Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma
(click to enlarge)
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.
The top figure shows Brain MRIs of two patients treated with nivolumab, one of whom showed disease progression following 2 months of treatment (left, NU 7) while the other showed stable disease without progression after 17 months of treatment (right, NU 11). The bottom figure is a Kaplan–Meier curve comparing overall survival of patients who responded to anti-PD-1 therapy (n = 13) with those that did not respond (n = 12).
“Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma”
AUTHORS: Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, Bordbar D, Shan D, Samanamud J, Mahajan A, Filip I, Orenbuch R, Goetz M, Yamaguchi JT, Cloney M, Horbinski C, Lukas RV, Raizer J, Rae AI, Yuan J, Canoll P, Bruce JN, Saenger YM, Sims P, Iwamoto FM, Sonabend AM, Rabadan R.
LINK TO PUBLICATION:
Nature Medicine. 2019 Feb 11. doi: 10.1038/s41591-019-0349-y.