Tumour burden and interleukin-2 dose affect the interaction between low-dose total body irradiation and interleukin 2

Abstract

Low-dose total body irradiation (LTBI) has a synergistic immune-mediated antitumour effect when used in combination with interleukin 2 (IL-2) in a murine metastatic malignant melanoma model. To optimise the use of this combination treatment this study was performed to test the effect of tumour burden and dose of both LTBI and IL-2 on the therapeutic potential of this treatment strategy. Ten-week-old female C57BL/6 mice were inoculated intravenously (day 0) with 1 million B16F1 malignant melanoma cells. Groups of mice received no treatment, a single fraction of LTBI alone, IL-2 treatment alone, or a combination of LTBI and IL-2. Two doses of LTBI and IL-2 were tested. LTBI was given on day +10 and IL-2 treatment started on day +11. On day +18 the mice were killed. The lungs were removed and analysed for tumour burden. Lung sections were also tested for infiltrating leucocytes using immunohistochemical staining. In one experiment, mice were treated at day +7 with low-dose IL-2 with and without LTBI. LTBI (in the two tested doses) showed no independent therapeutic effects. An IL-2 dose of 300,000 Cetus units (CU) that was effective and showed synergism with LTBI when mice were treated on day +7 failed to show a therapeutic effect when mice were treated on day +10, at which time the initial tumour burden had doubled. High-dose IL-2 (600,000 CU), in contrast, led to a significant reduction in metastatic burden compared to the control group. Combining high-dose IL-2 with LTBI led to a further significant reduction in tumour burden. Moreover, this combination was associated with a less severe vascular leakage syndrome compared to IL-2 alone. IL-2 and combination treatment was associated with an increase in the number of tumour-infiltrating immune cells, but only the number of tumour-infiltrating natural killer cells reflected therapeutic efficacy. It was concluded that tumour burden at the time of treatment and IL-2 dose are two crucial factors affecting the synergism between LTBI and IL-2. The combination may not only be more effective than IL-2 alone but also less toxic.