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Developing an mRNA Vaccine for Cancer Immunotherapy

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The COVID-19 global pandemic has cast a spotlight on mRNA vaccine technology, which is often referred to as part of "the new era" of vaccinology.

Prior to the SARS-CoV-2 outbreak, mRNA-based vaccines were already being developed for prophylactic and therapeutic applications, including cancer immunotherapy. The premise here is similar to COVID-19 vaccination, however, rather than attacking an infectious virus, the immune system is provoked to attack cancer-causing tumors. Both preclinical and clinical trials have demonstrated the utility of mRNA vaccines for treating cancer via this approach.  However, researchers have encountered several roadblocks on the path to developing mRNA vaccines for cancer immunotherapy.

One key challenge is the fact that mRNA is not a stable molecule. The body is quick to degrade it – an undesirable trait for cancer immunotherapy. Nanoparticles have been developed to tackle this issue; however, they are also often excreted from the body one to two days post-injection.

Professors Guangjun Nie and Hai Wang from the National Center for Nanoscience and Technology (NCNST) have developed a hydrogel that releases mRNA nanoparticles – along with an adjuvant – slowly when injected under the skin. They have tested it in a mouse model of melanoma, using ovalbumin as a model antigen, and found that the hydrogel released the mRNA and adjuvant over a 30-day period. The study results are published in NanoLetters.1  

Technology Networks interviewed Nie and Wang to learn more about the hydrogel, the results of the study and what their next research steps are.

Q: Can you talk to us about why cancer immunotherapy vaccines are advantageous over current methods for administering immunotherapy?

Immunotherapy is a type of cancer treatment that triggers the immune system to fight cancer. Therefore, it is crucial to help the immune system distinguish tumor cells from normal cells. RNA vaccines are usually designed to translate tumor-associated antigens in antigen-presenting cells, which help the immune cells recognize tumor cells and make the immunotherapy more efficient.

Q: Specifically, how does an mRNA cancer vaccine work to deliver immunotherapy?

mRNA cancer vaccines can encode proteins that are specifically made by tumor cells. After being delivered into antigen-presenting cells, the mRNA vaccine can translate and display those proteins on the cell surface to guide/trigger other immune cells to attack tumor cells. We have also encapsulated the immunoadjuvant (i.e., Resiquimod) in this system to further enhance the immune response.

Q: Why are nanoparticles often cleared from the body within one-to-two days after injection, and why is this not suitable for a cancer immunotherapy vaccine?

Foreign material is dealt with and cleared from the body in a variety of ways, such as renal and hepatobiliary clearance. Quick clearance from the body might be good for delivering toxic agents via nanoparticles. However, this is much shorter than natural infections that expose antigens to the immune system for one to two weeks. In order to achieve marked therapeutic outcomes, the nanoparticle-based vaccines need to be administrated repeatedly, which may generate unstable therapeutic outcomes and hinder its clinical transformation.

Q: Can you talk to us about the hydrogel that you have created?

This hydrogel is made of graphene oxide (negatively charged) and low molecular weight polyethylenimine (positively charged). Unlike traditional cross-linked (i.e., chemical reaction) hydrogels, this hydrogel is not stable at the interface when embedded in liquid solution and transforms to nanoparticles gradually.

Q: Can you provide a brief summary of the methods of your study? How many mice did you use in the study, and what experiments were key for measuring the success of the hydrogel approach?

The capability of this transformable system for durable cancer immunotherapy was confirmed with both subcutaneously injected B16-OVA melanoma model and metastasis models. In total, 65 mice were used in this study. The long-term release of antigens and adjuvants from the hydrogel to the lymph node is the key element for successful therapy.

Q: How does the hydrogel release the mRNA slowly over a 30-day period? Is it possible it releases mRNA for a substantially longer time period than 30 days?

The hydrogel should transform to nanoparticles at the liquid-hydrogel interface after subcutaneously injected, the mRNA laden-nanoparticles can be continually released for about 30 days. To release mRNA for longer time, it might be achieved by optimizing the feeding ratio of graphene oxide and polyethylenimine to control the transforming speed.

Q: Are there any limitations to the research that you would like to highlight?

Although we did not observe obvious side effects during the treatment of 30 days, the long-term safety of this system still needs to be investigated in future.

Q: What are your next research steps?

We will investigate the stability of the mRNA in this system for long-term preservation at both room temperature and 4 °C.

Q: Have the successes that have been observed with the mRNA-based COVID-19 vaccines encouraged your research?

Yes, mRNA-based COVID-19 vaccines became the frontrunners in fighting COVID-19. We hope mRNA-based cancer vaccines could also significantly improve current strategies for cancer immunotherapy.

Guangjun Nie and Hai Wang were speaking to Molly Campbell, Science Writer for Technology Networks.

Reference: Yin Y, Xiaoyang Li, Haixia Ma, et al. In Situ transforming RNA nanovaccines from polyethylenimine functionalized graphene oxide hydrogel for durable cancer immunotherapy. NanoLetters. 2021. doi:10.1021/acs.nanolett.0c05039