A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control

Zhichen Sun, Zhenhua Ren, Kaiting Yang, Zhida Liu, Shuaishuai Cao, Sisi Deng, Lily Xu, Yong Liang, Jingya Guo, Yingjie Bian, Hairong Xu, Jiyun Shi, Fan Wang, Yang-Xin Fu () and Hua Peng ()
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Zhichen Sun: Chinese Academy of Sciences
Zhenhua Ren: University of Texas Southwestern Medical Center
Kaiting Yang: Chinese Academy of Sciences
Zhida Liu: University of Texas Southwestern Medical Center
Shuaishuai Cao: Chinese Academy of Sciences
Sisi Deng: University of Chinese Academy of Sciences
Lily Xu: University of Wellesley College
Yong Liang: Chinese Academy of Sciences
Jingya Guo: Chinese Academy of Sciences
Yingjie Bian: Chinese Academy of Sciences
Hairong Xu: Chinese Academy of Sciences
Jiyun Shi: Chinese Academy of Sciences
Fan Wang: Chinese Academy of Sciences
Yang-Xin Fu: University of Texas Southwestern Medical Center
Hua Peng: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.

Date: 2019
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DOI: 10.1038/s41467-019-11782-w

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