Abstract 2409: Enhanced cell-based immunotherapy by IFNγ, IL-7 or COX-2 inhibition in a rat glioma model

Abstract

Abstract Introduction: Glioblastoma multiforme (GBM) is the most common brain tumor in adults and the median survival time after diagnosis is less than a year despite extensive surgical resection and adjuvant radio- and chemotherapy. Consequently, there is a need for new therapies, and immunotherapy represents a promising treatment approach. We have earlier described the regression of experimental gliomas in response to peripheral immunization with genetically modified tumor cells and a clinical trial is finalized using interferon-gamma (IFNγ) transduced tumor cells in adult patients with GBM. We are currently improving the therapy by adding different cytokines as well as targeting the immune suppression. Further on, to avoid the time consuming step of tumor cell transduction, the present study was undertaken to investigate the effect of immunization using wild-type (wt) tumor cells together with recombinant cytokines and inhibitors of immune suppression. Material and Methods: An experimental rat glioma model, N32 (established by transplacental ENU induction) was used in all experiments. Briefly, N32 rat glioma cells were injected into the right striatum in brains of syngeneic male Fischer 344 rats using a stereotactic frame. The rats were immunized subcutaneously in the thigh with irradiated N32 wt-cells (w/o recombinant IFNγ) or N32 cells genetically modified to produce IFNγ and/or interleukin-7 (N32-IFNγ, N32-IL7). Mini-osmotic pumps were used for the administration of the selective COX-2 inhibitor parecoxib. The immune response was measured in blood and lymph nodes using flow cytometry and ELISA. Results and conclusion: In the present survival study of glioma bearing rats we report that a combination of N32-IFNγ and N32-IL7 is superior compared to each monotherapy, demonstrating a better outcome when multiple steps of the immune activation is enhanced (i.e. antigen-presentation and maturation of T-cells). We also show that COX-2 inhibition results in significantly enhanced survival when combined with N32-IFNγ immunization. Continous parecoxib administration (day 1-28) was superior to intermittent administration (day 7-13 and 17-23), indicating that absence of PGE2 during immune activation improves the therapeutic effect. The COX-2 inhibition, when combined with N32-IFNγ immunization, resulted in a significant increase of IFNγ levels in plasma, which might explain the enhanced cure rate. In addition we show that only wt-immunization is not enough to protect any animals against tumor challenge, but when combined with recombinant IFNγ or COX-2 inhibition animals are cured. In conclusion, we demonstrate the ability to optimize cell-based immunotherapy by stimulating immune activation and inhibiting the immune suppression. These findings may have clinical applications in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2409.