Oncotarget

Research Papers:

The immunocytokine NHS-IL12 as a potential cancer therapeutic

Jonathan Fallon, Robert Tighe, Giorgio Kradjian, Wilson Guzman, Anna Bernhardt, Berend Neuteboom, Yan Lan, Helen Sabzevari, Jeffrey Schlom _ and John W. Greiner

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Oncotarget. 2014; 5:1869-1884. https://doi.org/10.18632/oncotarget.1853

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Abstract

Jonathan Fallon1,*, Robert Tighe2,*, Giorgio Kradjian2, Wilson Guzman2, Anna Bernhardt2, Berend Neuteboom2, Yan Lan2, Helen Sabzevari2, Jeffrey Schlom1, John W. Greiner1

1 Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland USA;

2 EMD Serono Research and Development Institute, Billerica, Massachusetts USA

* These authors contributed equally to this work.

Correspondence:

Jeffrey Schlom, email:

Keywords: immunocytokine, interleukin-12, tumor necrosis therapy, T cells, immunotherapy

Received: February 19, 2014 Accepted: March 23, 2014 Published: March 24, 2014

Abstract

Targeted delivery of IL-12 might turn this cytokine into a safer, more effective cancer therapeutic. Here we describe a novel immunocytokine, NHS-IL12, consisting of two molecules of IL-12 fused to a tumor necrosis-targeting human IgG1 (NHS76). The addition of the human IgG1 moiety resulted in a longer plasma half-life of NHS-IL12 than recombinant IL-12, and a selective targeting to murine tumors in vivo. Data from both in vitro assays using human PBMCs and in vivo primate studies showed that IFN-gamma production by immune cells is attenuated following treatment with the immunocytokine, suggesting an improved toxicity profile than seen with recombinant IL-12 alone. NHS-IL12 was superior to recombinant IL-12 when evaluated as an anti-tumor agent in three murine tumor models. Mechanistic studies utilizing immune cell subset-depleting antibodies, flow cytometric methods, and in vitro cytotoxicity and ELISA assays all indicated that the anti-tumor effects of NHS-IL12 were primarily CD8+ T cell-dependent and likely IL-12-mediated. Combining NHS-IL12 treatment with a cancer vaccine, radiation, or chemotherapy resulted in greater anti-tumor effects than each individual therapy alone. These preclinical findings provide a rationale for the clinical testing of this immunocytokine, both as a single agent and in combination with vaccines, radiation and chemotherapy.


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