title: The success of locoregional, low-dose recombinant interleukin-2 therapy in tumor-bearing mice is dependent on the time of rIL-2 administration.
abstract: The extremely different administration schedules that are used in testing recombinant interleukin-2 (rIL-2) therapies for cancer may account for the extreme variation in efficacy reported in various studies in animal models. A major point may be the variation of the time interval between tumor transplantation and rIL-2 therapy. We hypothesized that administration of rIL-2 before the immune system has mounted a specific cellular reaction against the tumor (associated antigens) might result in lesser efficacies than later rIL-2 administration. This hypothesis was tested in DBA/2 mice bearing a syngeneic SL2 lymphoma. When 7000 IV/day rIL-2 was administered to tumor-bearing mice for 5 consecutive days starting on day 1, 3, 4, 5, or 6 after tumor inoculation, the survival curve of the mice did not significantly differ from that of diluent-treated mice. In contrast, a significant difference was observed when treatment was begun on day 7, 8, 9, 10, or 12 (p < or = 0.004). rIL-2 therapies begun on day 9 or 10 were most effective, curing up to 80% of mice treated, despite there being an enormous burden of disseminated tumor present at that time (1-4% of the total body weight). When rIL-2 was administered for fewer than 5 consecutive days, beginning on day 10, the efficacy of the therapy dropped radically (p < or = 0.055). Involvement of a specific anti-tumor reaction was also tested. All mice that were cured of the tumor as a result of rIL-2 therapy proved to be specifically immune to the SL2 tumor. Furthermore, day 10-14 administration of rIL-2 was completely ineffective in CD4(+)-cell depleted mice (p = 0.0116 vs. rIL-2 therapy in non-depleted mice). Together, this implies that this form of rIL-2 therapy is mediated by tumor-specific T-cells. As a whole, these results indicate that T-cell mediated rIL-2 therapy of cancer in animal models is sensitive to the time when the rIL-2 is administered and to the length of time for which the rIL-2 is given. This should be taken into account when planning new therapy protocols and when analyzing published data.
authors.affiliation: Department of Functional Morphology, Utrecht University, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Everse
authors.forename: M R
authors.initials: MR
authors.lastname: Bernsen
authors.forename: H F
authors.initials: HF
authors.lastname: Dullens
authors.forename: W
authors.initials: W
authors.lastname: Den Otter
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D003470:Culture Media; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors; D014183:Transplantation, Heterologous
chemical_list: D003470:Culture Media; D007376:Interleukin-2; D011994:Recombinant Proteins