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강성훈Seounghun Kang

University of Chicago

Sci. Adv., Dec 2023, 9 (48) | https://doi.org/10.1126/sciadv.adh9879 Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity

Seounghun Kang ^1†, Aslan Mansurov^1†, Trevin Kurtanich ¹, Hye Rin Chun ², Anna J Slezak ¹, Lisa R Volpatti ¹, Kevin Chang ¹, Thomas Wang¹, Aaron T Alpar¹, Kirsten C Refvik ¹, O Isabella Hansen ¹, Gustavo J Borjas ¹, Ha-Na Shim ¹, Kevin T Hultgren ¹, Suzana Gomes ¹, Ani Solanki ³, Jun Ishihara⁴, Melody A Swartz ^1,2,5,6, Jeffrey A Hubbell ^1,2,6

¹Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.

²Committee on Immunology, University of Chicago, Chicago, IL, USA.

³Animal Resource Center, University of Chicago, Chicago, IL, USA.

⁴Department of Bioengineering, Imperial College London, London, UK.

⁵Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.

⁶Committee on Cancer Biology, University of Chicago, Chicago, IL, USA.

^†These authors contributed equally to this work.

^*Corresponding author: Jeffrey A Hubbell

Abstract

Cancer immunotherapy is moving toward combination regimens with agents of complementary mechanisms of action to achieve more frequent and robust efficacy. However, compared with single-agent therapies, combination immunotherapies are associated with increased overall toxicity because the very same mechanisms also work in concert to enhance systemic inflammation and promote off-tumor toxicity. Therefore, rational design of combination regimens that achieve improved antitumor control without exacerbated toxicity is a main objective in combination immunotherapy. Here, we show that the combination of engineered, tumor matrix-binding interleukin-7 (IL-7) and IL-12 achieves remarkable anticancer effects by activating complementary pathways without inducing any additive immunotoxicity. Mechanistically, engineered IL-12 provided effector properties to T cells, while IL-7 prevented their exhaustion and boosted memory formation as assessed by tumor rechallenge experiments. The dual combination also rendered checkpoint inhibitor (CPI)-resistant genetically engineered melanoma model responsive to CPI. Thus, our approach provides a framework of evaluation of rationally designed combinations in immuno-oncology and yields a promising therapy.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2023-12-01)
연구진국외 연구진
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