Comparison of gene therapy with interleukin-2 gene modified fibroblasts and tumor cells in the murine CT-26 model of colorectal carcinoma.
We compared the efficacy of gene therapy mediated by interleukin-2 (IL-2) gene-modified tumor cells to gene therapy mediated by IL-2 transduced fibroblasts in the CT-26 model of murine colorectal carcinoma. We transduced CT-26 tumor cells and BALB/c 3T3 fibroblasts with three different retroviral vectors using three different promoters for the human IL-2 gene: DC/TKIL-2 (thymidine kinase promoter), LXSN-iIL2 (long terminal repeat promoter), and LNCX-iIL2 (cytomegalovirus promoter). These transductions resulted in CT-26 and 3T3 subclones that secreted different amounts of IL-2. Immunization of animals with either CT-26/IL-2 cells or with fibroblast/IL-2 cells mixed with CT-26 induced similar levels of immunity that protected 62-82% of animals against a subsequent tumor challenge with parental CT-26. However, mice developed tumors at the site of inoculation in 46% of the animals immunized with CT-26/IL-2 cells. In a separate experiment, CT-26/IL-2 cells were exposed to 6,000 cGy of gamma irradiation to prevent tumor growth at the site of inoculation. Although the CT-26/IL-2 cells continued to secrete IL-2 after irradiation, they were no longer effective at inducing antitumor immunity. In contrast, both irradiated and nonirradiated fibroblast/IL-2 cells, mixed with irradiated CT-26, were equally effective at inducing antitumor immunity. These data suggest that in the CT-26 model, fibroblast-mediated IL-2 gene therapy has advantages for the induction of antitumor immunity and abrogation of tumorigenic potential at the site of inoculation compared with tumor cell-mediated IL-2 gene therapy.
Shawler
D L
DL
Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
Dorigo
O
O
Gjerset
R A
RA
Royston
I
I
Sobol
R E
RE
Fakhrai
H
H
D016475:3T3 Cells / Q000187:drug effects* / Q000528:radiation effects; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000494:pharmacology / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D014162:Transfection; D014407:Tumor Cells, Cultured
D007376:Interleukin-2