Enhancing T cell function potentiates the efficacy of a combined immunotherapeutic strategy in an aggressive glioma model.

MINEHARU; PUNTEL; KROEGER; LIU; BONDALE; LOWENSTEIN

San Diego, California, US

Congreso; Society for Neuroscience; 2010

Glioblastoma multiforme (GBM) is among the most lethal type of brain tumor. We tested and optimized cytotoxic/immunomodulatory gene therapy using adenoviral vectors expressing HSV1-TK (Ad-TK) and Flt3 ligand (Ad-Flt3L) in an agressive rat glioma model (RG2), which is refractory to most therapeutic modalities. Although Ad-TK combined with Ad-Flt3L lead to long term survival in other rat glioma models (CNS1, 9L, F98) as shown in our previous studies, the treatment only prolonged the median survival of RG2 bearing rats from 18 days to 33 days. To improve the treatment efficacy, we modified the regimen by delivering: (1) SR39, an HSV1-TK mutant which demonstrates superior tumor ablation (2) Flt3L-IgG2a fusion protein, which shows higher affinity to Flt3 and longer serum half-life, (3) combination Ad-TK/Ad-Flt3L treatment with temozolomide, (4) combination treatment with Ad-CCL3 or Ad-CXCL10 to increase dendritic cell migration, (5) combination treatment with Ad-CD40L or Ad-CCL2 to activate tumor infiltrating dendritic cells, (6) combination treatment with Ad-IL-2 or Ad-IFN gamma (Th1 cytokines) to enhance the function of T cells and NK cells. Our data showed that the combination Ad-TK/Ad-Flt3L with Ad-IL-2 or Ad-IFN gamma further enhanced treatment efficacy exhibiting a prolonged median survival of 51 or 42 days, respectively. Taken together our results indicate that enhancing T cells’ function will provide a novel therapeutic target to be used in combination with Ad-TK/Ad-Flt3L to improved therapeutic efficacy and increase median survival in this challenging intracranial syngeneic GBM model.