With its role in the still recent field of 'immunopeptidomics', in which tumours are analysed for cancer-specific antigens in the form of small proteins (peptides), VITO is helping to pave the way for what may soon develop into a form of immunotherapy tailored to the needs of the patient. But first, much more data is needed with regard to the identity of these antigens. VITO aims to obtain these data together with academic and industrial partners via an "identification platform" which allows the immediate identification of antigens in tumour tissue.
In immunotherapy, which has provided good results as an anticancer treatment in recent years, the aim is for the patient's immune system to clear away the tumour cells itself, partly by better recognising them. This recognition is performed by so-called antigens which are produced by all cells, not just cancer cells, and are "presented" to specific immune cells - neoantigens are antigens produced specifically by tumours and which allow the immune system to distinguish cancer cells from normal cells. Immunotherapy aims to strengthen the response of the immune system against these neoantigens (e.g. through vaccination) so that a strong(er) immune response can be generated.
Identifying antigens
In order to properly tune immunotherapy, it is important to know exactly which antigens are presented by the cancer cells. At present, this identification is not optimal. And that's because prediction of tumour cell neoantigens is based upon computer models which are often still far too little based upon real-life biological data. Using the immunopeptidomics platform, the antigens themselves are measured and their structure determined, rather than based upon predictions. This will allow us to improve prediction models and discover new antigens (not previously predicted).
With this prediction in hand, immunologists can develop immunotherapies, for example by imitating the neoantigens in the form of small proteins (so-called peptides) which then evoke the same immune response, however a much more powerful one. This can be done in several ways, via T-cell therapy, mRNA vaccines or by offering the peptides themselves. All these therapies aim to activate and strengthen the body's own immune system and clear away the cancer cells. This is a form of vaccination against cancer, except that in this case the pathogen is the body's own cells - and so the immune system's "natural" response is enhanced for that particular patient with that particular tumour.
But in order to apply this type of immunotherapy, it is important to properly characterise the tumour-specific antigens. Moreover, they differ not only from one type of tumour to another, but may also vary from one person to another. As such, this strategy forms the basis of a form of personalised immunotherapy.
To this end, researchers are currently developing a platform which can identify and characterise useful neoantigens, initially in colon cancer tumours - but with the potential subsequently to expand the platform to all types of cancer. The research is part of the ImmunoPepX project supported by VLAIO, in which not only VITO but also the KU Leuven, the VUB, the Janssen pharmaceutical company and the Ghent start-up, myNEO, are collaborating.
The platform will be built, following a complementary strategy of identifying the neoantigens of tumour cells, by combining a strong bioinformatics approach with enhanced immunopeptidomics (the analysis of immune-related peptides), whereby this should lead to the determination of both the specificity of neoantigens and the reactivity of immune cells to them.
The tip of the iceberg
Like proteomics, the more common brother of peptidomics in which all the proteins of a cell or an organism are mapped, peptidomics also aims to identify and characterise all peptides. The difference is that in both fields only the tip of the iceberg is analysed, but in proteomics researchers at least know how much is still underwater because we can predict the proteins from the known genes. "We can't do this to the same extent with peptidomics because we don't have a complete reference, such as a genome, and we are interested in what deviates from what we expect," says Geert Baggerman of VITO and UAntwerp, who wrote a PhD on peptidomics twenty years ago and can therefore be seen as a pioneer in this field. "Moreover, this is where it comes down to identifying what deviates from the norm (healthy cells), so we're actually looking for a needle in a haystack. In addition, tumour cells often create very few neoantigens, which means that you have to use very high resolution and sensitivity in order to be able to see them".
Identification and characterisation are performed with high-tech equipment in specialised proteomics labs at UAntwerp, including mass spectrometers which can distinguish molecules on the basis of their molecular mass. This equipment is unique in our country, although this also applies to the specific field of immunopeptidomics. The first scientific papers on this subject appeared a while ago but only recently technologies have matured sufficiently to do it with adequate sensitivity," says Baggerman. ImmunoPepX can be seen as a first important collaboration in this field, between both academic and industrial partners. The project brings together complementary expertises, whereby that of VITO can be summarised as high-resolution peptidomics.
At first, the project will compile a unique dataset based upon clinical data from 15 colon cancer patients. Baggerman: "This will include a full screening of the DNA, the RNA, the proteome, the immunopeptidome (the identified antigens) and this combined with analyses related to the immune response. Once we have the dataset, we will be able to predict and also validate the neoantigens of these patients with very high reliability." The fundamental research can also serve to prepare algorithms for identification and characterisation for future use. "ImmunoPepX will thus become the best platform available for the analysis of neoantigens, which will furthermore integrate all the necessary elements."
Neoantigens play a role not only in cancer, but also in other conditions such as infectious diseases. These are of course also fought by (the same) immune system. It is not proliferating tumour cells which produce and supply neoantigens, but cells infected by viral particles, for example. As such, immunopeptidomics research offers a broader perspective on immunotherapy, based upon a personalised approach whereby the treatment is tailored to the patient - allowing the most optimal immune response to be evoked.
More information
geert.baggerman@vito.be