Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

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Summary

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/ POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8 ⁺ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term “HGG” in the pediatric population.

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Highlights

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The HERBY trial tested the use of bevacizumab in pediatric non-brainstem HGG
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Parallel translational biology studies highlighted the diversity of the trial cohort
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Elevated levels of CD8 ⁺ T cells were seen in PXA-like and hypermutant tumors
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MAPK-associated immune signatures predicted response to bevacizumab

Abstract

In a pediatric high-grade non-brainstem glioma cohort, Mackay et al. show that hypermutator tumors and those resembling pleomorphic xanthoastrocytoma are highly infiltrated by CD8 ⁺ lymphocytes and benefit from the addition of bevacizumab, whereas the histone H3 subgroups are immune cold and have a poor outcome.

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Most cited references 38

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Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

Alan Mackay, Anna Burford, Diana Carvalho … (2017)

Summary We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

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MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade.

Peter J R Ebert, Jeanne Cheung, Yagai Yang … (2016)

Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.

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Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level.

Andreas Waha, Justyna Kmiecik, Jacques Zimmer … (2013)

We characterized GBM patients' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape, their impact on patient outcome, and identify targets for immunotherapy. Increased CD3(+) T-cell infiltration was associated with prolonged survival independent of age, MGMT promoter methylation and post-operative treatment that implies potential for immunotherapy for GBM. Several mechanisms of escape were identified: within the tumor microenvironment: induced CD8(+)CD28(-)Foxp3(+) Tregs that may tolerize antigen presenting cells, elevated CD73 and CD39 ectonucleotidases that suppress T-cell function, and at the systemic level: elevated IL-10 levels in serum, diminished helper T-cell counts, and upregulated inhibitory CTLA-4. © 2013. Published by Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Chris Jones

Journal

Journal ID (nlm-ta): Cancer Cell

Journal ID (iso-abbrev): Cancer Cell

Title: Cancer Cell

Publisher: Cell Press

ISSN (Print): 1535-6108

ISSN (Electronic): 1878-3686

Publication date PMC-release: 14 May 2018

Publication date (Print): 14 May 2018

Volume: 33

Issue: 5

Pages: 829-842.e5

Affiliations

[1 ]Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

[2 ]Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

[3 ]Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany

[4 ]Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

[5 ]Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

[6 ]Roche Innovation Center, New York, NY, USA

[7 ]Department of Radiology, Oncology and Anatomic-Pathology Sciences, Sapienza University, Rome, Italy

[8 ]IRCCS Neuromed, Pozzilli, Italy

[9 ]Institute of Neurology, Medical University of Vienna, Vienna, Austria

[10 ]Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

[11 ]DGNN Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany

[12 ]UCL Great Ormond Street Institute of Child Health, London, UK

[13 ]Department of Histopathology, Great Ormond Street Hospital for Children, London, UK

[14 ]Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, Marseille, France

[15 ]Nottingham University Hospitals, Nottingham, UK

[16 ]The Center for Data Driven Discovery in Biomedicine (D ³b), Children's Hospital of Philadelphia, Philadelphia, PA, USA

[17 ]Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA

[18 ]Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

[19 ]Pediatric Oncology Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy

[20 ]Centro di Neuro-Oncologia, Istituto Giannina Gaslini, Genoa, Italy

[21 ]F. Hoffmann-La Roche Ltd, Basel, Switzerland

[22 ]Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

[23 ]Berlin Institute of Health, Institute of Neuropathology, Berlin, Germany

[24 ]Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

[25 ]Department of Neurosurgery, Brain Tumor Center Amsterdam, VU Medical Center, Amsterdam, the Netherlands

[26 ]Genentech, South San Francisco, CA, USA

[27 ]Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France

[28 ]Sainte-Anne Hospital, Paris-Descartes University, Paris, France

Author notes

[∗ ]Corresponding author chris.jones@ 123456icr.ac.uk

[29]

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Article

Publisher ID: S1535-6108(18)30175-2

DOI: 10.1016/j.ccell.2018.04.004

PMC ID: 5956280

PubMed ID: 29763623

SO-VID: d2b6b45e-1996-4e77-baef-09a39676b8b7

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 12 January 2018

Date revision received : 28 February 2018

Date accepted : 10 April 2018

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Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 38

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade.

Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level.

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