Harnessing IVT mRNA technology against cancer

The rapid development of the mRNA vaccines for COVID-19 was only possible thanks to earlier years of research into the technology as a way of treating cancer.¹ Now, in vitro transcribed (IVT) mRNA cancer therapeutics are being tested in large-scale clinical trials and generating a lot of interest. 

Using IVT mRNA to target cancer is not just about vaccines though. There are many therapeutic approaches in development that offer different ways of activating the immune system. This can be through modifying immune cells, delivering antibodies or producing immune-stimulating chemicals. 

In this blog post, we review some of the key advances in this area as mRNA therapeutics continue to develop at pace. 

mRNA vaccines entering major trials for cancer

IVT mRNA therapeutics work by delivering instructions for assembling a protein in the cell. For vaccines, the mRNA triggers the cells to produce an antigen from the target disease, priming the immune system to recognise and attack the antigen if it’s detected again in the body.  

Compared to an infectious disease like COVID-19, cancer is a much more complex target. The COVID-19 vaccines primed the immune system to respond to the spike protein on the surface of the SARS-CoV-2 virus. Other than occasional updates to account for new variants, these vaccines could be mass-produced and given to anyone repeatedly.  

By contrast, each person’s cancer will have a unique constellation of mutations. In some cases, there might be particular mutations that are common in many patients, allowing a “one-size-fits-some” approach. However, some cancers vary so significantly that even tumours within a single person can differ in their genetic make-up. This means that the vaccine target(s) may need to be individually chosen to differentiate the cancerous cells from healthy ones. 

Moderna’s cancer vaccine mRNA-4157(V940) can target up to 34 antigens, which are tailored to the individual cancer. It is now being tested in a variety of cancers, including phase 3 trials in melanoma and non-small cell lung cancer. These trials are testing the vaccine in combination with the existing cancer drug pembrolizumab (Keytruda), which reverses immune suppression. A phase 2b trial showed an improvement in recurrence-free survival.² 

The other big name in mRNA vaccines, BioNTech, also has several cancer vaccines, including BNT111 which has shown positive initial results in phase 2 trials of melanoma patients. This takes a different approach by targeting four antigens commonly seen in melanoma, rather than being individually personalised. If successful, this “off-the-shelf” mRNA vaccine approach could be easier to mass produce and make widely available. 

Melanoma is one of the most common causes of cancer death, so there is an urgent need for new and effective therapies. mRNA vaccines also offer the advantage of being highly targeted, so developers hope that they might not cause the same degree of side effects as small molecule drugs, for example. 

IVT mRNA to create the next generation of CAR-T therapy

Beyond vaccines, there are a variety of other ways that mRNA could be used to treat cancer. One approach is to further advance CAR-T cell therapy – genetically engineered immune cells that have shown great success in treating some cancers.  

Current methods rely on extracting cells from the patients, modifying them in the lab using viral vectors, and re-infusing them back into the patient. mRNA offers a way to precisely generate CAR-T cells inside the body, known as in vivo CAR, simplifying the existing procedures.³ There are different ways to deliver the mRNA to in vivo T cells, including encasing the IVT mRNA in lipid nanoparticles, like in the COVID-19 vaccines. 

mRNA also allows for transient expression of CAR-T cells, compared to the permanent genetic changes induced by the viral vectors. This provides additional level of control as well as potentially reducing the safety concerns of CAR-T therapy that have led to extensive monitoring of patients. However, linear mRNA is short-lived in the body and so approaches using the more stable circular RNA are also being investigated.⁴ 

mRNA may also help CAR-T cells to penetrate solid tumours, which is a major stumbling block for current treatments. BioNTech are testing a combination of CAR-T cell therapy with an mRNA vaccine that boosts its activity.⁵ BNT211 targets cancer cells with the antigen CLDN6, found in many cancer types including ovarian, testicular and gastric. The CAR-T cells are paired with an mRNA vaccine called CARVac that encodes the CLDN6 antigen in an effort to improve the persistence of the CAR-T cells and overcome the immunosuppressive tumour microenvironment. A phase 1 trial showed that the additional vaccine was well-tolerated.⁵ 

To learn about delivering high-quality mRNA using enzymes, download our in-depth guide to in vitro transcription. 

