The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion

Ugur Uslu, Lijun Sun, Sofia Castelli, Amanda V. Finck, Charles-Antoine Assenmacher, Regina M. Young, Zhijian J. Chen () and Carl H. June ()
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Ugur Uslu: University of Pennsylvania Perelman School of Medicine
Lijun Sun: ImmuneSensor Therapeutics
Sofia Castelli: University of Pennsylvania Perelman School of Medicine
Amanda V. Finck: University of Pennsylvania Perelman School of Medicine
Charles-Antoine Assenmacher: University of Pennsylvania
Regina M. Young: University of Pennsylvania Perelman School of Medicine
Zhijian J. Chen: University of Texas Southwestern Medical Center
Carl H. June: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.

Date: 2024
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DOI: 10.1038/s41467-024-47692-9

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