Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• Immune checkpoint inhibitors like anti-PD-L1 are standard cancer treatments but benefit only a subset of patients.
• Interleukin-12 (IL12) shows promise for antitumor immunity, but systemic delivery caused toxicity and limited efficacy in early trials.

Purpose of the Study:

• To develop a novel intratumoral IL12 mRNA therapy for localized IL12 production, aiming to mitigate systemic toxicity.
• To evaluate the efficacy of intratumoral IL12 mRNA in promoting antitumor immunity and tumor regression.

Main Methods:

• Designed and administered intratumoral IL12 mRNA therapy in syngeneic mouse cancer models.
• Assessed tumor regression, immune cell infiltration (CD8+ T-cells, NK, NKT), and tumor microenvironment (TME) changes (TH1 transformation).
• Investigated combination therapy with anti-PD-L1 and evaluated responses in distal, uninjected lesions and ex vivo human tumor slice cultures.

Main Results:

• A single intratumoral dose of mouse IL12 mRNA induced CD8+ T-cell-dependent tumor regression and long-term immunity.
• IL12 mRNA therapy promoted a TH1 TME and was effective in PD-L1 blockade-resistant models, especially when combined with anti-PD-L1.
• Intratumoral IL12 mRNA therapy led to regression of distal lesions, suggesting a systemic immune response, with minimal circulating IL12p70.

Conclusions:

• Intratumoral IL12 mRNA therapy holds significant potential for transforming the TME towards a TH1 phenotype.
• This approach can induce robust, localized, and potentially systemic antitumor immunity, offering a new therapeutic strategy for various cancers.