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Article source: Medical Rubik's Cube Pro
Author: Li Yuan
mRNA therapy was first used in tumor treatment, by injecting mRNA encoding cytokines and other specific proteins into the tumor to activate the immune response
.
However, this technology also faces the problems of off-target toxicity and difficulty in intratumoral administration.
Sanofi cooperated with BioNTech to develop a melanoma mRNA therapy.
In the cover paper of Science Translational Medicine on September 8, researchers introduced the preclinical development data of this therapy
.
The above picture shows the distribution of CD8 T cells (green), CD4 T cells (red) and regulatory T cells (yellow) in mouse tumors after intratumoral treatment with mRNA encoding cytokines.
The nuclei are shown in blue ( Source: Science Translational Medicine)
This therapy consists of 4 types of IL-12 single-chain, type I interferon alpha (IFN-α), granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-15 sushi (IL-15 receptor).
The sushi domain of the α chain is fused to IL-15) mRNA mixture
.
Repeated injection of this mRNA mixture into the tumor can effectively control the growth of the tumor, and the tumors of most tumor-bearing mice have completely resolved (8 out of 10 B16F10 and 9 out of 10 CT26)
Source: Science Translational Medicine
Moreover, the treatment was well tolerated, and no animal weight loss was observed during the study, and the long-term survival rate of the animals was also improved
.
After the administration of the intratumoral mRNA mixture, the researchers performed immunofluorescence microscopy on the B16F10 tumor and observed that the mRNA mixture changed the tumor microenvironment, CD4+ and CD8+ T cell infiltration increased, and in a variety of tumor models, intratumoral injection of mRNA The mixture can induce effective effector T cell responses and protective immune memory against multiple antigens
.
Source: Science Translational Medicine
The anti-tumor activity of this mRNA mixture can also extend to distant tumor locations and control the growth of lung tumor metastases
.
Source: Science Translational Medicine
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 of mice
Source: Science Translational Medicine
The clinical trial of this cytokine mRNA mixture has started (NCT03871348) and is currently in phase I clinical trials
Reference materials:
Hotz C, Wagenaar TR, Gieseke F.
