Reference Detail

Ref Type

Journal Article

PMID

(30742119)

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

Title

Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature medicine			2019 Feb 11	462-469	Nat Med

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF mut IDH1 wild-type	glioblastoma	predicted - sensitive	Nivolumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, MAPK pathway mutations were significantly enriched in patients with IDH1 wild-type glioblastoma who responded to anti-PD-1 therapy with either Keytruda (pembrolizumab) or Opdivo (nivolumab), compared to those who did not respond (odds ratio=12.8, p=0.019), with 4 MAPK pathway mutations (2 in BRAF, 2 in PTPN11) identified in 13 responders and 1 (BRAF) in 32 non-responders (PMID: 30742119).	30742119
IDH1 wild-type PTEN mut	glioblastoma	resistant	Pembrolizumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, PTEN mutations were significantly enriched in patients with IDH1 wild-type glioblastoma who did not respond to anti-PD-1 therapy, with either Keytruda (pembrolizumab) or Opdivo (nivolumab), compared to those who responded (odds ratio=0.85, p=0.0063), with 23 PTEN mutations identified in 32 non-responders and 3 in 13 responders (PMID: 30742119).	30742119
IDH1 wild-type PTEN mut	glioblastoma	resistant	Nivolumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, PTEN mutations were significantly enriched in patients with IDH1 wild-type glioblastoma who did not respond to anti-PD-1 therapy with either Keytruda (pembrolizumab) or Opdivo (nivolumab), compared to those who responded (odds ratio=0.85, p=0.0063), with 23 PTEN mutations identified in 32 non-responders and 3 in 13 responders (PMID: 30742119).	30742119
BRAF mut IDH1 wild-type	glioblastoma	predicted - sensitive	Pembrolizumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, MAPK pathway mutations were significantly enriched in patients with IDH1 wild-type glioblastoma who responded to anti-PD-1 therapy with either Keytruda (pembrolizumab) or Opdivo (nivolumab), compared to those who did not respond (odds ratio=12.8, p=0.019), with 4 MAPK pathway mutations (2 in BRAF, 2 in PTPN11) identified in 13 responders and 1 (BRAF) in 32 non-responders (PMID: 30742119).	30742119