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

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Chimeric antigen receptor T cell (CART) therapy shows promise against solid tumors but faces challenges.
• Stimulator of interferon genes (STING) agonists represent a novel therapeutic strategy to enhance anti-tumor immunity.

Purpose of the Study:

• To evaluate the efficacy of combining CART therapy with a novel STING agonist, IMSA101, for treating solid tumors.
• To elucidate the underlying mechanisms by which IMSA101 enhances CART cell function.

Main Methods:

• Syngeneic mouse models of solid tumors were used to assess therapeutic outcomes.
• Intratumoral administration of IMSA101 combined with intravenous CART infusion.
• Transcriptomic analysis of tumor-infiltrating CART cells and measurement of cytokine levels (e.g., IL-18) in serum and tumor tissue.
• Assessment of anti-tumor responses using CART cells deficient in the IL-18 receptor.

Main Results:

• Combination treatment with IMSA101 and CART significantly improved overall survival in two distinct tumor models.
• Transcriptomic analysis revealed enhanced T cell activation and upregulated cytokine pathways, notably IL-18, in CART cells from the combination group.
• IMSA101 treatment led to increased IL-18 levels in both serum and tumor microenvironment.
• CART cells lacking the IL-18 receptor showed impaired anti-tumor responses in mice receiving combination therapy, highlighting IL-18's crucial role.

Conclusions:

• IMSA101, a STING agonist, effectively enhances the anti-tumor efficacy of CART therapy against solid tumors.
• The observed enhancement is mediated, in part, by STING agonist-induced IL-18 secretion, which promotes CART cell function.
• This combinatorial approach offers a promising strategy for improving cancer immunotherapy outcomes.