High dose IL-2 is registered for the treatment of melanoma and renal cell carcinoma, however this therapy has limited efficacy and severe toxicity. It has been shown that in patients HD IL-2 drives preferential expansion of regulatory T cells, which dampen the antitumor immunity. This results explain at least partially the limited efficacy of this therapy. In this work, we characterize a human IL-2 mutant which differs from wildtype IL-2 by four mutations at the interface with the a-subunit of IL-2R. In vitro, IL-2 mutant induces proliferation of CD8+CD44hi and NK1.1 cells as efficiently as wtIL-2 does, but it shows a reduced capacity to induce proliferation of CD4+Foxp3+ regulatory T cells. In vivo, IL-2 mutant clearly induces preferential proliferation of CD8+CD44hi witha quite reduced proliferation of CD4+Foxp3+ regulatory T cells. The IL-2 mutant shows higher antimetastatic effect than wtIL-2 in several transplantable tumor models. i.e. the experimental metastasis model of MB16F0; the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222 and the metastasis mammary carcinoma 4T1. Moreover initial data also support a higher potency of this IL2 mutant, when used in combination with other immune-therapies. Relevantly, the IL-2 mutant also exhibits lower lung and liver toxicity than does wtIL-2 when used at high doses in mice. The IL-2 mutant described could be a good candidate for improving cancer therapy based on IL-2.
Citation Format: Tania Carmenate, Magela Montalvo, Gertrudis Rojas, Dasha Fuentes, Kalet Leon. Human IL-2 mutant exhibits a higher antitumor efficacy and lower toxicity than wildtype IL-2 in different preclinical contexts [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B011.
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