Producing proteins with mRNA to reduce immunosuppression

Another approach to using mRNA takes advantage of its ability to directly initiate protein production.  

Monoclonal antibodies have become a vital part of the cancer therapy landscape, however they are difficult and expensive to manufacture and they have limited ability to penetrate some parts of the body.⁶ mRNA can help to avoid these problems by prompting the body to make the therapeutic protein itself. 

Researchers have tested this approach to generate rituximab and trastuzumab – antibodies used to treat lymphoma and breast cancer respectively – in mice, showing improved performance over direct application of the antibodies.^7,8 

Preclinical studies have also used mRNA to produce immune modulators, e.g. cytokines and stimulatory ligands and receptors, or cell death inducers, e.g. apoptotic proteins or caspases.⁹ These approaches would not necessarily need to be tailored for specific cancer types, although careful design would help the mRNA reach the tumour site without causing harmful side effects in healthy cells.  

An ongoing clinical trial in breast cancer is investigating another way to alter the tumour microenvironment and stimulate the immune system. The phase 1 trial is testing a TriMix mRNA cocktail that is injected directly into the tumour to activate dendritic cells, with the aim of producing a T cell response against the cancer.¹⁰

Conclusion

Innovations in immunotherapy have delivered many life-changing advances over the last three decades, however this has not benefited all types of cancer, particularly solid tumours. mRNA is a disruptive treatment modality that offers the potential for more targeted, safe and affordable cancer therapies. However, many of the ideas listed above are still at the early stages of development and large-scale trials will be needed to judge their impact. 

While cancer vaccines may be the most advanced of these in the clinic, the sheer breadth of approaches being tested demonstrates the many opportunities for IVT mRNA to replace or enhance existing therapeutics. 

If you are interested in developing mRNA therapeutics, read our ebook on enzymes for IVT.

References

1. Jain S et al. (2021) Messenger RNA-based vaccines: Past, present, and future directions in the context of the COVID-19 pandemic. Adv Drug Deliv Rev 179:114000. doi: 10.1016/j.addr.2021.114000
2. Weber JS et al. (2024) Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403(10427):632-644. doi: 10.1016/S0140-6736(23)02268-7 
3. Cai J et al. (2024) RNA technology and nanocarriers empowering in vivo chimeric antigen receptor therapy Immunology 173(4):634-653 doi: 10.1111/imm.13861 
4. Mabry R et al. (2022) In situ CAR therapy using oRNA™ lipid nanoparticles regresses tumors in mice. Journal for ImmunoTherapy of Cancer. 10(Suppl 2):A1267. doi: 10.1136/jitc-2022-SITC2022.1222 
5. Mackensen A et al. (2023) CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial. Nature Medicine 29:2844-2853 doi: 10.1038/s41591-023-02612-0  
6. Deal CE, Carfi A and Plante OJ (2021) Advancements in mRNA Encoded Antibodies for Passive Immunotherapy. Vaccines 9(2):108 doi: 10.3390/vaccines9020108 
   
7. Thran M et al. (2017) mRNA mediates passive vaccination against infectious agents, toxins, and tumors. EMBO Mol Med 9:1434–1447. doi: 10.15252/emmm.201707678 
8. Rybakova Y et al. (2019) mRNA Delivery For Therapeutic Anti-Her2 Antibody Expression In Vivo. Mol Ther 27:1415–1423. doi: 10.1016/j.ymthe.2019.05.012 
9. Van Hoecke et al. (2021) mRNA in cancer immunotherapy: beyond a source of antigen. Molecular Cancer 20:48. doi: 10.1186/s12943-021-01329-3  
10. Intratumoral TriMix Injections in Early Breast Cancer Patients (TMBA) https://clinicaltrials.gov/study/NCT03788083 Accessed 30 December 2024.