Tumour Mutational Burden: Immune Checkpoint Inhibitors Response

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Caris Molecular Intelligence tumour profiling includes Tumour Mutational Burden (TMB) status when Next-Generation Sequencing is performed. TMB is an emerging indicator for predicting response to immune checkpoint inhibitors across a wide spectrum of tumour types, including CRC, melanoma, NSCLC and urothelial carcinomas (bladder, renal, etc.).1-6

High TMB across Caris Molecular Intelligence cases

Genomic profiling with Caris Molecular Intelligence can help you make more informed therapy decisions when considering immune checkpoint inhibitors.

How it works

Tumour mutational burden by Next-Generation Sequencing measures the total number of non-synonymous, somatic mutations identified per megabase (Mb) of the genome coding area (a megabase is 1,000,000 DNA basepairs).

  • 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 TMB because the immune system has a higher likelihood of recognizing these alterations as normal.7

TMB: Immune checkpoint indication for response

Tumours with significant numbers of mutations resulting in altered proteins (neo-antigens) may respond more effectively to immunotherapies.

Unlock the power of immunotherapies

By harnessing the body’s immune system to detect and destroy tumour cells, immune checkpoint inhibitors are rapidly ushering in a new era of precision medicine.1,6,8,9 Although immune checkpoint inhibitors have demonstrated durable clinical responses across several tumour types, these therapies are costly and may present toxic side effects.1,4,6,8,10

Understanding the relationships between TMB, MSI and PD-L1 can help oncologists make more informed immunotherapy decisions.15

TMB (tumour mutational burden) measures the total number of non-synonymous somatic mutations identified per megabase of the genome coding area. Tumours with high TMB likely harbour neoantigens and may respond more favourably to immunotherapies.1,2,4

Caris Experience data across all lineages: 33,000+


MSI (microsatellite instability)
is caused by failure of the DNA mismatch repair (MMR) system.6 MSI-High correlates to an increased neoantigen burden, which may indicate the tumour is more likely to respond favourably to immunotherapies.

Caris Experience data across all lineages: 24,000+


PD-L1 (programmed death ligand-1)
is among the most important checkpoint proteins that mediate tumour-induced immune suppression through T-cell downregulation.4,11 PD-L1 expression may indicate a more likely response to immunotherapies.9,12-14

Caris Experience data across all lineages: 64,000+

Identify patients more likely to respond to immunotherapies through Comprehensive Genomic Profiling PLUS (CGP+) with Caris Molecular Intelligence.

 

References

  1. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 384(6230):124-8. [Abstract]
  2. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23):2189-99. [Abstract]
  3. Campesato LF, Barroso-Sousa R, Jimenez L, et al. Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget. 2015; 6(33):34221-7. [Abstract]
  4. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387(10031):1909-20. [Abstract]
  5. Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016; 7(12):13587-98. [Abstract]
  6. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372(26):2509-20. [Abstract]
  7. Stewart TJ, Abrams SI. How tumours escape mass destruction. Oncogene. 2008;27(45):5894-903. [Abstract]
  8. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54. [Abstract]
  9. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847-56. [Abstract]
  10. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373(19):1803-13. [Abstract]
  11. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-9. [Abstract]
  12. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-39. [Abstract]
  13. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-28. [Abstract]
  14. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064-74. [Abstract]
  15. Vanderwalde A, Spetzler D, Xiao N, et al. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018. doi:10.1002/cam4.1372. [Abstract]

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