Local low-dose interleukin-2 induces systemic immunity when combined with radiotherapy of cancer. A pre-clinical study

Abstract

Tumor recurrence and outgrowth of metastases limit the therapeutical effect of radiotherapy. We have tested whether these problems can be overcome by supplementing radiotherapy with locoregional interleukin‐2 (IL‐2) treatment. The SL2 lymphoma and the M8013 mammary carcinoma were used. Mice bearing a 10‐day‐old s.c. tumor were locally irradiated and were treated daily with IL‐2 peritumorally for 5 or 10 days. Low‐dose IL‐2 therapy improved local response (LR) and increased disease‐free survival (DFS) in both tumor models following either single‐dose irradiation or fractionated irradiation. For example, 93% of SL2‐bearing mice treated with single‐dose irradiation and 10 days of IL‐2 experienced long‐term DFS, compared with 17% for irradiation alone (p < 0.0001). Additionally, treatment of one tumor with irradiation +IL‐2 led to anti‐tumor effects in a second, untreated tumor in 80% of SL2‐bearing mice. LR was increased to 100% and DFS to 70% when the second, non‐irradiated tumor was also treated with peritumoral IL‐2. We conclude that supplementing local radiotherapy with low doses of IL‐2 results in increased local tumor control and regression of distant, non‐irradiated tumors. This type of radioimmunotherapy is a promising new approach for the clinic. Int. J. Cancer 72:1003–1007, 1997. © 1997 Wiley‐Liss, Inc.

Abscopal, immunological effects of radiotherapy: Narrowing the gap between clinical and preclinical experiences

“…Albeit an involvement of the immune system in tumor control was postulated already a long time ago by P. Ehrlich, it took more than 50 years after Mole's report until S. Demaria and S.C. Formenti expressed in 2004 that abscopal effects induced by IR are immune‐mediated (Figure ). They confirmed earlier reports which had already suggested a contribution of the immune system, and they were the first to explicitly draw this conclusion. Today, we know that the immune system represents the missing link between local RT and systemic abscopal effects, since RT is able to stimulate distinct forms of cell death that are recognized by the immune system as dangerous .…”

“…Earlier in vivo studies on RT‐induced anti‐tumor immunity and abscopal effects frequently tested the co‐administration of cytokines. By the 1980s, the T‐cell proliferation stimulating activity of interleukin (IL)‐2 had already been demonstrated in preclinical and clinical cancer immunotherapy, and this cytokine was consequently used in preclinical studies to explore its synergy with RT in murine models of melanoma, lymphoma, colorectal, mammary, and renal cell carcinoma . In order to reduce the severe side effects of systemic IL‐2 application, peri‐ or intratumoral administration was successfully employed .…”

“…By the 1980s, the T‐cell proliferation stimulating activity of interleukin (IL)‐2 had already been demonstrated in preclinical and clinical cancer immunotherapy, and this cytokine was consequently used in preclinical studies to explore its synergy with RT in murine models of melanoma, lymphoma, colorectal, mammary, and renal cell carcinoma . In order to reduce the severe side effects of systemic IL‐2 application, peri‐ or intratumoral administration was successfully employed . Apart from IL‐2, other mostly proinflammatory cytokines were combined with RT, including the DC‐stimulating Fms‐like tyrosine kinase receptor 3 ligand (Flt3‐L), IL‐12 alone or in combination with Granulocyte macrophage colony‐stimulating factor (GM‐CSF) or M‐CSF, respectively .…”

“…ablative, ≥15 Gy) irradiation strategies . Fractionated and hypofractionated IR elicited potent anti‐tumor immune responses in mouse models of melanoma, lymphoma, breast, colon, and lung carcinoma, and even brachytherapy (a technique where a radiation source is implanted into the tumor for continuous IR delivery with low dose rates) was successfully used in one study . In contrast, other groups reported that anti‐tumor immunity induced by ablative doses of ≥15 Gy was more potent than after fractionated treatments in murine melanoma and colon carcinoma, whereas Dewan et al .…”

How Does Ionizing Irradiation Contribute to the Induction of Anti-Tumor Immunity?

“…This abscopal effect was dependent of CD8+ lymphocytes, CD4+ lymphocytes, and NK1.1 cells, but independent of the tumor-type and genetic background (Shiraishi et al, 2008). An additional administration of Interleukin-2 (IL-2) to RT also results in a better local tumor control and regression of the not irradiated tumor within the same mouse (Everse et al, 1997; Jurgenliemk-Schulz et al, 1997). Others demonstrated an abscopal effect after manipulation of tumor cells with transgenes expressing several cytokines such as IL-2 (Kwong et al, 1997) or Flt3-L (Dong et al, 2003).…”