mRNA vaccines

Introduction

mRNA vaccines are one of many types of vaccines used to provide us with artificial active immunity. Despite having been in development for several decades, they gained traction after the use of the technology in Moderna and Pfizer-BioNTech’s COVID-19 vaccines. Following their success throughout the pandemic, clinical research into mRNA vaccines has been accelerated, with the ambition to create cancer vaccines. 

How the COVID-19 mRNA vaccine works

In the example of the COVID-19 vaccine, the genetic material that codes for the spike protein on the COVID-19 virus surface is isolated and used to create an mRNA molecule. The mRNA is then inserted into either a viral vector or a lipid nanoparticle so that once inside the body, it can enter cells. mRNA can then be translated at ribosomes to produce spike proteins, which are displayed on the cell surface membrane. Therefore, an immune response can be stimulated, producing both antibodies and memory cells, for a faster and stronger secondary immune response.¹

Using mRNA vaccines against cancer

More recently, there has been an influx in clinical trials aimed at utilising mRNA vaccines to fight cancer. Rather than preventing the development of cancer, they are aimed at helping the immune system to recognise and remove it. There have been two approaches to this, with some companies focussing on a general vaccine and others on a personalised one.

A general vaccine would contain mRNA coding for proteins found commonly in a range of cancers, stimulating an immune response against their respective antigens once they are synthesised. The two main advantages of this type of vaccine is the low cost, as well as the scope for large-scale production and distribution. Current trials involving them are targeting cancers such as advanced melanomas, prostate cancer and ovarian cancers. 

However, greater strides have been made in creating a personalised vaccine, which codes for neoantigens- proteins which are specific to an individual’s cancer. Since each cancer tends to present uniquely in different cases, it is important to identify the relevant antigens to ensure a high level of effectiveness; however this process can be expensive, costing several thousand pounds per dose. Ongoing phase two trials with personalised vaccines are targeting diseases such as melanoma and colorectal cancer.²

The image below, from BioNTech, summarises how a personalised cancer vaccine is created and subsequently stimulates an immune response:

There are numerous options for the delivery format of the mRNA vaccine, one of which is introducing mRNA into dendritic cells (DCs), in a process known as transfection, creating a cell-based cancer vaccine. Another alternative is injecting the mRNA directly into the body, without the use of a carrier. Whilst this technique is cheaper and quicker, without any protective carrier, the mRNA is prone to degradation by enzymes thus limiting their benefits. Currently, the most promising delivery method is through implementing a similar method to the COVID-19 vaccines by using lipid nanoparticles. These can be easily taken in by cells through endocytosis, followed by endosomal escape, enabling the mRNA to be translated at ribosomes and produce the desired antigen.³

Advantages and disadvantages

One of the greatest advantages of mRNA vaccines is the speed with which they can be developed, for example Moderna completed the whole process from design to manufacturing in just 7 weeks. In order to adapt the technology for other vaccines, all that would need to be changed is the mRNA base sequence to produce the desired protein. Although this makes it seem as if we could develop mRNA vaccines for every disease, it is the necessary, lengthy clinical trials which mean that very few are approved for use today.⁴

Another advantage is that such vaccines cannot be integrated into the genome, as the mRNA is broken down quickly after translation, as well as the absence of the enzyme reverse transcriptase. This reduces the risk of insertional mutagenesis (mutations in DNA caused by extra base pairs), which could otherwise have drastic effects on polypeptide synthesis and impact phenotype.⁵

However, one of the main limitations of mRNA is its lack of stability at high temperatures, and therefore the need for it to be transported in freezers. This is a major obstacle for those living in rural areas, as well as developing countries, both due to high transportation costs, as well as a lack of suitable infrastructure. Another limitation is potential long-term impacts, which are yet to be seen, due to the technology being relatively new compared to other forms of vaccines.⁴

Conclusion

Overall, the field of mRNA vaccine research is continually growing, with large strides being made towards a future where we can use it to treat a range of diseases. Although as of yet none have been approved for cancer treatment, there are several ongoing trials by a number of pharmaceutical companies, many of which are showing promising results. This technology has the potential to transform the way we tackle cancer and is definitely something to look out for in the near future.

References

1. Understanding covid-19 mrna vaccines [Internet]. Genome.gov. [cited 2023Mar11]. Available from: https://www.genome.gov/about-genomics/fact-sheets/Understanding-COVID-19-mRNA-Vaccines 
2. Sanderson K. How close are we to developing an mrna cancer vaccine? [Internet]. The Pharmaceutical Journal. 2022 [cited 2023Mar11]. Available from: https://pharmaceutical-journal.com/article/feature/how-close-are-we-to-developing-an-mrna-cancer-vaccine 
3. Vishweshwaraiah YL, Dokholyan NV. MRNA vaccines for cancer immunotherapy. Frontiers in Immunology. 2022;13. 
4. MRNA vaccines – here’s everything you need to know [Internet]. World Economic Forum. [cited 2023Mar11]. Available from: https://www.weforum.org/agenda/2021/07/everything-you-need-to-know-about-mrna-vaccines/ 
5. Lorentzen CL, Haanen JB, Met Ö, Svane IM. Clinical advances and ongoing trials of mrna vaccines for cancer treatment. The Lancet Oncology. 2022;23(10). 

