The aims of PAVE are
- to elicit long-term immunity against PDAC, using multicomponent nanovaccines;
- to produce adequate preclinical models and assays, which will be more relevant for testing these new immunological approaches; and
- to track vaccine biodistribution in vivo by incorporation of imaging contrast agents within biodegradable particles.
The basic concept is to establish new strategies and approaches for cancer vaccines as a primary objective, in conjunction with modulation of the tumour microenvironment (TME), in the treatment of pancreatic ductal adenocarcinoma (PDAC). In the PAVE project, we will use a new generation of nanoparticle (NP)-based vaccines for long-term immunity. In tandem, one of our study goals will be to also improve the availability of relevant experimental animal models that are replicative of the human immune system, where currently new cancer immunotherapies need to be evaluated.
Our hypothesis is that by manipulating the TME by the components of the first nanoparticle (NP1) and incorporating multiple immunomodulating components into a second nanoparticle (NP2) to make a nanovaccine, we can achieve both activation of the immune system and penetration of T cells to its site of action as illustrated in the following figure
As there are very limited human models, and at best, only inadequate mouse models available for testing all the aspects of immunotherapy, porcine models will be developed for the proposed work to help create new generation vaccines with enhanced anti-tumour potency.
Preliminary research by our partner DTU demonstrated the pig as an ideal model for human vaccine development (Overgaard NH et al, Frontiers in genetics, 2017). Indoleamine 2,3-dioxygenase and Ras homolog gene family member C, which are also important for human cancer development and progression, were shown to respond very well in the pig model.
These preliminary data will accelerate our understanding of how the cancer evades current (chemo -and radiotherapeutic) state-of-the-art interventions, which allows cancer to progress unchecked. Ultimately, the translation of cancer vaccines into clinical applicability will require overcoming the immune tolerance and suppression of the immune system in the TME. The similarity of the porcine model to human pathophysiology will allow testing innovative NP-based vaccines with multiple, rather than single, encapsulated immunomodulating components. This will provide more accurate translation of host-tumour interactions and tumour immune escape mechanisms towards understanding the process in humans. This is essential to prevent late stage failures in immune-therapeutics and to develop more effective cancer vaccines.
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