Tumor Mutations and anti-PD-1 Immunotherapy Response

Inhibitors of factors that themselves inhibit an anti-tumor response are promising therapeutic agents.  Here we see once again that response to such agents is related to the number of mutations a tumor has.  The more mutations, the more neoantigens produced – the more aberrant proteins produced that can be recognized by the immune system once the “brakes” are off.  Excerpts (figure shown is from the paper, which is freely accessible online):

Inhibitors of programmed death 1 (PD-1) protein or its ligand (PD-L1) have shown remarkable clinical benefit in many cancers. One emerging biomarker of response to anti–PD-1 therapy is the tumor mutational burden (i.e., the total number of mutations per coding area of a tumor genome). This finding is supported by the clinical activity of anti–PD-1 therapy in colorectal cancer with mismatch repair deficiency, a tumor subtype with a high tumor mutational burden, as compared with the colorectal cancer subtype with mismatch repair proficiency, which has a significantly lower tumor mutational burden and a poor response to these agents. 

To evaluate the relationship between the tumor mutational burden and the objective response rate, we plotted the objective response rate for anti–PD-1 or anti–PD-L1 therapy against the corresponding median tumor mutational burden across multiple cancer…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.