During the process of transformation from a normal cell into a cancer cell, a cell acquires a series of changes, or mutations, in its DNA. In most cancers, the tumor 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 these can be recognized by T cells. These mutated proteins are called neoantigens. Neoantigens are only present on tumor cells and are not found in normal, healthy tissues. Achilles uses the principles of tumor evolution and our AI-powered bioinformatics PELEUS™ platform to identify the earliest-forming neoantigens and develop T-cells to target them.
The mutations that accumulate as a normal cell transforms into a cancer cell will be carried by all the cells of the growing cancer. These mutations are referred to as clonal neoantigens and can be represented as the ‘trunk’ of the cancer’s growing evolutionary ‘tree’. Mutations that arise later in evolution 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 (branch) 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 for the entire tree to fall, it is necessary to target the original, clonal, neoantigens that are present in every cancer cell.
Achilles has built a world-leading, AI-powered bioinformatics platform called PELEUS™ to identify clonal neoantigens from each patient’s unique tumor profile. Our proprietary PELEUS™ platform was developed and validated with sequence data from the landmark TRACERx study led by our co-founder Professor Charles Swanton of the Crick Institute. Achilles has exclusive commercial rights to the TRACERx study, which has generated one of the largest data sets ever collected to analyse tumor evolution.