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Neoantigens and cancer vaccines

Despite efforts to amplify tumor-specific T-cell response, no meaningful antitumor activity was yet observed. New technologies are promising approaches for the development of individual treatment options.

The relevance of T-cells in immune response is well understood and their role in cancer control beyond doubt. Despite extensive research efforts, a breakthrough in amplifying the immune response is yet to be reported. No clinically relevant antitumor activity could be reached so far. The goal of these efforts is to make an active immunisation against neoantigens (tumor antigens) available in form of a »cancer vaccine”. The response rate of immune checkpoint inhibitors seems to correlate with the mutational load, a direction that warrants further investigation by means of modern genetic methods.

Specific antigens

Neoantigens are antigens that arise from somatic mutations in the tumor itself. Therefore they are very specific to the tumor. Because of the variety of these neoepitopes across individuals, this appears to be a promising treatment avenue for a personalised approach.

Next generation sequencing

The advent and improved availability of next generation sequencing methods makes it possible to selectively target neoantigens in individual patients. On April 15, Lelia Delamarre will present results that illustrate that neoantigen-directed tumor-infiltrating lymphocyte therapy can lead to regressions of metastasis in patients.

Problem of specificity

While the number of mutations in the tumor correlates with the overall response of patients to immune therapy, it is at this time unclear which mutations trigger T-cell response. Only mutant proteins that are represented in the MHC have the potential to be immunogenic.

Outlook

For an immune response to occur, the target peptide has to bind to the tumor MHCI and the T-Cell has to recognise the MHCI/peptide complex. At the time genetic methods are employed to identify potential mutations, expressed MHCs are investigated with mass spectrometry in a effort to build a database that can be modelled with bioinformatics. These studies are currently in a preclinical stage.

Reference

Wu et al, session description and abstracts available under the session link

 

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