High frequency of specific CD8+ T cells in the tumor and blood is associated with efficient local IL-12 gene therapy of cancer.
Cancer immunotherapy often aims at the reactivation and expansion of tumor-specific CTL. In an attempt to correlate in situ and/or systemic tumor-specific T cell expansion with tumor regression, we investigated the effects of adenovirus-mediated IL-12 or IFN-gamma gene transfer into established P815 murine tumors. While IFN-gamma was no more potent than the vector alone, IL-12 gene transfer promoted tumor eradication. Despite this antitumor effect, no significant cytolytic activity was detectable using classical cytotoxicity assays from in vitro restimulated splenocytes. Since intratumor gene delivery may induce a localized expansion of CTL, the presence of P815-specific CD8+ T cells in situ was assessed. Using the Immunoscope approach, we found a dramatic increase in clonotypic T cells at the tumor site following IL-12, but not IFN-gamma gene delivery. Antitumor CD8+ T cell frequencies were then re-evaluated using this molecular detection technique, which revealed a comparable expansion of specific T cells in the peripheral organs, most strikingly in the blood. These data show that local IL-12 gene transfer, in contrast to IFN-gamma, mediates a potent antitumor effect that correlates to clonal tumor-specific T cell expansions in situ and in the periphery.
Fernandez
N C
NC
Laboratoire de Vectorologie et Transfert de Gènes, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 1582, Institut Gustave Roussy, Villejuif, France.
Levraud
J P
JP
Haddada
H
H
Perricaudet
M
M
Kourilsky
P
P
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000097:blood*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D018655:Lymphocyte Count; D012515:Mast-Cell Sarcoma / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D011995:Recombination, Genetic; D012513:Sarcoma, Experimental / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D018984:Epitopes, T-Lymphocyte; D018664:Interleukin-12; D007371:Interferon-gamma