Before mRNA vaccines became valuable preventative tools against COVID-19, scientists around the world have studied the potential use of the technology in cancer therapy, but their success has so far been limited.
Now, scientists from China’s National Center for Nanoscience and Technology (NCNST) have designed a hydrogel to deliver an mRNA vaccine with an immunostimulatory additive. 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 journal Nano Letters.
The results showed that the hydrogel delivery system has potential to help mRNA vaccines bring about long-term anti-tumor effects as cancer immunotherapy, according to the researchers.
In COVID-19, mRNA vaccines contain the genetic information that instructs the body to produce a specific viral protein to elicit the desired immune response. In cancer, the vaccines are usually 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 that mRNA vaccines must reach the lymph nodes to work. For the FDA-authorized COVID-19 shot Comirnaty (BNT162b2), BioNTech used small fat particles, known as lipid nanoparticles, to protect the nuclear mRNA information. The nanoparticles degrade and release the mRNA as soon as they reach the target tissue. The mRNA itself also weakens rapidly after protein translation.
That brief immune involvement works to prevent COVID-19, but in cancer treatment, a longer-term delivery of mRNA is needed to achieve stable therapeutic outcomes.
To that end, the NCNST team designed a hydrogel containing graphene oxide and low-weight polyethyleneimine. The graphene oxide can efficiently load drugs due to its large surface area, and the polyethyleneimine binds the mRNA content for translation. To promote the stimulation and expansion of antigen-specific CD8 + T cells – which are critical for immune responses against tumors – in the presence of a hostile microenvironment, the team added Galderma’s TLR7 / 8 agonist reliquary as a tool.
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To test their mRNA platform, the researchers used ovalbumin, a protein found in chicken egg whites, as a model antigen. They mixed ovalbumin mRNA and the additive with the hydrogel and injected it under the skin of mice with melanoma tumors designed to express ovalbumin on their surface.
The hydrogel gradually released the vaccine into nanoparticles for at least 30 days, including the mRNA and adjuvant, and it migrated to lymph nodes, the team showed.
The animals that received only one injection of the complete therapy had significantly smaller tumors compared to mice that received free excipient and the mRNA without the hydrogel, or those that received an unused mRNA hydrogel. The scientists found that mice with the complete therapy showed the highest number of CD8 + T cells that invaded tumors.
What’s more, the new mRNA gel treatment has caused the highest level of ovalbumin-specific antibodies in the serum, compared to others, suggesting that it not only inhibits tumor growth but also prevents tumors from returning or a distant metastasis form. Indeed, there were no detectable metastases in the lung tissue of mice receiving the complete treatment, whereas the free mRNA adjuvant combination and the non-impaired mRNA gel solution only partially relieved metastases compared to control mice receiving saline or the gel delivery system only. , the scientists reported.
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The biopharmaceutical companies that have been marketing mRNA COVID-19 vaccines are still interested in applying the technology to cancer. But these are early days, and they have encountered many obstacles.
BioNTech and collaborator Roche reported only 8% response rates in 108 phase 1b patients who received a personalized mRNA cancer vaccine with control point inhibitor Tecentriq. Moderna’s personalized cancer vaccine was unable to 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 the hydrogel system has potential as an effective mRNA platform for use in cancer immunotherapy. “Collectively, the present study demonstrates the great potential of the GLP-RO Gel in achieving durable and effective cancer immunotherapy,” the researchers wrote in the study.