title: Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.
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.
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. david_reardon@dfci.harvard.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Prafulla C
authors.initials: PC
authors.lastname: Gokhale
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Klein
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Shakti H
authors.initials: SH
authors.lastname: Ramkissoon
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Amy Saur
authors.initials: AS
authors.lastname: Conway
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van Den Abbeele
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Lei
authors.initials: L
authors.lastname: Qin
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D007109:Immunity / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D056747:Immunomodulation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor