During the process of transformation from a normal cell into a cancer cell, a cell acquires a series of changes in its DNA (mutations). In certain cancers, the tumour evolves by acquiring mutations that confer growth advantages or resistance to therapies. However, DNA mutations can also result in changes to the proteins of the cancer cell that are displayed on the cell surface and can be recognised by T cells. These mutated proteins are called neoantigens. Neoantigens are only present on tumour cells and are not found in normal, healthy tissues. Achilles uses the principles of tumour evolution to identify patient-specific neoantigens present on all cancer cells of an individual in order to exploit cancer’s Achilles’ heel.
The mutations that have accumulated in the normal cell before it transforms into a cancer cell will be carried by all the cells of the growing cancer. These mutations are referred to as clonal neoantigens. In terms of the cancer cell’s evolution, they form the trunk of the growing evolutionary tree. Later mutations will be present in only a subset of the cancer cells. These are known as subclonal or branch mutations, as they represent the branches of the cancer’s evolutionary tree. Neoantigens can be targeted with immunotherapies which will attack the cancer cells. However, if the therapy targets only the subclonal mutations, this will result in the pruning of specific branches rather than the elimination of the whole cancer. This allows the cancer to evolve and develop resistance to the therapy. In order to fell the entire tree, it is necessary to target the clonal neoantigens that are present in every cancer cell.
Achilles has built a world-leading bioinformatics platform to identify clonal neoantigens from each patient’s unique tumour profile. Our proprietary PELEUS™ platform was developed from our co-founder Professor Charlie Swanton’s academic TRACERx bioinformatics pipeline and has been validated using our exclusive access to the TRACERx sequence data.