Proteogenomics Platforms Establishing Personalized and Precision Neoantigen Therapeutics in Cancer

Additional Supervisor: Dr George Rassidakis, MD, Karolinska Institutet

Background

Genome sequencing has revolutionized our understanding of cancer 1. However, highly penetrant mutated targets are not usually identified in any given patient population. This limits the wide-spread implementation of targeted therapeutics in stratified patients. Rather, emerging views in precision medicine require exploitation of personalized information towards patient-specific therapeutics.
A new paradigm in therapeutics involves stimulating the patients’ own immune system to eradicate cancer. The success of immune checkpoint antibodies indicate that the immune system is poised for exploitation as a therapeutic 2. Cancer cells also produce a unique landscape of mutant antigens that can function as immune stimulatory vaccines. A recent landmark study highlighted an inter-disciplinary roadmap for vaccinology 3 requiring the translation of the genomic cancer bar-code to mutant MHC class I mutated antigens from which to develop precision cancer vaccines.

Although many cancer types might benefit from precision neoantigen vaccinology therapeutics, we focus here on T-cell cancers. T-cell lymphomas (TCLs) represent approximately 10% of all non-Hodgkin lymphomas with generally poor survival because of treatment failure. Intensification of chemotherapy has generally not proved successful, and the strategy in relapse has been to aim for second-line chemotherapy and consolidation with autologous stem cell transplantation. There is an urgent need for novel, personalized therapeutic approaches including immunotherapy, which has shown very promising results in recent clinical trials of other lymphoma types.

Aims
Neoantigen cancer therapeutics are expected to be of benefit in cancers with a defined mutagen load or defined chromosome instability that generate novel fusion/mutant antigens. We will focus training on developing proteogenomics platforms in T-cell lymphoma which is considered of high unmet clinical need and which is of high priority focus in developed countries. This produces a rich source of mutant antigenic material, since a number of recurrent genetic abnormalities have been discovered in such lymphomas 4.

Year 1-2: Cancer neo-epitope discovery platform. The first training stage for the PhD student involves neo-epitope discovery using matched tumour and normal cells; the student would use (i) current bioinformatics software to define mutated genes, mutant mRNA, RNA editing events, intron-translation, and chromosomal fusions from next generation DNA and RNA sequencing to create a mutant protein reference database that is patient specific; and (ii) this reference database orthogonally to identify mutated MHC class I peptides using mass spectrometry.

Year 2-3: Developing cell models to measure the dominating neoantigen source in human cancers. Using this optimized platform, the student will develop key cells derived from T-cell lymphomas in order to define the sources of neoantigens in cancers. Mass spectrometric assays will measure the extent to which all sources of neopeptides are derived from tumour cells. The use of this model provides the opportunity for the student to be trained in mass spectrometry, cell biology, and to define the impact of chemical inhibitors on increasing the neoantigen landscape. This pipeline forms an in vitro drug-discovery cell model for human vaccination development.

Year 3-4: Developing vaccine models. Once the platform above is applied to tissue and cell lines, we would focus efforts on purify cytotoxic T-cell clones from patients, identify cancer neo-epitopes, and begin to test for T-cell killing of the lymphoma populations in vitro in combination with sets of mutant peptide vaccines. In particular, a key question would be whether inhibition of RNA splicing or non-sense RNA decay increases MHC Class I –mutated antigen presentation but also sensitize to existing T-cells isolated from patients. This produces a personalized and precision discovery platform to determine whether novel drug leads can be identified that increase T-cell killing of tumours.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you are encouraged to contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine