A report out of Nature Communications suggests a correlation between the use of low TMB and an increased survival rate among glioblastoma patients may be due to changes in the immunological status of tumor post therapy.
Tumor mutation burden (TMB) is the frequency of certain protein (tumor antigen)-altering mutations within tumor genes. The production of more tumor antigens increases the chances that one or more of those can be recognized and reacted upon by the immune system. Highly mutated tumors produce many antigens that can stimulate T cells to respond to the antigens. The observation regarding TMB is used to predict response to anti-tumor immunotherapy. For example, studies have shown that a high TMB in patients can predict response to immune checkpoint inhibitors against PD-1 or PD-L1.
Despite the association of high TMB with immunotherapy response, the case for glioblastoma is strikingly different. Low TMB appears to indicate a better response to immunotherapy than for those with a higher TMB. In patients in which glioblastoma recurs after standard-of-care chemotherapy treatment, about 10% of these patients respond to immunotherapy. To identify what distinguishes patients with longer survival after immunotherapy, scientists performed genomic analysis of tumor tissues collected from patients with recurrent WHO grade IV glioblastoma.
The results showed that a low TMB is associated with longer survival after patients received recombinant polio virotherapy or immune checkpoint blockade immunotherapy. The low TMB–survival relationship was not seen for patients classified as immunotherapy naïve newly diagnosed or for primary tumors. For patients with recurrent glioblastoma, low TMB was associated with an enhancement of inflammatory gene expression. Therefore, inherent tumor inflammation may be involved in glioblastoma recurrence.
The findings are encouraging with regard to the use of low TMB to predict response to immunotherapy in patients with recurrent glioblastoma. However, an important consideration is a likelihood that the increased survival was seen in patients with low TMB be due to the change in the immunological status of the tumors after chemotherapy or other therapies. Other factors that may contribute to the TMB-survival relationship are the time to recurrence, the extent of tumor development, and the nature of other drug treatments prescribed. Further studies in a larger patient sample may help to determine the reliability of TMB as a biomarker of immunotherapy response in patients with recurrent glioblastoma.
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Unexpectedly, Immunotherapy Response Linked to Low TMB in rGMB. (2021). Retrieved 19 February 2021, from https://www.medscape.com/viewarticle/944312#vp_1