OUR RESEARCH

CANCER VACCINES

Similar to how normal vaccines work, in cancer vaccines, the aim is to prime the patient’s adaptive immune system to specifically target the tumour cells while ignoring healthy cells. To achieve this, tumour specific antigens, or neoantigens, need to be identified and presented to the patient’s T-cells. These neoantigens that can be specifically recognized by T cells typically come in the form of short peptides of 8–12 amino acids, on human leukocyte antigen (HLA) molecules at the cancer cell surface (1). While non-patient specific vaccines have been developed for some cancers, such as cervical cancer, in Pancreatic Ductal Adenocarcinoma (PDAC) and many other cancers, the mutational profile differs so greatly from patient to patient that it becomes nearly impossible to identify a universal neoantigen effective in majority of patients. As such majority of cancer vaccine development takes a personalized approach to Neoantigen discovery.

While the high mutational burden of PDAC presents a challenge in developing a universal vaccine and leads to a poor clinical diagnosis, it also potentially results in tumour cells which are more highly differentiated from normal healthy tissue. This would allow for a strong immune response, suggesting that PDAC may benefit from immunotherapies such as neoantigen-targeted cancer vaccines. Most efforts in the discovery of neoantigen peptides have been through indirect means such as genomic and transcriptomic sequencing to identify mutations, followed by in-sillico computational analysis to predict MHC class I-binding affinity of the resulting peptides. However, this approach has had mixed results as it is not able to predict which neoantigens will be presented endogenously or are able to induce an immune response (2). Recently, liquid chromatography-mass spectrometry (LC-MS) based approaches have been developed which are now considered the gold standard of neoantigen identification. However, such methods have not been widely employed due to the large number of cells required for such procedures and the high barrier of entry due to limited access to MS technology (3)

Using our patient derived organoid (PDO) protocol, (see personalised therapy section above) we have the ability to grow and expand patient derived PDAC cells and organoids in large quantities. This along with our expertise and access to LC-MS technology puts us in a prime position for the discovery of patient specific neoantigens for the development of cancer vaccines. By expanding PDO lines verified to express HLA class I through immunofluorescence (IF) staining, we generated enough cells to purify through immunoprecipitation sufficient MHC class 1 molecules for analyses. Any peptides bound to the purified MHC class I molecules will be isolated and identified using LC-MS to provide us with potential neoantigens.

References:

1. Rist, M. J., Theodossis, A., Croft, N. P., Neller, M. A., Welland, A., Chen, Z., Sullivan, L. C., Burrows, J. M., Miles, J. J., Brennan, R. M., Gras, S., Khanna, R., Brooks, A. G., McCluskey, J., Purcell, A. W., Rossjohn, J., & Burrows, S. R. (2013). HLA Peptide Length Preferences Control CD8 + T Cell Responses. The Journal of Immunology, 191(2), 561–571. https://doi.org/10.4049/jimmunol.1300292

2. Blass, E., & Ott, P. A. (2021). Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. In Nature Reviews Clinical Oncology (Vol. 18, Issue 4, pp. 215–229). Nature Publishing Group. https://doi.org/10.1038/s41571-020-00460-2

3. Kote, S., Pirog, A., Bedran, G., Alfaro, J., & Dapic, I. (2020). Mass spectrometry-based identification of MHC-associated peptides. In Cancers (Vol. 12, Issue 3). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/cancers12030535