Intratumoral Gene Transfer of mRNAs Encoding IL12 in Combination with Decoy-Resistant IL18 Improves Local and...

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• Interleukin-12 (IL12) based gene therapy is a key area in cancer research.
• mRNA constructs offer a platform for delivering therapeutic cytokines like IL12 and IL18.
• Decoy-resistant IL18 (DR-18) retains bioactivity and bypasses the IL18 binding protein decoy receptor.

Purpose of the Study:

• To investigate the synergistic effects of combining IL12 and DR-18 mRNA for local cancer gene therapy.
• To evaluate the anti-tumor efficacy and immune cell activation of this combination therapy.
• To explore enhancement of treatment efficacy through combination with anti-PD-1 mAb therapy.

Main Methods:

• Experimental testing of combined mRNA constructs encoding IL12 and decoy-resistant IL18 (DR-18).
• Intratumoral administration in B16OVA tumor-bearing mouse models.
• Assessment of cytokine release (IFNγ), tumor efficacy, immune cell populations (CD8+ T cells, cDC1 dendritic cells), and combination with anti-PD-1 mAb.

Main Results:

• IL12 and DR-18 mRNA synergize to induce significant IFNγ release.
• Intratumoral co-transfer demonstrated efficacy against treated tumors and delayed distant lesions.
• Treatment increased activated CD8+ T cells in tumors and relied on CD8+ T cells and cDC1 dendritic cells for efficacy.
• Combination with anti-PD-1 mAb enhanced efficacy against distant tumors.

Conclusions:

• Local co-delivery of IL12 and DR-18 mRNA is an effective anti-tumor strategy.
• The therapy enhances CD8+ T cell responses and requires cDC1 dendritic cells.
• Combining this mRNA gene therapy with anti-PD-1 blockade presents a feasible synergistic immunotherapy approach for cancer.