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

Alan Mackay; Anna Burford; Valeria Molinari; David T.W. Jones; Elisa Izquierdo; Jurriaan Brouwer-Visser; Felice Giangaspero; Christine Haberler; Torsten Pietsch; Thomas S. Jacques; Dominique Figarella-Branger; Daniel Rodriguez; Paul S. Morgan; Pichai Raman; Angela Jae Waanders; Adam C. Resnick; Maura Massimino; Maria Luisa Garrè; Helen Smith; David Capper; Stefan M. Pfister; Thomas Würdinger; Rachel Tam; Josep Garcia; Meghna Das Thakur; Gilles Vassal; Jacques Grill; Tim Jaspan; Pascale Varlet; Chris Jones

doi:10.1016/j.ccell.2018.04.004

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

Alan Mackay, Anna Burford, Valeria Molinari, David T.W. Jones, Elisa Izquierdo, Jurriaan Brouwer-Visser, Felice Giangaspero, Christine Haberler, Torsten Pietsch, Thomas S. Jacques, Dominique Figarella-Branger, Daniel Rodriguez, Paul S. Morgan, Pichai Raman, Angela Jae Waanders, Adam C. Resnick, Maura Massimino, Maria Luisa Garrè, Helen Smith, David CapperStefan M. Pfister, Thomas Würdinger, Rachel Tam, Josep Garcia, Meghna Das Thakur, Gilles Vassal, Jacques Grill, Tim Jaspan, Pascale Varlet, Chris Jones^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

152 Scopus citations

Abstract

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. 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.

Original language	English (US)
Pages (from-to)	829-842.e5
Journal	Cancer cell
Volume	33
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2018.04.004
State	Published - May 14 2018

Funding

The HERBY clinical trial was carried out as a collaboration between the European Innovative Therapies for Children with Cancer (ITCC) consortium, the SIOPE Brain Tumor Group, the Australian Children's Cancer Trials Group (ACCT), and the C-17 Council (Canada). The translational research study was funded by an unrestricted grant from F. Hoffmann-La Roche Ltd allied to the HERBY trial (study number BO25041; clinicaltrials.gov NCT01390948). The funder provided infrastructure for sample acquisition, shipping, storage, and record keeping. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. We acknowledge the excellent technical assistance of staff at the Tumor Profiling Unit at the Institute of Cancer Research, London, UK, Sainte-Anne Hospital, Paris, France, and HistoGeneX, Antwerp, Belgium. A.M., A.B., V.M., E.I.D., and C.J. acknowledge NHS funding to the NIHR Biomedical Research Center at The Royal Marsden and the ICR; T.S.J. acknowledges NHS funding to the NIHR Biomedical Research Center at Great Ormond Street Hospital. M.L.G. recognizes the support from the Associazione per la Ricerca sui Tumori Cerebrali del Bambino. We would like to thank the local investigators, pathologists and radiologists who took part in the HERBY study, and the patients and families who consented to inclusion in the translational research program. C.J. received a research grant from F. Hoffmann-La Roche Ltd. C.J., P.V., M.M., J. Grill, G.V., D.R., P.M., and T.J. received consultancy fees from F. Hoffmann-La Roche Ltd. F.G., C.H., T.P., T.S.J., D.F.-B., and P.V. received travel reimbursement from F. Hoffmann-La Roche. J.B.-V., H.S., and J. Garcia are employees of F. Hoffmann-La Roche Ltd. R.T. and M.D.T. are employees of Genentech. The HERBY clinical trial was carried out as a collaboration between the European Innovative Therapies for Children with Cancer (ITCC) consortium, the SIOPE Brain Tumor Group, the Australian Children's Cancer Trials Group (ACCT), and the C-17 Council (Canada). The translational research study was funded by an unrestricted grant from F. Hoffmann-La Roche Ltd allied to the HERBY trial (study number BO25041; clinicaltrials.gov NCT01390948 ). The funder provided infrastructure for sample acquisition, shipping, storage, and record keeping. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. We acknowledge the excellent technical assistance of staff at the Tumor Profiling Unit at the Institute of Cancer Research, London, UK, Sainte-Anne Hospital, Paris, France, and HistoGeneX, Antwerp, Belgium. A.M., A.B., V.M., E.I.D., and C.J. acknowledge NHS funding to the NIHR Biomedical Research Center at The Royal Marsden and the ICR ; T.S.J. acknowledges NHS funding to the NIHR Biomedical Research Center at Great Ormond Street Hospital. M.L.G. recognizes the support from the Associazione per la Ricerca sui Tumori Cerebrali del Bambino . We would like to thank the local investigators, pathologists and radiologists who took part in the HERBY study, and the patients and families who consented to inclusion in the translational research program.

