Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas

Jing Zeng, Alfred P. See, Jillian Phallen, Christopher M. Jackson, Zineb Belcaid, Jacob Ruzevick, Nicholas Durham, Christian Meyer, Timothy J. Harris, Emilia Albesiano, Gustavo Pradilla, Eric Ford, John Wong, Hans Joerg Hammers, Dimitris Mathios, Betty Tyler, Henry Brem, Phuoc T. Tran, Drew Pardoll, Charles G. Drake & 1 others Michael Lim

Research output: Contribution to journalArticle

358 Citations (Scopus)

Abstract

Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon- γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.

Original languageEnglish (US)
Pages (from-to)343-349
Number of pages7
JournalInternational Journal of Radiation Oncology Biology Physics
Volume86
Issue number2
DOIs
StatePublished - Jun 1 2013

Fingerprint

death
Glioma
mice
Radiation
tumors
Survival
radiation
Glioblastoma
antibodies
Brain Neoplasms
brain
therapy
implantation
T-Lymphocytes
Immunotherapy
Therapeutics
Antibodies
Radiotherapy
interferon
spleen

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. / Zeng, Jing; See, Alfred P.; Phallen, Jillian; Jackson, Christopher M.; Belcaid, Zineb; Ruzevick, Jacob; Durham, Nicholas; Meyer, Christian; Harris, Timothy J.; Albesiano, Emilia; Pradilla, Gustavo; Ford, Eric; Wong, John; Hammers, Hans Joerg; Mathios, Dimitris; Tyler, Betty; Brem, Henry; Tran, Phuoc T.; Pardoll, Drew; Drake, Charles G.; Lim, Michael.

In: International Journal of Radiation Oncology Biology Physics, Vol. 86, No. 2, 01.06.2013, p. 343-349.

Research output: Contribution to journalArticle

Zeng, J, See, AP, Phallen, J, Jackson, CM, Belcaid, Z, Ruzevick, J, Durham, N, Meyer, C, Harris, TJ, Albesiano, E, Pradilla, G, Ford, E, Wong, J, Hammers, HJ, Mathios, D, Tyler, B, Brem, H, Tran, PT, Pardoll, D, Drake, CG & Lim, M 2013, 'Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas', International Journal of Radiation Oncology Biology Physics, vol. 86, no. 2, pp. 343-349. https://doi.org/10.1016/j.ijrobp.2012.12.025
Zeng, Jing ; See, Alfred P. ; Phallen, Jillian ; Jackson, Christopher M. ; Belcaid, Zineb ; Ruzevick, Jacob ; Durham, Nicholas ; Meyer, Christian ; Harris, Timothy J. ; Albesiano, Emilia ; Pradilla, Gustavo ; Ford, Eric ; Wong, John ; Hammers, Hans Joerg ; Mathios, Dimitris ; Tyler, Betty ; Brem, Henry ; Tran, Phuoc T. ; Pardoll, Drew ; Drake, Charles G. ; Lim, Michael. / Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. In: International Journal of Radiation Oncology Biology Physics. 2013 ; Vol. 86, No. 2. pp. 343-349.
@article{a9b10626c1e64a74b8db4cde1e104663,
title = "Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas",
abstract = "Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15{\%}-40{\%}) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon- γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.",
author = "Jing Zeng and See, {Alfred P.} and Jillian Phallen and Jackson, {Christopher M.} and Zineb Belcaid and Jacob Ruzevick and Nicholas Durham and Christian Meyer and Harris, {Timothy J.} and Emilia Albesiano and Gustavo Pradilla and Eric Ford and John Wong and Hammers, {Hans Joerg} and Dimitris Mathios and Betty Tyler and Henry Brem and Tran, {Phuoc T.} and Drew Pardoll and Drake, {Charles G.} and Michael Lim",
year = "2013",
month = "6",
day = "1",
doi = "10.1016/j.ijrobp.2012.12.025",
language = "English (US)",
volume = "86",
pages = "343--349",
journal = "International Journal of Radiation Oncology Biology Physics",
issn = "0360-3016",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas

AU - Zeng, Jing

AU - See, Alfred P.

AU - Phallen, Jillian

AU - Jackson, Christopher M.

AU - Belcaid, Zineb

AU - Ruzevick, Jacob

AU - Durham, Nicholas

AU - Meyer, Christian

AU - Harris, Timothy J.

AU - Albesiano, Emilia

AU - Pradilla, Gustavo

AU - Ford, Eric

AU - Wong, John

AU - Hammers, Hans Joerg

AU - Mathios, Dimitris

AU - Tyler, Betty

AU - Brem, Henry

AU - Tran, Phuoc T.

AU - Pardoll, Drew

AU - Drake, Charles G.

AU - Lim, Michael

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon- γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.

AB - Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon- γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.

UR - http://www.scopus.com/inward/record.url?scp=84877581852&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877581852&partnerID=8YFLogxK

U2 - 10.1016/j.ijrobp.2012.12.025

DO - 10.1016/j.ijrobp.2012.12.025

M3 - Article

VL - 86

SP - 343

EP - 349

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

SN - 0360-3016

IS - 2

ER -