Removing inhibitory signals
Immune checkpoint inhibitors block signals such as PD-1/PD-L1, releasing the brake on T cells that already recognize the tumor.
The science
Neoantigen cancer vaccines
Teaching the immune system what to look for
The immune system continuously surveys the body for anything that does not belong: viruses, bacteria, abnormal or damaged cells.
Cancer is a harder problem. Because it arises from the body's own cells, a tumor can closely resemble healthy tissue and avoid detection.
Antigen presentation
How the immune system recognizes a cancer cell
Every cell continuously breaks down a share of the proteins it makes into short fragments called peptides. Molecules known as MHC (major histocompatibility complex) carry these peptides to the cell surface and display them.
T cells inspect the displayed peptides through their T-cell receptors (TCRs). When a peptide looks sufficiently abnormal and the right activation signals are present, a T-cell response can begin.
- Protein synthesisThe cell produces proteins encoded by its genes, including any that carry mutations.
- Protein processingA portion of these proteins is broken down into short peptide fragments.
- MHC presentationMHC molecules bind the peptides and display them on the cell surface.
- T-cell recognitionA T cell whose receptor matches the displayed peptide recognizes the cell.
Recognition alone is not enough. Turning recognition into an effective attack requires a coordinated sequence of immune events.
Neoantigens
What is a neoantigen?
As cancer develops, cells accumulate mutations that alter the proteins they produce. Some of these mutations create peptide sequences that are not found in any normal cell.
These tumor-specific peptides are called neoantigens. Because they are absent from healthy tissue, the immune system can recognize them as foreign, which makes them highly specific targets for distinguishing cancer cells from normal ones.
Normal cell
DNA…CTGGCCAAG…Protein…LeuAlaLys…
Displayed peptide
Self peptide: T cells remain tolerant and do not attack.
Tumor cell
DNA…CTGGTCAAG…Protein…LeuValLys…
Displayed peptide
Neoantigen: T cells can recognize and target the cell.
Immune evasion
Why doesn't the immune system always eliminate cancer?
Even when T cells can recognize tumor-specific peptides, an effective anti-tumor response may not develop. Tumors can suppress immunity in several ways:
- Engaging immune checkpoints, inhibitory signals that reduce T-cell activity
- Creating a local microenvironment that suppresses immune-cell function
- Interfering with the activation and function of immune cells
One of the best-characterized checkpoint pathways involves PD-1, a receptor on T cells, and its ligand PD-L1, which tumor cells can express. When PD-1 binds PD-L1, T-cell activity is reduced.
The T-cell receptor binds a tumor peptide displayed by MHC on the cancer cell.
The cancer cell expresses PD-L1, which binds the PD-1 receptor on the T cell.
PD-1 sends an inhibitory signal into the T cell, dampening its activity even though the target is recognized.
With the T cell suppressed, the cancer cells survive and continue to grow.
Cancer immunotherapy
Where cancer immunotherapy comes in
Cancer immunotherapies aim to strengthen the body's own anti-tumor immune response. They act at different points: helping the immune system recognize cancer, become activated against it, or sustain its attack.
Providing targets for recognition
Cancer vaccines present specific cancer-associated targets to the immune system, directing T cells toward the tumor.
A personalized neoantigen vaccine takes the second approach, using targets drawn from the patient's own tumor.
Mechanism of action
How a neoantigen vaccine activates the immune response
A personalized neoantigen vaccine contains a selected set of neoantigen peptides derived from the mutations in the patient's own tumor. Once administered, it presents these targets to the immune system.
- VaccinationSelected neoantigen peptides from the patient's tumor are administered.
- Antigen presentationDendritic cells take up the peptides, process them, and present them on MHC molecules.
- T-cell activationT cells that recognize the neoantigens through their TCRs become activated and expand.
- Tumor targetingThese tumor-specific T cells recognize cancer cells displaying the same neoantigen–MHC complexes and contribute to an anti-tumor immune response.
From the science to the clinic
Our Helios Platform identifies each patient's neoantigens and designs SQK01, our personalized neoantigen cancer vaccine.