Before mRNA vaccines became valuable preventive tools against COVID-19, scientists around the world studied the potential use of the technology in cancer therapy, but their success has been limited so far.
Now scientists at China’s National Center for Nanoscience and Technology (NCNST) have designed 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 the results published in the American Chemical Society journal Nano Letters.
The results showed that the hydrogel delivery system has the potential to help mRNA vaccines achieve long-lasting anti-tumor effects as an immunotherapy for cancer, the researchers said.
In COVID-19, mRNA vaccines contain the genetic information that instructs the body to produce a specific viral protein to activate the desired immune response. In cancer, the vaccines are typically designed to translate tumor-associated antigens so that the immune system can recognize and eliminate the cancer.
The problem is that RNA is very unstable and mRNA vaccines have to reach the lymph nodes in order to work. For its FDA-authorized COVID-19 shot Comirnaty (BNT162b2), BioNTech used tiny fat particles known as lipid nanoparticles to protect key mRNA information. The nanoparticles break down and release the mRNA as soon as they reach the target tissue. The mRNA itself is also rapidly degraded after protein translation.
That brief immune involvement works to prevent COVID-19, but cancer treatment would require a more sustained release of mRNA to achieve stable therapeutic results.
For that purpose, the NCNST team designed a hydrogel with graphene oxide and lightweight polyethyleneimine. The graphene oxide can efficiently load drugs due to its large surface area, and the polyethylenimine binds the mRNA content for translation. To further enhance the stimulation and expansion of antigen-specific CD8 + T cells – which are crucial for anti-tumor immune responses – in the presence of a hostile tumor microenvironment, the team added Galderma’s TLR7 / 8 agonist resiquimod as adjuvant.
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To test their mRNA platform, the researchers used ovalbumin, a protein found in chicken protein, as the model antigen. They mixed ovalbumin mRNA and the adjuvant with the hydrogel and injected it under the skin of mice with melanoma tumors designed to express ovalbumin on their surface.
The hydrogel steadily released the vaccine – including both the mRNA and the adjuvant – in nanoparticles for at least 30 days, and it migrated to the lymph nodes, the team showed.
The animals that received only one injection of the full therapy had significantly smaller tumors compared to mice that received free adjuvant and the mRNA without the hydrogel, or that received a non-adjuvanted mRNA hydrogel. Mice given the full therapy also showed the highest number of CD8 + T cells entering tumors, the scientists found.
In addition, the new mRNA gel treatment induced the highest level of ovalbumin-specific antibodies in the serum compared to others, suggesting that it not only inhibited tumor growth but also prevented tumors from recurring or forming distant metastases. Indeed, there were no detectable metastases in the lung tissues of mice that received the full regimen, while the free mRNA-adjuvant combination and the non-adjuvanted mRNA gel solution only partially alleviated the metastases compared to control mice that received saline or the gel delivery system alone. , the scientists reported.
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The biopharma companies that marketed mRNA COVID-19 vaccines are still interested in applying the technology to cancer. But it’s early days, and they’ve met many hurdles.
BioNTech and collaborator Roche reported a response rate of only 8% in 108 phase 1b patients who received a personalized mRNA cancer vaccine along with checkpoint inhibitor Tecentriq. Moderna’s personalized cancer vaccine did not work with Merck’s checkpoint inhibitor Keytruda in colorectal cancer in a small phase 1 study, although it did shrink tumors in half of patients with head and neck cancer.
The NCNST team suggests that its hydrogel system has potential as an efficient mRNA platform for use in cancer immunotherapy. “Collectively, the current study demonstrates the great potential of the GLP-RO gel in achieving sustainable and efficient anti-cancer immunotherapy,” the researchers wrote in the study.