Unlocking the Potential of MEDI1191: Enhancing Tumor Microenvironment for TH1 Transformation

3 June 2024
Patients with a TH1-dominant tumor microenvironment (TME) often show positive responses to PD-L1/PD-1 inhibitors, which is associated with the presence of interferon-γ (IFNγ) and PD-L1. The development of new treatments that can induce a TH1 shift in the TME is crucial for boosting anti-tumor immunity. Interleukin 12 (IL-12) is a pivotal cytokine in TH1 responses, triggering IFNγ production from various immune cells and is essential for anti-tumor effects. However, systemic administration of recombinant IL-12 has shown tolerability issues in clinical trials.

MEDI1191 is an innovative IL-12 mRNA-based therapy, encapsulated in a lipid nanoparticle (LNP) and intended for direct tumor injection. Previous studies have indicated that intratumoral injection of mouse IL-12 mRNA, serving as a proxy for MEDI1191, can enhance cytotoxic T cell-mediated immunity against tumors and improve the efficacy of PD-L1 inhibitors in preclinical settings. The current research underscores the necessity of IFNγ for the anti-tumor efficacy of mouse IL-12 mRNA. A single administration of this mRNA notably increased IFNγ and TH1 gene expression in mice with MC38 tumors. Neutralization of IFNγ with a specific antibody negated the anti-tumor effects of the mRNA treatment. Moreover, the combination of mIL-12 mRNA and anti-PD-L1 therapy led to tumor rejection, which was linked to increased infiltration of cytotoxic T cells and expansion of tumor-reactive T cells in peripheral blood.

Further investigation into MEDI1191's pharmacodynamic effects in models derived from patient tumors revealed that a single intratumoral dose induced human IL-12p70 expression in mice with xenograft tumors from different patients. An ex vivo assay using patient tumor slices showed that MEDI1191 triggered a dose-dependent release of IL-12, upregulation of IFNγ expression, and an increase in TH1-signature genes. IL-12 secretion was observed in all tested patient tumor slices, although the IFNγ response to MEDI1191 varied. A correlation was found between the baseline tumor NK cell presence and the IFNγ release induced by MEDI1191.

The findings from these preclinical studies suggest that MEDI1191 has the potential to induce a TH1 transformation in the TME that is dependent on IFNγ, which supports its further development as a possible treatment for patients with solid tumors, both as a standalone therapy and in combination with PD-1/PD-L1 inhibitors. The study was presented at the American Association for Cancer Research Annual Meeting 2019 by a team of researchers led by Joshua Frederick.

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The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

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Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

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By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

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