Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas
By J. Zeng, A. See, J. Phallen, Christopher M. Jackson, Z. Belcaid, J. Ruzevick, N. Durham, C. Meyer, T. Harris, E. Albesiano and 11 more. International Journal of Radiation Oncology, Biology, Physics, 2013
859 citations recorded by the source corpus.
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.
Subfields: Genetics, Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/c5699a8a97ec2d85bdd410bc27ed51a31d3d0a6f
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Genetics
In Immunology
In Oncology
Citations in the corpus
- Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment (2017, background): “Preclinical studies suggested that radiation may increase the recruitment of T cells in the tumor microenvironment (Deng et al., 2014; Zeng et al., 2013).”
- Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Anti-Tumor Immune Responses via Cross-Presentation of Tumor Antigen (2014, methodology): “As previously demonstrated by our group (36) and others (33, 37), the combination of directed XRT and immune checkpoint blockade resulted in increased inhibition of tumor outgrowth (Fig.”
- Immunotherapy for glioma: current management and future application. (2020, positive): “In a GL261 cell implanted mouse model, the combination of anti-PD-1 immunotherapy and stereotactic radiosurgery prolonged the median survival to 52 days compared with 27 days achieved with radiotherapy-alone and 30 days achieved with anti-PD-1-immunotherapy alone [29].”