We have discussed mutational burden previously on this blog – in essence, the concept is that tumors with more mutations are more visible to the immune system because the generation of new novel antigenic epitopes allows for adaptive immune responses even when previous adaptive antigen-specific immune responses have been blunted by PD-1 expression.
It follows that anti-PD1 therapy would work best against cancers that present neo-antigens to the immune system since these have a higher likelihood of expressing PD-1 and a lower likelihood of having induced antigen-specific Treg’s. The more immunogenic the tumor, the more likely that anti-PD1 therapy will be effective since PD-1 is an immune abrogating signal that is induced by tumors with a microenvironment characterized by an IFN-γ inflammatory signature on gene expression profiling (GEP) analysis.
Merck’s Keytruda (pembrolizumab) garnered FDA approval for the treatment of tumors with high microsatellite instability (MSI-H, or mismatch repair deficient – dMMR), irrespective of tissue of origin. This marks the first approval based on a genetic signature, as opposed to cancer type. It was based on analyses from five clinical trials including 149 patients.
MSI-H/dMMR is identified using polymerase chain reaction for mutated mismatch repair genes (MLH1, MSH2, MSH6, or PMS2 ) or immunohistochemistry for loss of expression of these proteins.
Tumor mutational burden (TMB) evaluates to coding sequences of the genome, not the integrity and expression of mismatch repair enzymes. It is evaluated via whole genome sequencing or through targeted sequencing panels – it measures the number of non-synonymous DNA coding sequence changes per megabase of sequenced DNA. (Non-synonymous mutations are base substitutions that result in altered amino acid sequences compared to wild type.)
Researchers at Johns Hopkins looked at 27 different cancer types to evaluate TMB as a as prognostic biomarker for checkpoint therapy. In general, the higher the TMB, the better response to immune checkpoint blockade:
We observed a significant correlation between the tumor mutational burden and the objective response rate (P<0.001). The correlation coefficient of 0.74 suggests that 55% of the differences in the objective response rate across cancer types may be explained by the tumor mutational burden.
There were some outliers, however:
Some cancer subtypes have a response to therapy that is better than would be predicted by the tumor mutational burden (e.g., Merkel-cell carcinoma), and some have a response that is worse than would be predicted (e.g., colorectal cancer with mismatch repair proficiency). The higher-than-anticipated objective response rates for Merkel-cell carcinoma and some other cancers that have been associated with viruses suggest that the presentation of viral antigens on certain tumor types may confer an increased response rate to anti–PD1 therapy.
As can be seen in Figure 2, Kidney cancer responds well to anti-PD1 therapy, but it does not have a particularly high TMB. This is because kidney cancers have a high number of “indel” (insertion and deletion mutations resulting in frameshifts) mutations, which are highly mutagenic. Colorectal cancers with proficient MMR do not respond as well to anti-PD1 therapy as other tumors with a similar level of TMB. And, tumors driven by oncogenic viruses respond better to anti-PD1 therapy than other tumors of similar TMB because viral proteins are very immunogenic.
“Although mismatch repair deficiency is a biomarker for PD-1 response that already captures some patients with high TMBs, there are clearly other patients with high TMBs who do not have mismatch repair deficiency,” said Mark Yarchoan, MD. “In the future, TMB might guide the use of anti-PD1 therapy in a tissue-agnostic manner, similar to mismatch repair deficiency.”
The researchers are interested in how to get cancers with low mutational burden to be made to behave like those with higher mutational burden: “How do we make immunologically ‘cold’ tumors, which usually have lower TMBs, behave more like immunologically ‘hot’ tumors? We are hopeful that therapeutic cancer vaccines might be able to augment responses to anti-PD1 therapy in ‘cold’ tumors,” said Yarchoan, adding that vaccine combinations may prime the tumor microenvironment to make tumors more amenable to anti-PD1 therapy.