Biological Sciences Division
Published November 29, 2023 | Version v1
Journal article Open

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

Creators

  • 1. University of Chicago
  • 2. Imperial College London

Description

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.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

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Additional details

Identifiers

DOI
10.1126/sciadv.adh9879
Other
oai:uchicago.tind.io:10041

Funding

NCI
R01-CA219304
University of Chicago
Chicago Immunoengineering Innovation Center

UChicago Information

Division(s)
Biological Sciences Division, Pritzker School of Molecular Engineering
Department(s)
Ben May Department for Cancer Research, Cancer Biology, Immunology