Keywords

CD8
H3F3A
MAPK
hypermutator
immune
pediatric high-grade glioma

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2018.04.004

Cite this

Mackay, A., Burford, A., Molinari, V., Jones, D. T. W., Izquierdo, E., Brouwer-Visser, J., Giangaspero, F., Haberler, C., Pietsch, T., Jacques, T. S., Figarella-Branger, D., Rodriguez, D., Morgan, P. S., Raman, P., Waanders, A. J., Resnick, A. C., Massimino, M., Garrè, M. L., Smith, H., ... Jones, C. (2018). Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer cell, 33(5), 829-842.e5. https://doi.org/10.1016/j.ccell.2018.04.004

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

abstract = "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. 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.",

keywords = "CD8, H3F3A, MAPK, hypermutator, immune, pediatric high-grade glioma",

author = "Alan Mackay and Anna Burford and Valeria Molinari and Jones, {David T.W.} and Elisa Izquierdo and Jurriaan Brouwer-Visser and Felice Giangaspero and Christine Haberler and Torsten Pietsch and Jacques, {Thomas S.} and Dominique Figarella-Branger and Daniel Rodriguez and Morgan, {Paul S.} and Pichai Raman and Waanders, {Angela Jae} and Resnick, {Adam C.} and Maura Massimino and Garr{\`e}, {Maria Luisa} and Helen Smith and David Capper and Pfister, {Stefan M.} and Thomas W{\"u}rdinger and Rachel Tam and Josep Garcia and Thakur, {Meghna Das} and Gilles Vassal and Jacques Grill and Tim Jaspan and Pascale Varlet and Chris Jones",

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year = "2018",

month = may,

day = "14",

doi = "10.1016/j.ccell.2018.04.004",

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Mackay, A, Burford, A, Molinari, V, Jones, DTW, Izquierdo, E, Brouwer-Visser, J, Giangaspero, F, Haberler, C, Pietsch, T, Jacques, TS, Figarella-Branger, D, Rodriguez, D, Morgan, PS, Raman, P, Waanders, AJ, Resnick, AC, Massimino, M, Garrè, ML, Smith, H, Capper, D, Pfister, SM, Würdinger, T, Tam, R, Garcia, J, Thakur, MD, Vassal, G, Grill, J, Jaspan, T, Varlet, P & Jones, C 2018, 'Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial', Cancer cell, vol. 33, no. 5, pp. 829-842.e5. https://doi.org/10.1016/j.ccell.2018.04.004

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T1 - Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

AU - Mackay, Alan

AU - Burford, Anna

AU - Molinari, Valeria

AU - Jones, David T.W.

AU - Izquierdo, Elisa

AU - Brouwer-Visser, Jurriaan

AU - Giangaspero, Felice

AU - Haberler, Christine

AU - Pietsch, Torsten

AU - Jacques, Thomas S.

AU - Figarella-Branger, Dominique

AU - Rodriguez, Daniel

AU - Morgan, Paul S.

AU - Raman, Pichai

AU - Waanders, Angela Jae

AU - Resnick, Adam C.

AU - Massimino, Maura

AU - Garrè, Maria Luisa

AU - Smith, Helen

AU - Capper, David

AU - Pfister, Stefan M.

AU - Würdinger, Thomas

AU - Tam, Rachel

AU - Garcia, Josep

AU - Thakur, Meghna Das

AU - Vassal, Gilles

AU - Grill, Jacques

AU - Jaspan, Tim

AU - Varlet, Pascale

AU - Jones, Chris

PY - 2018/5/14

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N2 - 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. 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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KW - H3F3A

KW - MAPK

KW - hypermutator

KW - immune

KW - pediatric high-grade glioma

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

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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