mRNA therapy was first used in tumor therapy by injecting mRNA encoding specific proteins such as cytokines into the tumor to intrigue the immune response. However, it still faces the problems of off-target toxicity and difficult intratumoral administration. Previously, cytokine-based cancer immunotherapy has not achieved much clinical success.

Sanofi developed a mRNA therapy for melanoma, and in the cover paper of Science Translational Medicine, the researchers presented data on its preclinical development.

The therapy is a mixture of four mRNAs that encode IL-12 single strand, type I interferon alpha (IFN-α), granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-15 sushi (fusion of the sushi domain of the IL-15 receptor alpha chain with IL-15). The tumor growth was effectively controlled by repeated intratumoral injection of this mRNA mixture, and the tumors of most tumor-bearing mice disappeared completely (8 out of 10 B16F10 and 9 out of 10 CT26).

Moreover, the treatment was well tolerated, with no weight loss observed during the study, and the long-term survival rate of the mice was improved.

After intratumoral administration of mRNA mixture, the researchers examined B16F10 tumor under immunofluorescence microscope, and observed that mRNA mixture changed the tumor microenvironment and increased the infiltration of CD4+ and CD8+ T cells. In many tumor models, intratumoral injection of mRNA mixture can induce effective T cell response and protective immune memory against multiple antigens.

The anti-tumor activity of this mRNA mixture can also be extended to the distal tumor site to control the growth of lung tumor metastases.

In addition, the combination of mRNA mixture and PD-1 inhibitor can further enhance its anti-tumor effect. In the three tumor models tested, the combined use of cytokine mRNA and PD-1 antibody increased the overall survival time of mice. The combination was also very effective in 40% of metastatic mice, with subcutaneous and lung tumors regressing, and no lesions were detected at the end of the study. In addition, mRNA mixture can also improve the survival rate of mice with tumors that are resistant to PD-1 antibodies.

The clinical trial of this cytokine mRNA mixture has initiated (NCT03871348) and is currently in phase I stage.