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BioNTech: Injecting mRNA to promote anti-tumor immune response
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BioNTech latest paper: Injecting mRNA to promote anti-tumor immune response and tumor eradication.
Systemic administration of recombinant cytokines, such as interleukin-2 and interferon-a, has been approved for the treatment of renal cell carcinoma and melanoma.
However, systemic therapy based on immune cytokines faces some difficulties in clinical practice. The short half-life results in frequent dosing, which ultimately leads to severe dose-limiting toxicity.
These difficulties can be overcome by local administration, increasing the concentration of cytokines in the tumor microenvironment, promoting in situ anti-tumor immune response and reducing systemic exposure.
Although viral and non-viral gene therapy vectors can be used to evaluate local, combined cytokine therapy in mice. However, by triggering the nucleic acid sensing receptors of the innate immune system, this method has potential risks of unnecessary genome rearrangement, anti-vector immunity, and skeletal effects.
In contrast, mRNA is an ideal treatment method to ensure the instantaneous and local translation of cytokines. It can deliver cytokine optimization formulas through special channels and further adjust its translation and activity on natural immune receptors.
On September 8, 2021, the research team of BioNTech of Germany and Sanofi of France published a titled: Local delivery of mRNA-encoding cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models in Science Translational Medicine. Research papers.
The study showed that injecting a mixture of mRNA encoding four cytokines (IL-12sc, GM-CSF, IFN-a and IL-15 sushi) into a tumor can generate a powerful anti-tumor immune response and lead to tumor regression. Combining these mRNAs with immunomodulatory antibodies can further increase the effect. The research team is currently conducting clinical trials of this kind of cytokine-encoding mRNA to treat cancer.
First, the research team used methods including N1-methylpseudouridine triphosphate to transcribe firefly luciferase-encoded mRNA instead of uridine 5′-triphosphate to reduce the innate immune-stimulating effect of RNA. They injected mRNA into the subcutaneous tumors of mice and observed an increase in luciferase activity in the tumors, indicating that the modified mRNA had started local translation within the tumors.
After proving the feasibility of mRNA delivery in tumors, the research team explored the therapeutic potential of expressing immunomodulatory proteins in tumors. Through repeated in vivo anti-tumor activity screening processes, they determined that a mixture of mRNAs encoding four cytokines (IL-12sc, GM-CSF, IFN-a and IL-15 sushi) has significant anti-tumor activity. Repeated intratumoral injection of cytokine mRNAs mixture can effectively control tumor growth.
Six out of 10 mice treated with the four-component cytokine mRNAs mixture showed complete tumor regression, while the animals treated with a single mRNA did not show complete tumor regression. In the melanoma model, some complete responders have localized vitiligo at the original tumor site, indicating that T cells respond to tumor-associated antigens shared between the tumor and normal melanocytes.
Finally, the research team evaluated the combined effect of immune checkpoint inhibitors and a mixture of four-component cytokine mRNAs. Compared with single-agent therapy, combination therapy enhances anti-tumor activity and overall survival. Compared with single-dose mRNA therapy, combination therapy more frequently observed complete responses in animals with larger tumors.
Next, they evaluated the combined effects of cytokine mRNAs and immune checkpoint inhibitors in bilateral tumor models and pseudometastasis models. These tumor models show varying degrees of sensitivity to single-agent anti-PD-1 therapy, while pseudo-metastasis models are not sensitive to checkpoint inhibition.
In all three models, the combination of cytokine mRNAs and anti-PD-1 antibodies increased overall survival. In 40% of pseudo-metastatic mice, the combination of cytokine mRNAs and anti-PD-1 antibodies was very effective, leading to tumor regression of injected subcutaneous and lung tumors.
The research team also observed the same effect in drug-resistant tumors. The above results indicate that the combination of cytokine mRNAs and immune checkpoint inhibitors can enhance anti-tumor activity.
In conclusion, this work proved that in multiple tumor models, intratumoral injection of saline-formulated mRNAs encoding four different cytokines can induce effective effector T cell responses and protective immune memory against multiple antigens.
This protective response is also seen in untreated lesions outside the source tissue, and acts synergistically with immune checkpoint inhibitors in the treatment resistance model.
(source:internet, reference only)