Cytokine gene therapy with interleukin-2-transduced fibroblasts: effects of IL-2 dose on anti-tumor immunity.
We evaluated the effects of different doses of interleukin-2 (IL-2)-transduced fibroblasts in the treatment of colorectal carcinoma in the CT-26 murine tumor model. Immunization with a mixture of irradiated tumor cells and IL-2-transduced fibroblasts (100 units of IL-2/24 hr) induced significantly greater protection against a live tumor challenge compared to irradiated tumor cells alone (22/35, 65% vs. 10/30, 33%, p < 0.02). Protective effects were observed with doses of IL-2-transduced fibroblasts secreting from 5 to 100 units of IL-2/24 hr. Parallel experiments in nude mice produced no protection, indicating that the effects of immunization were mediated by a T-cell-dependent mechanism. In animals with established tumors, complete tumor remissions were observed following immunization with a mixture of irradiated tumor cells and IL-2-transduced fibroblasts secreting 100 units of IL-2/24 hr, but not after immunization with irradiated tumor cells alone (7/16 vs. 0/11 complete remissions, p < 0.02). Fibroblasts secreting higher doses of IL-2 were ineffective in generating systemic immunity, but were required to prevent tumor implantation. A statistically significant difference in the prevention of tumor implantation was observed between groups inoculated with a mixture of live tumor cells and IL-2-transduced fibroblasts (1,750 units of IL-2/24 hr) compared to control fibroblasts (6/8 vs. 0/12, p < 0.001). Similar results were observed in nude mice, suggesting that the implantation rejection response is mediated in part by cells other than thymus-derived T cells. Our data support the utility of IL-2-transduced fibroblasts and indicate that the level of IL-2 expression is an important variable in activating different effector components of antitumor immune responses in IL-2 gene therapy.
Fakhrai
H
H
San Diego Regional Cancer Center, Sharp HealthCare Affiliate, San Diego, CA 92121, USA.
Shawler
D L
DL
Gjerset
R
R
Naviaux
R K
RK
Koziol
J
J
Royston
I
I
Sobol
R E
RE
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D005347:Fibroblasts; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D007376:Interleukin-2