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Clin Cancer Res. 2015 Mar 1;21(5):1151-60. doi: 10.1158/1078-0432.CCR-14-2676. Epub 2014 Dec 31.

Radiotherapy combined with the immunocytokine L19-IL2 provides long-lasting antitumor effects.

Author information

1
Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands. karen.zegers@maastro.nl.
2
Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands.
3
Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands. Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
4
Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
5
Department of Transplantation Immunology, Maastricht University Medical Centre, Maastricht, the Netherlands.
6
Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
7
Bioceros, Utrecht, the Netherlands.
8
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland.

Abstract

PURPOSE:

Radiotherapy modifies the tumor microenvironment and causes the release of tumor antigens, which can enhance the effect of immunotherapy. L19 targets the extra domain B (ED-B) of fibronectin, a marker for tumor neoangiogenesis, and can be used as immunocytokine when coupled to IL2. We hypothesize that radiotherapy in combination with L19-IL2 provides an enhanced antitumor effect, which is dependent on ED-B expression.

EXPERIMENTAL DESIGN:

Mice were injected with syngeneic C51 colon carcinoma, Lewis lung carcinoma (LLC), or 4T1 mammary carcinoma cells. Tumor growth delay, underlying immunologic parameters, and treatment toxicity were evaluated after single-dose local tumor irradiation and systemic administration of L19-IL2 or equimolar controls.

RESULTS:

ED-B expression was high, intermediate, and low for C51, LLC, and 4T1, respectively. The combination therapy showed (i) a long-lasting synergistic effect for the C51 model with 75% of tumors being cured, (ii) an additive effect for the LLC model, and (iii) no effect for the 4T1 model. The combination treatment resulted in a significantly increased cytotoxic (CD8(+)) T-cell population for both C51 and LLC. Depletion of CD8(+) T cells abolished the benefit of the combination therapy.

CONCLUSIONS:

These data provide the first evidence for an increased therapeutic potential by combining radiotherapy with L19-IL2 in ED-B-positive tumors. This new opportunity in cancer treatment will be investigated in a phase I clinical study for patients with an oligometastatic solid tumor (NCT02086721). An animation summarizing our results is available at https://www.youtube.com/watch?v=xHbwQuCTkRc.

PMID:
25552483
DOI:
10.1158/1078-0432.CCR-14-2676
[Indexed for MEDLINE]
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