期刊
CANCER RESEARCH
卷 65, 期 16, 页码 7194-7204出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-04-3434
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- FIC NIH HHS [1 R03 TW006273-01, R03 TW006273] Funding Source: Medline
- NINDS NIH HHS [U54 NS045309-01, 1 R01 NS 42893.01, 1R21 NS047298-01, R01 NS042893, U54 NS045309, 1R01 NS4455.01, R21 NS047298, R01 NS044556] Funding Source: Medline
In spite of preclinical efficacy and recent randomized, controlled studies with adenoviral vectors expressing herpes simplex virus-1 thymidine kinase (HSV1-TK) showing statistically significant increases in survival, most clinical trials using single therapies have failed to provide major therapeutic breakthroughs. Because glioma is a disease with dismal prognosis and rapid progression, it is an attractive target for gene therapy. Preclinical models using microscopic brain tumor models (e.g., <= 0.3 mm(3)) may not reflect the pathophysiology and progression of large human tumors. To overcome some of these limitations, we developed a syngeneic large brain tumor model. In this model, administration of single therapeutic modalities, either conditional cytotoxicity or immunostimulation, fail. However, when various immunostimulatory therapies were delivered in combination with conditional cytotoxicity (HSV1-TK), only the combined delivery of fins-like tyrosine kinase ligand (F1t3L) and HSV1-TK significantly prolonged the survival of large tumor-bearing animals (>= 80%; P <= 0.005). When either macrophages or CD4(+) cells were depleted before administration of viral therapy, TK + F1t3L therapy failed to prolong survival. Meanwhile, depletion of CD8(+) cells or natural killer cells did not affect TK + F1t3L efficacy. Spinal cord of animals surviving 6 months after TK + F1t3L were evaluated for the presence of autoimmune lesions. Whereas macrophages were present within the corticospinal tract and low levels of T-cell infiltration were detected, these effects are not indicative of an overt autoimmune disorder. We propose that combined F1t3L and HSV1-TK adenoviral-mediated gene therapy may provide an effective antiglioma treatment with increased efficacy in clinical trials of glioma.
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