Before mRNA vaccines became valuable preventive tools against COVID-19, scientists around the world were studying the potential use of technology in cancer therapy, but their success has so far been limited.
Now, scientists at the National Center for Nanoscience and Technology of China (NCNST) have developed a hydrogel to deliver an mRNA vaccine with an immunostimulatory adjuvant. When injected into mice with melanoma, the vaccine remained active for at least 30 days, inhibiting tumor growth and preventing metastasis, according to results published in the American Chemical Society’s Nano Letters.
The results showed that the hydrogel delivery system has the potential to help mRNA vaccines achieve long-lasting anti-tumor effects such as cancer immunotherapy, the researchers said.
In COVID-19, mRNA vaccines carry the genetic information that instructs the body to produce a specific viral protein to trigger the desired immune response. In cancer, vaccines are usually designed to translate tumor-associated antigens so that the immune system can recognize and eliminate cancer.
The problem is that RNA is very unstable and mRNA vaccines must reach lymph nodes to function. For its COVID-19 shot Comirnaty (BNT162b2), authorized by the FDA, BioNTech used small fat particles known as lipid nanoparticles to protect the nucleus’ mRNA information. Nanoparticles degrade and release mRNA as soon as they reach the target tissue. The mRNA itself also degrades rapidly after protein translation.
This short immune involvement works to prevent COVID-19, but, in the treatment of cancer, a longer-lasting delivery of mRNA would be necessary to achieve stable therapeutic results.
For this, the NCNST team designed a hydrogel with graphene oxide and low weight polyethyleneimine. Graphene oxide can carry drug substances efficiently, thanks to its large surface area, and polyethyleneimine binds to the mRNA content for translation. To further increase stimulation and expansion of antigen-specific CD8 + T cells – which are critical for antitumor immune responses – in the presence of a hostile tumor microenvironment, the team added resiquimod agonist TLR7 / 8 from Galderma as an adjuvant.
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To test their mRNA platform, the researchers used ovalbumin, a protein found in chicken egg white, as a model antigen. They mixed the ovalbumin mRNA and the adjuvant with the hydrogel and injected it under the skin of mice with melanoma tumors designed to express ovalbumin on its surface.
The hydrogel continuously released the vaccine – including mRNA and adjuvant – into nanoparticles for at least 30 days and migrated to the lymph nodes, the team showed.
Animals that received only one injection of complete therapy had significantly smaller tumors compared to mice that received free adjuvant and mRNA without the hydrogel, or those that received an mRNA hydrogel without adjuvant. The mice that received complete therapy also exhibited the greatest number of CD8 + T cells that entered the tumors, the scientists found.
Furthermore, the new mRNA gel treatment induced the highest level of antibodies specific to ovalbumin in the serum compared to others, suggesting that it not only inhibited tumor growth, but also prevented tumors from returning or forming distant metastases. In fact, there were no observable metastases in the lung tissues of mice that received the full regimen, while the combination of free mRNA-adjuvant and the non-adjuvant mRNA gel solution only partially relieved metastases compared to control mice that received saline or just the gel delivery system, the scientists reported.
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The biopharmaceutical companies that launched the COVID-19 mRNA vaccines to the market are still interested in applying the technology to cancer. But it is still early and they have encountered many obstacles.
BioNTech and collaborator Roche reported a response rate of just 8% in 108 patients in the phase 1b study who received a personalized cancer mRNA vaccine along with the checkpoint inhibitor Tecentriq. Moderna’s personalized cancer vaccine failed to work alongside Merck’s Keytruda checkpoint inhibitor in colorectal cancer in a small phase 1 study, although it did reduce tumors in half of head and neck cancer patients.
The NCNST team suggests that its hydrogel system has the potential as an efficient mRNA platform for use in cancer immunotherapy. “Collectively, the present study demonstrates the great potential of GLP-RO Gel in obtaining durable and efficient immunotherapy against cancer,” wrote the researchers in the study.