@article {702911, title = {Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.}, journal = {Cancer Immunol Res}, volume = {4}, number = {2}, year = {2016}, month = {2016 Feb}, pages = {124-35}, abstract = {Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50\%, 20\%, and 15\% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75\% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma. Cancer Immunol Res; 4(2); 124-35. {\textcopyright}2015 AACR.}, issn = {2326-6074}, doi = {10.1158/2326-6066.CIR-15-0151}, author = {Reardon, David A and Gokhale, Prafulla C and Klein, Sarah R and Ligon, Keith L and Rodig, Scott J and Ramkissoon, Shakti H and Jones, Kristen L and Conway, Amy Saur and Liao, Xiaoyun and Zhou, Jun and Wen, Patrick Y and Van Den Abbeele, Annick D and Hodi, F Stephen and Qin, Lei and Kohl, Nancy E and Sharpe, Arlene H and Dranoff, Glenn and Freeman, Gordon J} }