Perspectives on Cancer Genome Profiling

PGDx BLOG

MSI 2.0

On May 23, the FDA announced it has granted accelerated approval of Merck’s PD-1 inhibitor Keytruda (pembrolizumab) for use as a pan-cancer therapeutic in solid tumors with detectable levels of the microsatellite instability-high (MSI-H) biomarker. This is the first time the FDA has approved a cancer treatment targeting a specific genetic feature (MSI) for patients who have multiple types of solid tumors.

 

MSI is a genomic by-product of mismatch-repair (MMR) deficiency, the inability to correct errors accumulated because of routine replication and recombination, or from DNA damage.1 Cancer patients with MMR-deficient tumors have roughly 100 times more mutations found per cell than patients with MMR-proficient tumors.1,2,3 In addition, neoantigens, or proteins made in the cancer cells from the mutated DNA can be recognized as foreign by the immune system.  Therefore, a tumor cell with higher mutational burden will likely have many more neoantigens. Theoretically, these unrecognized neoantigens should trigger an immune response led by T-cells that would ultimately cause the death of the tumor cell. However, tumor cells have been shown to upregulate immune checkpoint pathways such as PD-1/PD-L1, leading to the loss of a T-cell response.1,4 Keytruda inhibits the PD-1/PD-L1 immune checkpoint so that T-cells may freely attack tumor cells.

Figure 1. Patients with mismatch repair (MMR)-deficient tumors often have a greater mutational load.  In this figure, Luis Diaz et al. demonstrated that these patients respond better to immune checkpoint inhibitors, leading to a greater probability of overall survival.

 




















In a 2012 study, only 1 out of 33 patients with colorectal cancer responded to immunotherapy treatment with the immune checkpoint inhibitor pembrolizumab, even though in similar studies among patients with other tumor types, a higher percentage responded to immunotherapy.5,6 Dr. Luis Diaz, co-founder of PGDx, along with other researchers at Johns Hopkins University, was the first to clinically investigate the activity of pembrolizumab in two different populations of colorectal patients:  those who have MMR-proficient tumors and those who have MMR-deficient tumors.   In his 2015 paper in The New England Journal of Medicine, Dr. Diaz reported the results of a prospective clinical trial of 41 colorectal cancer patients. The results concluded that the detection of MSI as a predictive biomarker could successfully select patients who would be more likely to respond to immune checkpoint inhibitors since patients with MMR-deficient tumors exhibited greater response and had improved overall survival [Figure 1].1

 

Personal Genome Diagnostics Inc. (PGDx), a leading provider of advanced cancer genome testing products and services, announced on October 20, 2016, that it has licensed rights to a patent pending microsatellite instability (MSI) testing technology from Johns Hopkins University to help identify candidates for immune checkpoint inhibition.   “The growing prominence of immuno-oncology treatments for cancer highlights the therapeutic importance of determining whether patients have microsatellite instability present in their tumors,” said Doug Ward, CEO of PGDx. “We, therefore, welcome the opportunity to expand the use of the Johns Hopkins MSI testing technology in our product line. This is especially timely as we advance plans for FDA review and clearance of our assays.”

 

Since 2014, PGDx has included MSI detection in its pan-cancer genomic tissue panels for patients and drug developers and currently offers it in its CancerSELECTTM125 tissue assay. In addition, PGDx is now the only genomic diagnostics company to offer MSI detection in plasma (PlasmaSELECTTM 64 + MSI), solidifying its position as a true leader in the race to cure cancer.

 

Notes

  1. Le et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 372: 2509-2520.
  2. Timmermann et al. Somatic Mutation Profiles of MSI and MSS Colorectal Cancer Identified by Whole-Exome Next-Generation Sequencing and Bioinformatics Analysis. PLoS ONE. 2010; 5(12): e15661.
  3. Eshleman et al. Increased Mutation Rate at the HPRT Locus Accompanies Microsatellite Instability in Colon Cancer. Oncogene. 1995; 10(1): 33-37.
  4. Dolcetti et al. High Prevalence of Activated Intraepithelial Cytotoxic T Lymphocytes and Increased Neoplastic Cell Apoptosis in Colorectal Carcinomas with Microsatellite Instability. Am J Path. 1999; 154(6): 1805-1813.
  5. Topalian et al. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med. 2012; 366: 2443-2454.
  6. Brahmer et al. Phase I Study of Single-Agent Anti-Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates. J Clin Oncol. 2010; 28(19): 3167-3175.