IMMU-07. CELLULAR IMMUNOTHERAPY TO OVERCOME TEMOZOLOMIDE INDUCED T CELL EXHAUSTION IN GLIOBLASTOMA
Abstract INTRODUCTION We have previously demonstrated that standard dose (SD) temozolomide results in T cell exhaustion in glioblastoma. In this study, we hypothesized that cellular immunotherapies will prevent T cell exhaustion. We tested temozolomide treatment with adoptive T cell transfer alone, dendritic cell (DC) vaccines alone and T cell transfer in combination with DC vaccines. METHOD GL-261-gp100 tumor-bearing mice were treated with SD (50 mg/kg for 5 days) or metronomic dose (MD) (25 mg/kg for 10 days) temozolomide. CD3+ T cells were isolated from Pmel mice and infused intravenously. Antigen-specific DC vaccines (gp-100) were given intradermally at the concentration of 50×104. Peripheral blood T cell populations were evaluated by flow cytometry. IFN-gamma secretion was measured for evaluation of T cells function. Survival was compared between groups. RESULTS Survival analysis demonstrated that naïve T cell transfer alone and DC vaccine alone add no survival benefit to temozolomide treatment for tumor-bearing animals. There were no significant differences in the expression of exhaustion markers of Tim-3 and Lag-3 on T cells of animals that received a combination of activated T cells and DC vaccines in the context of temozolomide therapy compared to the animals that just received temozolomide. Combination of activated T cell transfer and DC vaccines did not increase IFN-gamma secretion from T cells compared to temozolomide treated animals. Combination of naïve T cell transfer and two DC vaccines increased IFN-gamma secretion from T cells of GL-261 gp100 tumor-bearing animals. However, naïve T cell transfer and two DC vaccines in the context of temozolomide was not potent enough to extend the survival of these tumor-bearing animals. CONCLUSION Combinatorial treatment with naïve antigen-specific T cells and three dendritic cell vaccine boosters in the context of temozolomide is a promising approach to preserve T cell function and avoid T cell exhaustion.