title: Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas.
abstract: OBJECTIVE
  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
  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.
authors: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland, USA.
authors: Jing
authors: J
authors: Zeng
authors: Alfred P
authors: AP
authors: See
authors: Jillian
authors: J
authors: Phallen
authors: Christopher M
authors: CM
authors: Jackson
authors: Zineb
authors: Z
authors: Belcaid
authors: Jacob
authors: J
authors: Ruzevick
authors: Nicholas
authors: N
authors: Durham
authors: Christian
authors: C
authors: Meyer
authors: Timothy J
authors: TJ
authors: Harris
authors: Emilia
authors: E
authors: Albesiano
authors: Gustavo
authors: G
authors: Pradilla
authors: Eric
authors: E
authors: Ford
authors: John
authors: J
authors: Wong
authors: Hans-Joerg
authors: HJ
authors: Hammers
authors: Dimitris
authors: D
authors: Mathios
authors: Betty
authors: B
authors: Tyler
authors: Henry
authors: H
authors: Brem
authors: Phuoc T
authors: PT
authors: Tran
authors: Drew
authors: D
authors: Pardoll
authors: Charles G
authors: CG
authors: Drake
authors: Michael
authors: M
authors: Lim
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D001921:Brain / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods / Q000401:mortality; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D007167:Immunotherapy / Q000379:methods* / Q000401:mortality; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009333:Neck; D016634:Radiosurgery / Q000379:methods* / Q000401:mortality; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen