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Radiotherapy

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Conventional treatment

1997

Everse LA, Renes IB, Jurgenliemk-Schulz IM, Rutgers DH, Bernsen MR, Dullens HF, Den Otter W, Battermann JJ. Local low-dose interleukin-2 induces systemic immunity when combined with radiotherapy of cancer. A pre-clinical study. Int J Cancer. (1997) 72, 1003 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.

Everse et al. (1997)

Jurgenliemk-Schulz IM, Renes IB, Rutgers DH, Everse LA, Bernsen MR, Den Otter W, Battermann JJ. Anti-tumor effects of local irradiation in combination with peritumoral administration of low doses of recombinant interleukin-2 (rIL-2). Radiat Oncol Investig. (1997) 5, 54. The aim of this work was to improve radiotherapy results by immune stimulation. We tested the effects of a combination of radio- and immunotherapy, i.e., local low dose recombinant interleukin-2 (rIL-2) treatment, in two murine tumor models. Syngeneic tumors (SL2 lymphoma or M8013 mammary carcinoma) were induced subcutaneously on one or both flanks of mice. Irradiation was given either as a single dose (20 Gy) or fractionated (25 Gy) in 2 weeks. One or two cycles of rIL-2 were given concurrent with or subsequent to radiotherapy. One cycle of rIL-2 consisted of peritumoral injections administered on 5 consecutive days. Treatment effects were measured in terms of local tumor response and disease-free survival (DFS). The combined treatment modality was significantly better than treatment with either irradiation alone or rIL-2 alone. When tumors were inoculated on both flanks of the mice, combined radioimmunotherapy of one of the tumors also resulted in regression of the contralateral untreated tumor, indicating that a systemic anti-tumor immune reaction was induced. Additional rIL-2 injections did not enhance radiation toxicity. In conclusion supplementing irradiation with locally administered low doses of rIL-2 results in better local anti-tumor responses and DFS rates than either treatment alone without enhanced treatment toxicity. Furthermore, the local treatment induces a systemic anti-tumor reaction, influencing the growth patterns of a second, untreated tumor.

2005

Jacobs JJL, Hordijk GJ, Jürgenliemk-Schulz IM, Terhaard CHJ, Koten JW, Battermann JJ, Den Otter W Treatment of stage III-IV nasopharyngeal carcinomas by external beam irradiation and local low doses of IL-2 Cancer Immunol. Immunother. (in press) The therapeutic effect of intratumoural application of IL-2 was studied in patients with stage III-IV nasopharyngeal carcinoma that received radiotherapy. Patients with stage III-IV nasopharyngeal carcinoma receiving a standard treatment of 7000 cGy external beam irradiation have a mean disease free survival of about 1.5 years. In this paper we describe 10 of these patients which were treated with additional peritumoural and intratumoural injections with 3 x 10^4 U IL-2 on 5 days in weeks 2, 4, and 6 of the 7 weeks' irradiation period. This combined treatment group was compared with a historical group of patients treated with standard irradiation alone. Local IL-2 therapy showed a marked clinical and statistical significant improvement of disease-free survival. After five years 63% of the IL-2 treated patients were disease-free versus 8% of the control patients. These results suggest that the therapeutic results of radiotherapy can be significantly improved by combining it with local IL-2 treatment. To our knowledge, this is the first clinical report showing that local IL-2 therapy is effective against an infiltrative and locally metastasizing tumour in human patients. Publication Types: Clinical Trial, Phase I, Phase II

Conventional treatment

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Our research is supported by Stichting ter bevordering van het onderzoek in de Experimentele Pathologie en in het bijzonder in de TumourImmunologie. Stichting EPTI, IJselstein, The Netherlands