Abstract 3771: Concurrent GVAX and anti-OX40 therapy in murine intracranial glioma model

Abstract

Abstract Introduction: Malignant glioma is the most aggressive brain tumor with a median survival time of less than 1.5 years post diagnosis despite standard treatments. However, recent advancements in immunotherapy hold significant promise. Irradiated whole tumor cell vaccination stimulates antitumor immunity and prolongs survival in mice with intracranial glioma tumors. We have shown that vaccination and immune checkpoint blockade is synergistic and these efforts are underway in the clinic. In contrast to immune checkpoint blockade, agonist stimulation of OX40, a member of the TNFR/TNF superfamily that is expressed on activated CD4 and CD8 T lymphocytes increases T cell proliferation, clonal memory differentiation, and cytokine release. We hypothesized that subcutaneous vaccination with irradiated GM-CSF expressing glioma cells (GVAX) would, therefore, synergize with systemic delivery of stimulating anti-OX40 antibody and provide effective immunity against intracranial gliomas. Methods: Gl261 cells were implanted in the right frontal lobes of syngeneic c57/bl6 mice using a stereotactic implantation technique. Mice received concurrent subcutaneous injection of irradiated GM-CSF expressing glioma cells and intraperitoneal injection of OX40 antibody, either monotherapy, or control treatment on days 3, 6 and 9 following tumor implantation. Results: Combination immunotherapy with irradiated GM-CSF expressing glioma cells and intraperitoneal delivery of agonist monoclonal antibody against OX40 was more effective than either therapy alone and prolonged survival in mice with established intracranial GL261 tumors. Elispot analyses of peripheral lymphocytes revealed that combination immunotherapy reverses the Th2 cytokine skew that is induced by the presence of intracranial glioma. OX40 signaling alone and in combination with vaccination drove high levels of interferon gamma expression by splenocytes harvested from glioma-bearing animals, while IL-10 expression was little changed. In the tumor microenvironment, vaccination improves the CD8+ /FoxP3+ T lymphocyte ratio, while OX40 ligation overcomes tumor-driven lymphocyte exhaustion, demonstrated by reduced expression of PD1 and LAG3, measured by flow cytometery 2 weeks after initiation of treatment. Conclusions: Combination treatment with GVAX and OX-40 agonist antibody increased survival in mice bearing intracranial gliomas and are mechanistically complementary. Citation Format: Nusrat Jahan, Hammad Talat, William T. Curry. Concurrent GVAX and anti-OX40 therapy in murine intracranial glioma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3771. doi:10.1158/1538-7445.AM2017-3771