TY - JOUR
T1 - Inflammatory and anti-glioma effects of an adenovirus expressing human soluble Fms-like tyrosine kinase 3 ligand (hsFlt3L)
T2 - Treatment with hsFlt3L inhibits intracranial glioma progression
AU - Ali, Sumia
AU - Curtin, James F.
AU - Zirger, Jeffrey M.
AU - Xiong, Weidong
AU - King, Gwendalyn D.
AU - Barcia, Carlos
AU - Liu, Chunyan
AU - Puntel, Mariana
AU - Goverdhana, Shyam
AU - Lowenstein, Pedro R.
AU - Castro, Maria G.
N1 - Funding Information:
Gene therapy projects for neurological diseases are funded by National Institutes of Health/National Institute of Neurological Disorders & Stroke Grant 1R01 NS44556.01; National Institute of Diabetes, Digestive and Kidney Diseases Grant 1 RO3 TW006273-01 to M.G.C.; National Institutes of Health/National Institute of Neurological Disorders & Stroke Grants NS 42893.01, U54 NS045309-01, and 1R21 NS047298-01 and Bram and Elaine Goldsmith Chair in Gene Therapeutics to P.R.L.; and The Linda Tallen & David Paul Kane Annual Fellowship to M.G.C and P.R.L. We thank Professors Hans Lassmann (Vienna) and Georg Kreutzberg (Munich) for their help in identifying the phenotype of the MHCII-and 33D1-expressing cells. We also thank the generous funding our institute receives from the Board of Governors at Cedars–Sinai Medical Center and the encouragement and support of each and every one of its members. We also acknowledge the unparalleled support and academic leadership of Dr. Shlomo Melmed. We are grateful to Mr. Richard Katzman for his superb administrative and organizational skills and to Mr. Danny Malaniak for his encouragement, support, and commitment. We also acknowledge Dr. C. A. Gerdes, for useful advice and assistance with Adobe PhotoShop.
PY - 2004/12
Y1 - 2004/12
N2 - 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 × 107 pfu RAdhsFlt3L (P < 0.0005). In addition we demonstrate in both naïve 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.
AB - 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 × 107 pfu RAdhsFlt3L (P < 0.0005). In addition we demonstrate in both naïve 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=10344265483&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2004.08.025
DO - 10.1016/j.ymthe.2004.08.025
M3 - Article
C2 - 15564139
AN - SCOPUS:10344265483
VL - 10
SP - 1071
EP - 1084
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 6
ER -