Inflammatory and anti-glioma effects of an adenovirus expressing human soluble Fms-like tyrosine kinase 3 ligand (hsFlt3L): treatment with hsFlt3L inhibits intracranial glioma progression

ALI; CURTIN; ZIRGER; XIONG; KING; BARCIA; LIU; PUNTEL; GOVERDHANA; LOWENSTEIN; CASTRO

MOLECULAR THERAPY (PRINT)

NATURE PUBLISHING GROUP

Año: 2004 p. 1071 - 1084

1525-0016

Glioblastoma multiforme is an intracranial tumor that has very poor prognosis. Patients usuallysuccumb to their disease 6 to 12 months after they are diagnosed despite very aggressive treatmentmodalities. We tested the efficacy of a potent differentiation and proliferation factor for theprofessional antigen-presenting dendritic cells (DCs), i.e., Flt3L, for its potential role as a noveltherapy for gliomas. We investigated the ability of recombinant adenoviral vectors encoding humansoluble Flt3L (hsFlt3L) to improve the survival of Lewis rats bearing intracranial syngeneic CNS-1gliomas. We show that RAdhsFlt3L can improve survival in a dose-dependent manner. Seventypercent of rats survive when treated with 8 107 pfu RAdhsFlt3L ( P b 0.0005). In addition wedemonstrate in both naRve Lewis rats and C57BL/6 mice the presence of increased numbers of cellsbearing DC markers (OX62 and MHCII, in rats, or CD11C, 33D1, MHCII, and F4/80, but not DEC205, inmice) in sites of brain delivery of RAdhsFlt3L. These results show that expression of hsFlt3L in thebrain leads to the presence of cells displaying DC markers. We demonstrate that treatment withhsFlt3L leads to inhibition of tumor growth and significantly increased life span of animals implantedwith syngeneic CNS-1 glioma cells. Animals that had survived for long periods, i.e., 6 months, hadeliminated the implanted tumors after neuropathological analysis; on the other hand, some of the 3-month survivors still appeared to harbor brain tumors. Our results have profound implications forimmune-mediated brain tumor therapy and also suggest the ability to recruit DC-like cells within thebrain parenchyma in response to the local expression of Flt3L from adenoviral vectors