In contrast to what has been seen in other types of cancer, in which high tumor mutational burden (TMB) predicts response to immunotherapy, the situation appears to be reversed in cases of recurrent glioblastoma.
There’s an “unexpected correlation between TMB, tumor-intrinsic inflammation, and survival after immunotherapy” in this patient population, note researchers in a recent Nature Communications report.
Cases of recurrent glioblastoma in which TMB is low are more likely to respond to immunotherapy than cases in which TMB is higher, the investigators conclude from an analysis of tumor tissue from more than 100 patients.
“We need to do a prospective study and establish a threshold in a particular assay format,” senior author David Ashley, MBBS, PhD, a neurosurgery professor at Duke University, Durham, North Carolina, said in an email.
Asked for comment, Andrew Sloan, MD, a neurosurgery professor at the Seidman Cancer Center, Cleveland, Ohio, said, “Many have given up on immunotherapy for GBM [glioblastoma multiforme] because these tumors tend to have lower TMB than tumors that typically respond to immunotherapy including checkpoint inhibitors.” (Examples include melanoma and lung cancer).
“If the findings are confirmed, it would be very useful clinically to select” patients for immunotherapy, Sloan commented.
Correlation Seen With rGMB, Not Primary Tumor
Recurrence of GBM (rGBM) is almost inevitable even when aggressive standard-of-care therapy given initially. In about 10% to 20% of patients with rGBM, disease responds to subsequent immunotherapy, and patients live beyond the predicted median survival of about 12 months. It’s been unclear, however, what distinguishes these survivors from the other patients.
Ashley and colleagues assessed for common genetic factors that distinguish survivors.
The tumor tissue they analyzed came from three studies. The first was a trial of an intratumoral infusion of a recombinant nonpathogenic poliorhinovirus chimera (PVSRIPO), developed originally at Duke, that induces innate inflammation and T-cell attack. Among 61 patients, 21% were alive at 3 years, vs 4% of historical control patients.
The second study was a review of 66 patients with GBM who underwent treatment with pembrolizumab or nivolumab. The median survival was 14.3 months among those who experienced a response, vs 10.1 months for those who did not. The third study involved more than 1000 patients with advanced cancer who underwent treatment with checkpoint inhibitors. There was no survival benefit among the 117 patients with glioma who were treated with checkpoint inhibitors.
In the PVSRIPO trial, rGBM tumors from patients who survived longer than 20 months harbored very low TMB, less than 0.6 mutations/Mb. In the two checkpoint inhibitor trials, among 110 patients with rGBM, survival was longer for those whose TMB was at or below the median level.
The differences in survival were not driven by differences in steroid dosing, unfavorable responses among patients with hypermutations, or the presence or absence of IDH1 or PTEN mutations or MGMT promoter methylation, the team notes.
“Increased survival of immunotherapy-treated rGBM patients with very low TMB is due to immunotherapy response,” the investigators conclude.
As for the explanation, they also found that rGBM tumors with lower TMB levels had enriched inflammatory gene signatures compared with those with higher levels. The correlation ― and longer survival with low TMB ― was not observed in primary GBM tumors, “indicating that a relationship between tumor-intrinsic inflammation and TMB develops upon recurrence…. We postulate that the baseline inflammatory status of rGBM tumors determines their susceptibility to immunotherapy,” they write.
Because the correlation between tumor inflammation and TMB was robust in rGBM but not in primary tumors, it might well have been due to standard-of-care therapy, which affects mutation levels.
“Chemotherapy, which is the standard of care for newly diagnosed glioblastoma, might be altering the inflammatory response in these tumors” and priming an inflammatory process that increases vulnerability to immunotherapy in recurrent tumors, Ashley said in a press release.
Shorter time to recurrence also correlated with lower TMB and favorable response to PVSRIPO, so shorter duration of standard therapy or shorter time from initial surgery might improve immunotherapy response, he speculated.
The study was funded by the National Institutes of Health and other organizations. Ashley and other investigators own intellectual property related to PVSRIPO, which has been licensed to Istari Oncology. Several investigators hold equity in and/or are paid consultants for Istari. Sloan is the Ohio principal investigator for an rGBM PVSRIPO and pembrolizumab study funded by the company.
Nat Commun. Published online January 13, 2021. Full text
M. Alexander Otto is a physician assistant with a master’s degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape, including McClatchy and Bloomberg. He is an MIT Knight Science Journalism fellow. Email: [email protected]