Flt3 ligand expressing adenoviral vectors promote anti-tumor immunity and improve survival in a glioblastoma model.

CURTIN; XIONG; KING; ZIRGER; PUNTEL; LIU; LOWENSTEIN; CASTRO

San Diego, California, USA

Congreso; Society for neuroscience; 2004

Neuroscience 2004 AbstractPresentation Number:233.11Abstract Title:Flt3 ligand expressing adenoviral vectors promote anti-tumor immunity and improve survival in a glioblastoma model.Authors:Curtin, J. F.*1; Xiong, W.1; King, G. D.1; Zirger, J. M.1; Puntel, M.1; Liu, C.1; Lowenstein, P. R.1,2; Castro, M. G.1,2 1Gene Therapeut. Res. Inst., Cedars-Sinai Med. Ctr., Los Angeles, CA 2CA, Research Pavillion, #R5090, 90048,Primary Theme and TopicsNeurological and Psychiatric Conditions - Neuro-OncologySession:233. Neurooncology I PosterPresentation Time:Sunday October 24, 2004 10:00 AM-11:00 AMLocation:Convention Center Exhibit Hall, Poster Board CCC24Keywords:Glioblastoma multiforme is the most commonly diagnosed brain tumor in adults. We combined conditional cytotoxicity and immunotherapy to treat pre-clinical models of glioma. Flt3L is a potent inducer of dendritic cell differentiation and activation and is used in this study to stimulate an anti-glioblastoma immune response. We implanted syngeneic CNS-1 cells into the striatum of Lewis rats which became moribund within 2 to 3 weeks when left untreated. Recombinant adenoviral vectors expressing HSV-TK or Flt3L were injected intra-striatially after 3 days or 10 days. In the 3 day tumor model, Flt3L and HSV-TK resulted in long-term survival in 60% and 100% of animals respectively. In the 10 day tumor model, HSV-TK and Flt3L failed to increase survival when compared to control rats. In contrast, >80% of animals treated with both Flt3L and HSV-TK survived. Inflammatory markers including CD8, OX42 and ED1 were present in areas containing tumor cells. This combined therapy was ineffective in immunocompromised rats, suggesting that the anti-tumor response was immune-mediated. Chronic Flt3L expression may induce autoimmune disease or brain inflammation, consequently we developed high capacity adenoviral vectors with tetracycline-inducible Flt3L and constitutive HSV-TK expression cassettes. These high capacity vectors are not eliminated by the host immune response and are suitable for pre-clinical and clinical trials. In conclusion, combined delivery of Flt3L and HSV-TK to the tumor site using adenoviral vectors elicits an immune response against the tumor and significantly improves survival in a macroscopic model of glioma.