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Cancer Immunol Immunother. 2016 Aug;65(8):1003-13. doi: 10.1007/s00262-016-1863-0. Epub 2016 Jul 4.

Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models.

Author information

1
Department of Radiation Oncology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. franziska.eckert@med.uni-tuebingen.de.
2
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tübingen, Röntgenweg 13, 72076, Tübingen, Germany.
3
Department of Radiation Oncology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
4
Provenance Biopharmaceuticals, Carlisle, MA, USA.
5
Merck Serono R&D, Global Early Development, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
6
Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany.

Abstract

PURPOSE:

NHS-IL12 is an immunocytokine targeting necrotic tumour areas. IL12 shows anti-tumour activity. As local irradiation might induce additional necrosis in solid tumours, we aimed to evaluate the increase in intratumoural accumulation of NHS-IL12 after irradiation and correlate the findings with diffusion-weighted MRI studies in two xenograft models.

METHODS:

Human rhabdomyosarcoma (A204) and prostate cancer (PC3) cells were studied in vitro and as subcutaneous xenografts. Radiation sensitivity of the cell lines was assessed in vitro by colony formation assays. In vivo tumour necrosis was assessed based on apparent diffusion coefficients (ADC). Biodistribution of NHS-IL12 was evaluated with and without tumour irradiation using in vivo small-animal PET and ex vivo biodistribution.

RESULTS:

A204 and PC3 differed in their intrinsic radiation sensitivity. Accordingly, radiation-induced tumour necrosis was found only in A204 xenografts. In comparison with control, ADC was significantly increased after irradiation of A204 tumours with 1 × 8.0 Gy and 5 × 2.0 Gy, whereas no change in ADC was observed in PC3 xenografts in all irradiation regimes. ADC correlated with histology. An enhanced uptake of radiolabelled NHS-IL12 in A204 tumours was detected by PET and ex vivo biodistribution after tumour irradiation. In PC3 tumours, no increase in NHS-IL12 uptake was observed.

CONCLUSIONS:

In dependence of the tumour model, tumour irradiation enhanced tumour necrosis measured in MRI and histology. In vivo PET and ex vivo biodistribution showed enhanced binding of NHS-IL12 in rhabdomyosarcoma xenografts. Thus, enhanced binding of necrosis-targeting immunocytokines might be a novel mechanism of additive effects in combination with irradiation.

KEYWORDS:

ADC; Immunocytokine; Interleukin 12; Irradiation; MRI; PET

PMID:
27376889
DOI:
10.1007/s00262-016-1863-0
[Indexed for MEDLINE]

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