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 M. Durham,Christian F. Meyer,Timothy J. Harris,Emilia Albesiano,Gustavo Pradilla,Eric C. Ford,John Wong,Hans J. Hammers,Dimitris Mathios,Betty Tyler,Henry Brem,Phuoc T. Tran,Drew M. Pardoll,Charles G. Drake,Michael Lim +20 more
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TLDR
The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors, providing strong preclinical evidence to support combination trials in patients with GBM.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 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.read more
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Pembrolizumab for the treatment of non-small cell lung cancer
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Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
TL;DR: The roles of VEGF and ANG2 are outlined, and ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes are suggested, and avenues of future research are highlighted.
References
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Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates
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Fractionated but not single dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody
M. Zahidunnabi Dewan,Ashley E. Galloway,Noriko Kawashima,J. Keith DeWyngaert,James S. Babb,Silvia C. Formenti,Sandra Demaria +6 more
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TL;DR: It is shown that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway.
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