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

• Published in: Biomaterials science 2019-03, Vol.7 (4), p.1345-1357
• Main Authors: Xie, Yu-Qing, Arik, Hacer, Wei, Lixia, Zheng, Yiran, Suh, Heikyung, Irvine, Darrell J, Tang, Li
• Format: Article
• Language: English
• Subjects: Animals; Backpacks; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Crosslinking; Cytokines; Differentiation; Exhaustion; Female; Interleukin-2 - chemical synthesis; Interleukin-2 - chemistry; Interleukin-2 - pharmacology; Interleukins; Melanoma - immunology; Melanoma - pathology; Mice; Mice, Inbred C57BL; Molecular Structure; Nanogels; Organic chemistry; Oxidation-Reduction; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacology; Polyethyleneimine - chemical synthesis; Polyethyleneimine - chemistry; Polyethyleneimine - pharmacology; Precursors; Proteins; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Toxicity; Tumors
• ISSN: 2047-4830; 2047-4849; 2047-4849
• DOI: 10.1039/c8bm01556b

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.