Immune Checkpoint Inhibition (ICI)

Immune checkpoints are cell surface proteins that regulate the activity of the host’s immune system. They are crucial for immune homeostasis as they prevent uncontrolled immune responses that may cause collateral tissue damage and autoimmune diseases. In the case of cancer, immune checkpoint pathways are often activated and promote suppression against nascent anti-tumor immune reactions. Blocking of immune checkpoint pathways by targeting the CTLA-4 or PD/PD-L1 axis have proven clinical response to a variety of tumor entities [1, 2]. Thus, immune checkpoint inhibition has the potential to become a pillar of cancer therapy.

Help to provide informed decisions for ICI

Although some of the FDA- and EMA-approved agents depend on the protein-based expression detection of PD-1 and PD-L1, there is still great heterogeneity in responding to immune checkpoint inhibition. Therefore, the need for predictive biomarkers still exists [3]. Several studies have revealed that microsatellite instability (MSI), which is a surrogate marker for mismatch repair deficiency (dMMR), is a suitable indicator for predicting the clinical benefit for checkpoint blockade[4,5]. As dMMR is a common event in cancers and inflammation processes, MSI testing is a promising approach to determine the response to immune checkpoint inhibitors for those indications [5, 6, 7].

MSI testing could be complemented by the detection of somatic exonuclease domain mutations (EDMs) of the polymerase epsilon (POLE) and -delta 1 subunit (POLD1). POLE and POLD1 EDMs markedly affect the fidelity of DNA replication through a reduced ability to correct the impairment of base pairs [8]. Furthermore, somatic POLE mutations are associated with hyper-mutated and MSS phenotypes in colorectal and endometrial tumors [9, 10]. Therefore, several studies have suggested that somatic POLE EDMs may be another promising candidate for immune checkpoint therapy [10,11].

 

ICI Tests
MSI
POLE/POLD1


Referenzen:

[1] D.M. Pardoll, “The blockade of immune checkpoints in cancer immunotherapy”, Nature Reviews Cancer, vol. 12, pp.252-264, 2012.
[2] M.A. Postow et al, “Immune Checkpoint Blockade in Cancer Therapy”, Journal of Clinical Oncology, vol. 33, no. 17, pp. 1974-1983, 2015.
[3] R.W. Jenkins et al, “Molecular and Genomic Determinants of Response to Immune Checkpoint Inhibition in Cancer”, Annu. Re. Med., vol. 69, pp. 333-347, 2018.
[4] D.T. Le et al, “PD-1 Blockade in tumors with Mismatch-Repair Deficiency”, N. Engl. J. Med., vol. 372, pp. 2509-2520, 2015.
[5] D.T. Le et al, “Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade”, Science, vol. 357, no. 6349, pp. 409-413, 2017.
[6] G.M. Frampton et al, “Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden”, Genome Medicine, vol. 9, no. 34, 2017.
[7] H. Westdorp et al, “Opportunities for immunotherapy in microsatellite instable colorectal cancer”, Cancer Immunol. Immunother. vol. 65, no. 10, pp.1249-1259, 2016.
[8] E. Heitzer et al, “Replicative DNA polymerase mutations in cancer”, Curr. Opin. Genet. Dev. vol. 24, pp. 107-113, 2014.
[9] R. Bourdais et al, “Polymerase proofreading domain mutations: New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency”, Crit. Rev. Oncol. Hematol., vol. 113, pp. 242-248, 2017.
[10] J.M. Mehnert et al, “Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer”, J. Clin. Invest., vol. 126, no. 6, pp. 2334-2340, 2016.
[11] J. Gong et al, “Response to PD-1 Blockade in Microsatellite Stable Metastatic Colorectal Cancer Harboring a POLE Mutation”, J. Nati. Compr. Canc. Netw., vol. 15, no. 2, pp. 142-147, 2017.