Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity


Kang Seounghun1ORCID,Mansurov Aslan1ORCID,Kurtanich Trevin1ORCID,Chun Hye Rin2ORCID,Slezak Anna J.1ORCID,Volpatti Lisa R.1ORCID,Chang Kevin1ORCID,Wang Thomas1ORCID,Alpar Aaron T.1ORCID,Refvik Kirsten C.1ORCID,Hansen O. Isabella1ORCID,Borjas Gustavo J.1ORCID,Shim Ha-Na1,Hultgren Kevin T.1,Gomes Suzana1ORCID,Solanki Ani3ORCID,Ishihara Jun4ORCID,Swartz Melody A.1256ORCID,Hubbell Jeffrey A.126ORCID


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

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

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

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

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

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


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.


American Association for the Advancement of Science (AAAS)









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