The Modi-2 vaccine exploits a second post-translational modification, stimulating the production of CD4 T cells using tumour-associated peptide epitopes in which the lysine residues are converted to homocitrulline. This change occurs via a process known as carbamylation, leading to a change in molecular charge which, in turn, alters antigenic properties and can result in the generation of unique T cell epitopes. Carbamylation can be mediated in vivo by an enzyme called myeloperoxidase (MPO) which is produced by a range of immune cells, including myeloid-derived suppressor cells (MDSCs), the major suppressor population of the immune system, particularly within the immunosuppressive tumour microenvironment.
Scancell has identified homocitrullinated epitopes derived from several proteins, including vimentin, aldolase, cytokeratin 8, immunoglobulin binding protein (BiP), nucleophosmin (NPM), α-enolase and heat shock protein (HSP-60), all of which generate potent T cell responses in preclinical models. Evidence exists for all of these proteins having a link to a wide range of cancer types:
- Aldolase (like α-enolase) is a glycolytic protein which is highly expressed in a number of cancers and upregulation of the aldolase gene has also been linked to poor prognosis in colon cancer, renal cell carcinoma and colorectal cancer.
- Keratins are the largest family of intermediate filament proteins and have a wide tissue distribution, multiple functions and disease associations. Cytokeratin expression, along with the cytoskeletal protein vimentin, results in increased invasion and metastasis in breast cell carcinomas and melanomas.
- BiP is preferentially expressed on the surface of stressed cancer cells, where it is involved in the regulation of critical oncogenic signalling pathways.
- NPM plays a variety of roles in cellular metabolism and overexpression of NPM has been reported in multiple human cancers including those of the pancreas, prostate, liver, colon, stomach and thyroid.
- High expression levels of HSP60 have been noted in several cancers; it favours the survival of certain types of tumour cells and, in some cases, may be essential for tumour-cell growth.
For the first time, Scancell has been able to demonstrate that anti-carbamylated T cell responses can be stimulated against these proteins and that these can mediate potent anti-tumour therapy. A short list of specific homocitrullinated peptides have now been selected for clinical development as the Modi-2 vaccine, that have the potential to address different cancer indications to Modi-1, including tumours with a particularly immunosuppressive environment.