IMMUNE CHECKPOINT BLOCKADE FOR GLIOBLASTOMA: PRECLINICAL ACTIVITY OF SINGLE AGENT AND COMBINATORIAL THERAPY

    loading  Checking for direct PDF access through Ovid

Abstract

BACKGROUND: Outcome for glioblastoma (GBM) remains dismal and innovative treatment strategies are desperately needed. Growing data support the contribution of local and systemic immune checkpoint molecules to regulating immunosuppression by GBM tumors. METHODS: Luciferized GL261 cells (GL261-Luc) were stereotactically implanted intracranially in albino C57BL/6 mice. Cohorts of mice with growing tumors (increasing bioluminescence) were treated with murine monoclonal antibodies (MAb) against PD-L1, PD-L2, CTLA-4 and combinations thereof every 3 days X 8 doses beginning 6 days following tumor implantation. Treated mice and appropriate controls were followed for overall survival and subsets of mice underwent magnetic resonance imaging (MRI) as well as analysis of tumor infiltrating immune cells, and evaluation of systemic immune cells and immunocytokines. Tumor re-challenge experiments were performed among long-term surviving treated mice. RESULTS: Improved survival was noted among mice treated with immune checkpoint blockade compared to appropriate controls. The most robust survival benefit was noted among mice treated with combinatorial therapy. MRI imaging among long-term surviving animals demonstrated clear evidence of initial tumor growth followed by regression and eradication of tumors. Long-term surviving mice appeared fully intact neurologically and exhibited no evidence of tumor growth following re-challenge of GL261-Luc cells injected subcutaneously. Characterization of tumor infiltrating immune cells as well as systemic immune cells and immunocytokines is ongoing. CONCLUSIONS: Immune checkpoint blockade provides significant survival benefit and appears safe in this immunocompetent, orthotopic GBM model. Re-challenge experiments demonstrate evidence of long-term immunologic memory and further elucidation of underlying mechanisms of immune-mediated anti-tumor activity is ongoing. These data strongly support the evaluation of immune checkpoint inhibitors among patients with GBM. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.

Related Topics

    loading  Loading Related Articles