent research environment in Leeds University and also provided input from the Leeds group into a strategic collaboration with the Mayo Clinic and regular exchange between the groups. It was an essential component of our research group throughout the five years.