Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model

ALI; KING; CURTIN; CANDOLFI; XIONG; LIU; PUNTEL; CHENG; PRIETO; RIBAS; KUPIEC-WEGLINSKI; VAN ROOIJEN; LASSMAN; LOWENSTEIN; CASTRO

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2005 p. 7194 - 7204

0008-5472

In spite of preclinical efficacy and recent randomized,controlled studies with adenoviral vectors expressing herpessimplex virus-1 thymidine kinase (HSV1-TK) showing statisticallysignificant increases in survival, most clinical trials usingsingle therapies have failed to provide major therapeuticbreakthroughs. Because glioma is a disease with dismalprognosis and rapid progression, it is an attractive target forgene therapy. Preclinical models using microscopic braintumor models (e.g., V0.3 mm3) may not reflect the pathophysiologyand progression of large human tumors. To overcomesome of these limitations, we developed a syngeneic large braintumor model. In this model, administration of single therapeuticmodalities, either conditional cytotoxicity or immunostimulation,fail. However, when various immunostimulatorytherapies were delivered in combination with conditionalcytotoxicity (HSV1-TK), only the combined delivery of fms-liketyrosine kinase ligand (Flt3L) and HSV1-TK significantlyprolonged the survival of large tumor-bearing animals(z80%; P V 0.005). When either macrophages or CD4+ cellswere depleted before administration of viral therapy, TK +Flt3L therapy failed to prolong survival. Meanwhile, depletionof CD8+ cells or natural killer cells did not affect TK + Flt3Lefficacy. Spinal cord of animals surviving 6 months after TK +Flt3L were evaluated for the presence of autoimmune lesions.Whereas macrophages were present within the corticospinaltract and low levels of T-cell infiltration were detected, theseeffects are not indicative of an overt autoimmune disorder. Wepropose that combined Flt3L and HSV1-TK adenoviral mediatedgene therapy may provide an effective antigliomatreatment with increased efficacy in clinical trials of glioma.