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.
Glioblastoma multiforme is an intracranial tumor that has very poor prognosis. Patients usually succumb to their disease 6 to 12 months after they are diagnosed despite very aggressive treatment modalities. We tested the efficacy of a potent differentiation and proliferation factor for the professional antigen-presenting dendritic cells (DCs), i.e., Flt3L, for its potential role as a novel therapy for gliomas. We investigated the ability of recombinant adenoviral vectors encoding human soluble Flt3L (hsFlt3L) to improve the survival of Lewis rats bearing intracranial syngeneic CNS-1 gliomas. We show that RAdhsFlt3L can improve survival in a dose-dependent manner. Seventy percent of rats survive when treated with 8 x 10(7) pfu RAdhsFlt3L (P < 0.0005). In addition we demonstrate in both naive Lewis rats and C57BL/6 mice the presence of increased numbers of cells bearing DC markers (OX62 and MHCII, in rats, or CD11C, 33D1, MHCII, and F4/80, but not DEC205, in mice) in sites of brain delivery of RAdhsFlt3L. These results show that expression of hsFlt3L in the brain leads to the presence of cells displaying DC markers. We demonstrate that treatment with hsFlt3L leads to inhibition of tumor growth and significantly increased life span of animals implanted with syngeneic CNS-1 glioma cells. Animals that had survived for long periods, i.e., 6 months, had eliminated 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 for immune-mediated brain tumor therapy and also suggest the ability to recruit DC-like cells within the brain parenchyma in response to the local expression of Flt3L from adenoviral vectors.
Ali
Sumia
S
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90048, USA.
Curtin
James F
JF
Zirger
Jeffrey M
JM
Xiong
Weidong
W
King
Gwendalyn D
GD
Barcia
Carlos
C
Liu
Chunyan
C
Puntel
Mariana
M
Goverdhana
Shyam
S
Lowenstein
Pedro R
PR
Castro
Maria G
MG
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003390:Cranial Nerve Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D051381:Rats; D012995:Solubility; D015996:Survival Rate; D013997:Time Factors
D008565:Membrane Proteins; C084881:flt3 ligand protein