Total Mutational Load (TML) is an emerging, quantitative indicator for predicting response to novel immune checkpoint inhibitors across a wide spectrum of tumor types.1-6 Also referred to as tumor mutational burden, TML measures the total number of non-synonymous, somatic mutations identified per megabase of the genome coding area (a megabase is 1,000,000 DNA basepairs).

Tumors with high TML likely harbor neoantigens and may respond more favorably to immune checkpoint inhibitors. 1-2  Caris Molecular Intelligence defines TML as 17 or more mutations per megabase. TML is included for all MI Profile orders, at no additional cost, added tissue or delay in turnaround time.

Chart - High TML Across CMI
Data on File

How it Works

  • Non-synonymous mutations are changes in DNA that result in amino acid changes in the protein.2,6
  • The new protein changes result in new shapes (neo-antigens) that are considered to be foreign to the immune system.2,4
  • Immune checkpoint inhibitors are able to stimulate and allow the immune system to detect these neoantigens and destroy the tumor.2
  • Germline (inherited) mutations are not included in TML because the immune system has a higher likelihood of recognizing these alterations as normal.7

Chart - TML: Immune Checkpoint Indication for Response

 

  1. Rizvi NA. Science. 2015; 384(6230):124-128. doi:10.1126/science.aaa1348.
  2. Snyder A. N Engl J Med. 2014; 371:2189-2199. doi:10.1056/NEJMoa1406498.
  3. Campesato LF. Oncotarget. 2015; 6(33):34221-34227.  doi:10.18632/oncotarget.5950.
  4. Rosenberg JE. The Lancet. 2016; 387(10031):1909-1920. doi:10.1016/S0140-6736(16)00561-4.
  5. Strickland KC. Oncotarget. 2016; 7(12):13587-13598. doi:10.18632/oncotarget.7277.
  6. Le DT. N Engl J Med. 2015;372:2509-2520. doi:10.1056/NEJMoa1500596.
  7. Stewart TJ. Oncogene. 2008;27:5894-5903. doi:10.1038/onc.2008.268.