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Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

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Date
2021-01-13
Authors
Gromeier, Matthias
Brown, Michael C
Zhang, Gao
Lin, Xiang
Chen, Yeqing
Wei, Zhi
Beaubier, Nike
Yan, Hai
He, Yiping
Desjardins, Annick
Herndon, James E
Varn, Frederick S
Verhaak, Roel G
Zhao, Junfei
Bolognesi, Dani P
Friedman, Allan H
Friedman, Henry S
McSherry, Frances
Muscat, Andrea M
Lipp, Eric S
Nair, Smita K
Khasraw, Mustafa
Peters, Katherine B
Randazzo, Dina
Sampson, John H
McLendon, Roger E
Bigner, Darell D
Ashley, David M
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Abstract
Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
Type
Journal article
Subject
Humans
Glioblastoma
Brain Neoplasms
Neoplasm Recurrence, Local
Inflammation
Immunotherapy
Proportional Hazards Models
Survival Analysis
Cohort Studies
Gene Expression Profiling
Genomics
Gene Expression Regulation, Neoplastic
Mutation
Oncolytic Virotherapy
Biomarkers, Tumor
Outcome Assessment, Health Care
Permalink
https://hdl.handle.net/10161/22380
Published Version (Please cite this version)
10.1038/s41467-020-20469-6
Publication Info
Gromeier, Matthias; Brown, Michael C; Zhang, Gao; Lin, Xiang; Chen, Yeqing; Wei, Zhi; ... Ashley, David M (2021). Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy. Nature communications, 12(1). pp. 352. 10.1038/s41467-020-20469-6. Retrieved from https://hdl.handle.net/10161/22380.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Ashley

David Michael Ashley

Rory David Deutsch Distinguished Professor of Neuro-Oncology
Dr. Ashley's primary research focus is laboratory based, investigating the role of immunotherapy as a novel approach to the treatment of tumors of the central nervous system (CNS). Since beginning his appointment at the faculty level at Duke in August of 1995 his activities have centered on two main areas of investigation. The first involves both in vivo and in vitro studies of the use of molecular therapeutics to target a CNS tumor associated antigen. The second area of interest comprises a det
Bigner

Darell Doty Bigner

E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS). There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to
Desjardins

Annick Desjardins

Professor of Neurosurgery
Friedman

Allan Howard Friedman

Guy L. Odom Distinguished Professor of Neurosurgery, in the School of Medicine
At the present time, I am participating in collaborative research in the areas of primary malignant brain tumors, epilepsy and subarachnoid hemorrhage. Primary malignant brain tumors are increasing in frequency. Patients harboring glioblastoma, the most malignant primary brain tumor, have a life expectancy of less than one year. In colloboration with the Division of Neurology and the Department of Pathology, clinical and laboratory trials have been initiated to identify better
Friedman

Henry Seth Friedman

James B. Powell, Jr. Distinguished Professor of Pediatric Oncology, in the School of Medicine
Overview: Our laboratory is pursuing a comprehensive analysis of the biology and therapy of adult and childhood central nervous system malignancies, particularly high-grade medulloblastoma, glioma, and ependymoma. Laboratory Studies: Active programs, using human adult and pediatric CNS tumor continuous cell lines, transplantable xenografts growing subcutaneously and intracranially in athymic nude mice and rats, and as well as in the subarachnoid space of the ath
Gromeier

Matthias Gromeier

Professor of Neurosurgery
I am a classically trained virologist with a focus on molecular mechanisms of RNA virus pathogenesis. My career is dedicated to unraveling RNA virus:host relations and devising methods of exploiting them for cancer immunotherapy and vaccine design. My background is in translation regulation and mRNA metabolism, viral RNA sensing and innate immunity, and cancer immunology and immunotherapy. Basic mechanistic research in my laboratory is supporting an ambitious clinical translational research prog
He

Yiping He

Associate Professor in Pathology
Herndon

James Emmett Herndon II

Professor of Biostatistics & Bioinformatics
Current research interests have application to the design and analysis of cancer clinical trials. Specifically, interests include the use of time-dependent covariables within survival models, the design of phase II cancer clinical trials which minimize some of the logistical problems associated with their conduct, and the analysis of longitudinal studies with informative censoring (in particular, quality of life studies of patients with advanced cancer).
Khasraw

Mustafa Khasraw

Professor of Neurosurgery
I am a medical oncologist, neuro-oncologist, tenured professor of medicine and neurooncology, and Deputy Director of the Center for Cancer Immunotherapy, Duke Cancer Institute, where are tasked to speed up clinical research and translation for scientists across all departments and all tumor types at Duke, who have made discoveries that show promise for developing new immunotherapies. I am leading several clinical and translational programs with significant laboratory collaborations wi
McLendon

Roger Edwin McLendon

Professor of Pathology
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum.  My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understan
Nair

Smita K Nair

Professor in Surgery
I have 22 years of experience in the field of cancer vaccines and immunotherapy and I am an accomplished T cell immunologist. Laboratory website:https://surgery.duke.edu/immunology-inflammation-immunotherapy-laboratory Current projects in the Nair Laboratory:1] Dendritic cell vaccines using tumor-antigen encoding RNA (mRNA, total tumor RNA, amplified tumor mRNA)<br
Peters

Katherine Barnett Peters

Associate Professor of Neurosurgery
Dr. Katy Peters, MD PhD FAAN is an associate professor of neurology and neurosurgery at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.   Her academic medical career started at Stanford University School of Medicine where she received an MD and PhD in Cancer Biology.  After completing a neurology residency at Johns Hopkins University and a fellowship in cognitive neurosciences, Katy joined the PRTBTC as a neuro-oncology fellow.  In 2009, she became a faculty member a
Sampson

John Howard Sampson

Robert H., M.D. and Gloria Wilkins Professor of Neurosurgery, in the School of Medicine
Current research activities involve the immunotherapeutic targeting of a tumor-specific mutation in the epidermal growth factor receptor. Approaches used to target this tumor-specific epitope include unarmed and radiolabeled antibody therapy and cell mediated approaches using peptide vaccines and dendritic cells. Another area of interest involves drug delivery to brain tumors. Translational and clinical work is carried out in this area to formulate the relationship between various direct intratu
Yan

Hai Yan

Adjunct Professor of Pathology
Our research activities center on the molecular genetics and biology of cancer with a focus on the identification, characterization, and therapeutic targeting of driver mutations involved in the genesis and progression of brain cancers.  Gliomas are the most common type of primary brain tumor. Through genomic studies, we have identified mutations in IDH1 and IDH2 in 70% of progressive malignant gliomas. These are somatic missense mutations that alter a conserved arginine residue and gain a
Zhang

Gao Zhang

Assistant Professor in Neurosurgery
   It is my aspiration to build a translational cancer research group that combines experimental biology and computational biology approaches to understand and overcome therapeutic resistance and to eradicate brain metastasis for patients with recurrent and metastatic diseases.  I aim to dissect and target various molecular mechanisms that (1) underlie both intrinsic and acqu
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