A mixture of four mRNAs cured melanoma in mice
Anastasia Kuznetsova-Fantoni, N+1
American and German doctors tested a mixture of mRNA encoding four cytokines for the treatment of cancer in two mouse models. In mice with melanoma, a drug injected locally into the tumor caused its regression, and in animals that, in addition to melanoma, also induced lung cancer, the mRNA mixture not only cured melanoma, but also reduced the volume of the tumor in the lungs. The study was published in Science Translational Medicine (Hotz et al., Local delivery of mRNA-encoding cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models).
Usually, in cancer immunotherapy, cytokines that trigger an immune response against the tumor are administered systemically. They are rapidly destroyed in the body, so they have to be injected repeatedly, and this increases the frequency of side effects in patients. Scientists are currently developing methods of local administration of drugs. Usually, gene therapy is used for this, for the delivery of which viral vectors are used. In this case, side effects also often occur — unwanted changes in the genome or an immune response against the viral vector.
American and German researchers led by Dmitry Wiederschain from Sanofi have developed local immunotherapy, which is devoid of these disadvantages. They combined four mRNAs in one preparation that induce immune cells to produce four cytokines: interleukin 12 (IL-12), granulocyte-macrophage colony stimulating factor (GM-CSF), a small section of interleukin 15 (IL-15 sushi) and interferon alpha 4 (IFN-alpha-4). These cytokines are synthesized by immune cells to fight various antigens. By local administration of these cytokines, the scientists wanted to minimize side effects, and at the same time launch an immune response against tumor antigens.
The medics tested the mRNA mixture on several models. In the first case, they implanted melanoma cells subcutaneously into mice, and after 11 days (when the average tumor size in mice was 60 cubic millimeters), they began treatment with a drug that was administered locally every four days. In 8 out of 10 mice in the experimental group, melanoma regressed by day 35 after its implantation, and in 10 mice from the control group, the tumor progressively increased all this time.
Tumor volume in mice from the experimental group (right) and the control group (left). Figures from the article by Hotz et al.
In the second model, the researchers, in addition to melanoma, induced lung cancer in mice. A mixture of mRNA was injected locally into the melanoma area, but after 20 days, scientists observed not only a regression of melanoma, but also a decrease in lung cancer. Doctors explain this by the fact that the activated immune cells migrated to the lungs.
Melanoma volume (upper graph) and lung tumor volume (lower graph). The red line is the experimental group, the black line is the control group.
Currently, a mixture of mRNA is being tested in clinical trials on 231 people with melanoma, breast cancer and other tumors located close to the surface of the skin. In the future, the researchers plan to inject the drug under ultrasound control into other types of tumors.
Recently, British scientists have completed trials of combined cancer therapy in mice. The treatment method developed by them consists in the simultaneous use of a vaccine that triggers an immune response against tumor cell antigens, as well as a PD-1 inhibitor that prevents the tumor from being recognized by T-lymphocytes.
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