Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model.
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., < or =0.3 mm3) 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 fms-like tyrosine kinase ligand (Flt3L) and HSV1-TK significantly prolonged the survival of large tumor-bearing animals (> or =80%; P < or = 0.005). When either macrophages or CD4+ cells were depleted before administration of viral therapy, TK + Flt3L therapy failed to prolong survival. Meanwhile, depletion of CD8+ cells or natural killer cells did not affect TK + Flt3L efficacy. Spinal cord of animals surviving 6 months after TK + Flt3L 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 Flt3L and HSV1-TK adenoviral-mediated gene therapy may provide an effective antiglioma treatment with increased efficacy in clinical trials of glioma.
Ali
Sumia
S
Molecular Medicine and Gene Therapy Unit, University of Manchester, Manchester, United Kingdom.
King
Gwendalyn D
GD
Curtin
James F
JF
Candolfi
Marianela
M
Xiong
Weidong
W
Liu
Chunyan
C
Puntel
Mariana
M
Cheng
Queng
Q
Prieto
Jesus
J
Ribas
Antoni
A
Kupiec-Weglinski
Jerzy
J
van Rooijen
Nico
N
Lassmann
Hans
H
Lowenstein
Pedro R
PR
Castro
Maria G
MG
D000260:Adenoviruses, Human / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D001921:Brain / Q000276:immunology; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000276:immunology; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000276:Adjuvants, Immunologic; D008565:Membrane Proteins; C084881:flt3 ligand protein; D016572:Cyclosporine; D013937:Thymidine Kinase