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Issue 4, 2019
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Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells

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Abstract

Interleukin-2 (IL-2) is a potent T-cell mitogen that can adjuvant anti-cancer adoptive T-cell transfer (ACT) immunotherapy by promoting T-cell engraftment. However, the clinical applications of IL-2 in combination with ACT are greatly hindered by the severe adverse effects such as vascular leak syndrome (VLS). Here, we developed a synthetic delivery strategy for IL-2 via backpacking redox-responsive IL-2/Fc nanogels (NGs) to the plasma membrane of adoptively transferred T-cells. The NGs prepared by traceless chemical cross-linking of cytokine proteins selectively released the cargos in response to T-cell receptor activation upon antigen recognition in tumors. We found that IL-2/Fc delivered by T-cell surface-bound NGs expanded transferred tumor-reactive T-cells 80-fold more than the free IL-2/Fc of an equivalent dose administered systemically and showed no effects on tumor-infiltrating regulatory T-cell expansion. Intriguingly, IL-2/Fc NG backpacks that facilitated a sustained and slow release of IL-2/Fc also promoted the CD8+ memory precursor differentiation and induced less T-cell exhaustion in vitro compared to free IL-2/Fc. The controlled responsive delivery of IL-2/Fc enabled the safe administration of repeated doses of the stimulant cytokine with no overt toxicity and improved efficacy against melanoma metastases in a mice model.

Graphical abstract: Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells

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Publication details

The article was received on 01 Dec 2018, accepted on 16 Jan 2019 and first published on 22 Jan 2019


Article type: Paper
DOI: 10.1039/C8BM01556B
Biomater. Sci., 2019,7, 1345-1357

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    Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells

    Y. Xie, H. Arik, L. Wei, Y. Zheng, H. Suh, D. J. Irvine and L. Tang, Biomater. Sci., 2019, 7, 1345
    DOI: 10.1039/C8BM01556B

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