Evidence Builds for Tumor Mutational Burden as Immunotherapy Biomarker

Jane De Lartigue, PhD
Published: Wednesday, Sep 05, 2018
Amid a pressing need to identify patients most likely to respond to immune checkpoint inhibitors (ICIs), tumor mutational burden (TMB) has emerged as a highly promising and clinically validated biomarker, at least in the setting of lung cancer. Results from studies have demonstrated that subsets of patients with high TMB exist across almost all cancer types and that assessing TMB through whole-exome sequencing (WES) or next-generation sequencing (NGS) can predict response to a range of different types of immunotherapy.

TMB has been a hot topic at oncology conferences this year. Investigators and test developers must overcome a variety of challenges before it is ready for prime time as a biomarker, but it appears poised to bring immunotherapy into the era of personalized medicine.

A Heavy Load

It is a central tenet of cancer biology that tumors arise and evolve as a result of the acquisition of damage to the genome, generating characteristic genomic alterations that lead to the dysregulation of key cellular processes termed cancer hallmarks.1,2 In addition to identifying individual frequently altered genes that function as drivers of particular cancer types, results from genome sequencing studies have revealed the global spectrum of somatic mutations across a given tumor, known as the TMB or mutational load. TMB is defined as the number of mutations per megabase (Mb) of DNA.

Seeds of Their Own Destruction

It has long been suspected that cancers with a greater number of gene mutations may provoke a stronger antitumor immune response. The thinking behind this hypothesis relates to the production of neoantigens—fragments of proteins expressed on the surface of cancer cells that are encoded by mutated genes. Neoantigens are unique to cancer cells because they are derived from a mutant gene, which may encode a mutant protein that differs from that expressed by normal cells. Therefore, neoantigens have the potential to be recognized as foreign by the cells of the immune system that patrol the body. A greater number of neoantigens might mean increased stimulation of those immune cells and a stronger immune response. In this way, cancer cells may generate the seeds of their own destruction.6,7

Figure. TMB Prevalence Across Solid Cancer Types: Findings from A Large-Scale Study

TMB Prevalence Across Solid Cancer Types

 

My Kingdom for a Biomarker

MSI and dMMR and are just 2 of the many phenotypes that can cause hypermutant tumors and contribute to high levels of TMB. If tumors with higher TMB provoke a stronger immune response, then it stands to reason that TMB could provide a means for more comprehensive assessment of patients who might respond to ICIs and potentially other immunotherapies. In the past several years, investigators have started to evaluate TMB in this capacity, and it has emerged as a powerful predictor of response to ICIs in a range of tumor types (Table 1).5,11-27 Investigators are seeking to correlate TMB with clinical and biological outcomes in a number of ongoing clinical trials (Table 2).
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