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 PELEUSTM 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.
CLONAL NEOANTIGEN T CELLS
Achilles’ therapeutic approach is to target clonal neoantigens with a T cell therapy. Since every cancer has a unique set of neoantigens, this involves generating a personalised T cell product for each patient. Achilles manufactures clonal neoantigen T cells (cNeT) which are exquisitely tailored using a proprietary process to the specific set of clonal neoantigens present in the tumour.
The starting material for our product are T cells isolated from the patient’s tumour sample. These T cells are known as tumour infiltrating lymphocytes (TIL). Prior clinical studies have shown that expanded TIL can debulk solid tumours and have demonstrated durable and potent responses. The advantage of using TIL as a starting material is that they are already programmed to invade and attack the tumour.
CNeT are isolated from the TIL using our proprietary specific expansion process. The T cells are removed from the suppressive tumour microenvironment and re-activated in the lab. The resulting cNeT have been demonstrated to be fitter and more active than conventional expanded TIL products.
From tumour to treatment: generating clonal neoantigen T cells
The diagram below provides an overview of our proprietary process. More information about each step can be found by clicking on the icons.
A tumour sample is obtained from the patient and is processed to isolate T cells. A portion of the tumour is also used to generate a DNA sample for sequencing.
A blood sample is taken from the patient and is processed to isolate monocytes, a type of white blood cell. These monocytes are then used to generate dendritic cells. A portion of the blood sample is also used to provide a DNA sample for sequencing.
Sequence tumour and blood
DNA samples from the tumour and blood of the same patient are sequenced. The DNA sequence obtained from the tumour cell is compared to the DNA sequence of healthy blood cells in order to identify mutations in the tumour DNA that are unique to the cancer.
PELEUSTM bioinformatics platform
The PELEUSTM bioinformatics platform uses proprietary software to analyse the tumour mutations and identify clonal neoantigens. These are mutations that: (1) occur in a gene encoding a protein; (2) are displayed on the surface of the tumour cell where they can be recognised by a T cell; and (3) are present in every cancer cell (clonal).
Clonal neoantigen peptides
Peptides are manufactured which each contain a clonal neoantigen in their amino acid sequence.
T cells are a type of white blood cell which play a key role in the immune system and are responsible for directly killing cancer cells. The T cells used as starting material in the Achilles process are known as “tumour infiltrating lymphocytes” (TIL). These are T cells that have left the bloodstream and migrated into a tumour. TIL that have been isolated and stimulated in the laboratory before being returned to a patient have been shown to be capable of killing tumour cells in clinical trials.
Dendritic cells are a type of immune cell that show antigen to T cells in order to activate them. Their role is to take up the clonal neoantigen peptides and display them on their cell surface so that they can be recognised by the T cells.
The T cells are combined with dendritic cells displaying clonal neoantigens on their surface. When a T cell encounters a dendritic cell presenting a clonal neoantigen that matches its T cell receptor, the T cell receives a signal to start growing and proliferating. This step ensures that only T cells that specifically target clonal neoantigens are expanded to high levels.
Clonal neoantigen T cells
The resulting clonal neoantigen T cells (cNeT) are fitter and more active than conventional TIL. They also have the capacity to expand further once they are administered to the patient.
Before the clonal neoantigen T cells (cNeT) are administered, the patient receives lymphodepletion therapy. This is a combination of chemotherapy drugs that reduces the number of T cells present in the body, to make space for the cNeT that will be reinfused.
CANCER EVOLUTION AND TARGETING CLONAL NEOANTIGENS
This video provides an introduction to tumour evolution and architecture, and explains why targeting clonal neoantigens is vital to avoid the development of treatment resistance and immune evasion.