Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.
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 articleSubject
HumansGlioblastoma
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
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https://hdl.handle.net/10161/22380Published Version (Please cite this version)
10.1038/s41467-020-20469-6Publication Info
(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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Show full item recordScholars@Duke
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
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
Annick Desjardins
Professor of Neurosurgery
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
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
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
Yiping He
Associate Professor in Pathology
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).
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
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
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
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
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
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
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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