MSI Testing and the Efficacy of Cancer Immunotherapies

Cancer immunotherapy aims to improve the immune system’s response to tumour cell growth by enhancing T-cell immune responses. One therapeutic intervention, which has been demonstrated to be effective in several solid tumours (2,3), involves targeting a surface receptor called PD-1. PD-1 is found on immune cells called T cells and normally acts as a type of "off switch" that helps keep the T cells from attacking other cells in the body. PD-1 attaches to PD-L1, a protein found on some normal (and tumour) cells. This interaction basically tells the T cell to leave the other cell alone and not to neutralise it. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack.

Recently approved immunotherapies have been developed to target either PD-1 or PD-L1 in order to prevent the proteins from binding together, and thereby help prevent cancer cells from hiding from the T-cell response. Such types of immunotherapies are known as Immune Checkpoint Inhibitors (ICIs).

ICI drugs have been shown to be effective against cancers such as aggressive metastatic melanoma, some lung cancers, kidney, bladder, head and neck cancers. These therapies have succeeded in pushing many aggressive cancers below detectable limits, though these cases are notably not relapse-free or necessarily “cured” (2,3).

One challenge of implementing immunotherapy in a cancer treatment regime is that certain tumours are far more likely to respond to immune checkpoint therapy than others and the application of the treatment requires high selectivity. Recently, following research led by Dr Le (3), Microsatellite Instability (MSI) High status has been used as a biomarker for prolonged and durable response to immune checkpoint inhibitors, making MSI status an important tool in genetic- and immuno-oncology.

MSI is the accumulation of insertion or deletion (INDEL) errors at microsatellite DNA repeat sequences in cancerous cells as a result of a deficiency within one or more major DNA mismatch repair (MMR) proteins. MSI testing functionally measures the genomic accumulation of these errors caused by cells deficient mismatch-repair system (dMMR) that occurs in certain types of solid tumours. Establishing the MSI status can guide therapeutic choices as tumour MSI-High status can be predictive of a positive response to immune checkpoint inhibitors in several types of solid tumours.

Historically, MSI status has been used to screen for Lynch Syndrome, a dominant hereditary condition associated with a genetic predisposition to different cancer types. Many laboratories in the UK already routinely use a highly sensitive and specific MSI test to screen certain cancer patients for Lynch syndrome – the same test could be used to establish the likely clinical efficacy of immune checkpoint anti-PD-1 therapy.

A widely used MSI assay in the UK is the Promega MSI Analysis System v1.2, a PCR and Capillary Electrophoresis-based test that is specifically designed to work with fragmented DNA extracted from FFPE samples. Promega has recently launched a CE-Marked in vitro diagnostic version of this MSI assay (called OncoMate™) using the same loci set as the MSI Analysis System v1.2. The availability of a CE-Marked in vitro diagnostic MSI assay will hopefully have a positive impact on the clinical application of the solid tumour MSI status testing and the outcome of currently available and future immune checkpoint inhibitor therapies.

For more information on the Promega OncoMate™ assay go to: https://www.promega.co.uk/Products/microsatellite-instability-msi-testing/clinical-msi-testing-ivd/oncomate-msi-dx-analysis-system/?catNum=MD3140