Advertisement

Efficacy of CAR-T cell Therapy in Patients with Hodgkin lymphoma who Relapse or Experience Primary Refractory Disease

Background

Chimeric antigen receptor (CAR) T-cell therapy is a novel form of treatment for primarily blood cancers. CAR-T cell therapies involve engineering individual patients’ T-cells to target specific cancer cells. First, blood is taken from a patient to acquire their T-cells. Secondly, CAR-T cells are produced in the lab where the CAR genes are inserted into the T-cells. Afterward, CAR proteins appear on the surface of the T-cells and they are then reproduced millions of times so that they can be infused into the patient. Then the goal for the CAR-T cells becomes binding to cancer cells to kill them (National Cancer Institute, 2019). This is as illustrated below in figure 1:

Figure 1: How CAR-T cell therapies work (National Cancer Institute, 2019).

Hodgkin’s lymphoma (HL) is a type of cancer that manifests itself in the lymphatic system and the cancer presents itself with supra-diaphragmatic lymphadenopathy meaning swollen lymph nodes above the diaphragm. The cancer cells are characterized as Hodgkin and Reed-Sternberg (HRS) cells. 

Additionally, it is one of the most prevalent cancer types in adolescents. The B-cell lymphoproliferative disorder can be divided into classical HL (cHL) and nodular lymphocyte-predominant HL (NLPHL), however, cHL accounts for over 90% of the cases, which is why it will be the main focus of this article. Though, one thing that all HL subtypes have in common is that they all share an immunophenotypic pattern of CD15+, CD30+ as well as CD45-, antigens that indicate Hodgkin’s lymphoma.

HL has various treatment options ranging from chemotherapy to radiotherapy. The treatments have high rates of curability, even in cases of a patient advancing through the stages of HL (Shanbhag & Ambinder, 2017).

When CAR-T cell therapy should be considered the favorable treatment option

Most cases of HL are sufficiently cured with first-line therapy. However, 15% of HL patients relapse or acquire primary refractory disease, which means they do not go into complete remission. The usual first-line therapy alternative is high-dose chemotherapy and autologous stem cell transplantation (aSCT). aSCT refers to capturing stem cells before going into treatment and injecting them back into the body following the treatment. Around 50% of individuals going through this treatment relapse after transplantation. The issues with the alternative treatment to aSCT are that allogeneic stem cell transplantation (alloSCT) results in high morbidity as well as mortality, even though it provides the most optimal chances for achieving sustained remission. alloSCT shares similarities with aSCT, however the difference in alloSCT is that stem cells are extracted from a donor instead to replace damaged stem cells as a result of radiation or chemotherapy (Ramos et al., 2020).

In July 2021 in America, the treatment for early-stage cHL was comprised of doxorubicin (or adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), a series of chemotherapies. The former is the most common front-line therapy there is, but this form of treatment does not come without side effects. Generally, cHL patients will be at risk for long-term complications such as cardiopulmonary toxicities, secondary malignancies, and quality of life (QoL) impairment. The latter is, among other things, why the spotlight has been on improving the side effects of being treated with front-line therapy. The first, second, and third line of treatment is shown below in figure 2 (Mohty et al., 2021). 

Figure 2: Lines of treatment for cHL in advanced stages (Mohty et al., 2021).

When the time finally comes to consider CAR-T cell therapy for treating cHL the potential side-effects and the efficacy of CAR-T cell therapy must be taken into consideration.

CAR-T cell therapy has one significantly dangerous side effect, which is cytokine release syndrome (CRS) (National Cancer Institute, 2019). CRS is a condition where an abundance of cytokines are released as a result of immunotherapies like CAR-T cell therapy. The danger lies in the cytokines’ function. They are meant to maintain a healthy amount of blood cells and immune cells, but this becomes difficult when the body is overloaded with cytokines (Cleveland Clinic, 2022). The more cancer cells there are in the body the more likely it is to experience CRS when treated with CAR-T cells. Mild courses of CRS are mostly controllable with first-line therapies and more serious cases of CRS are becoming easier to treat as well, as more experience with CAR-T cell therapies is gained through research. CAR-T cell therapy becomes ineffective when it has to deal with solid tumors. This is especially true for tumor heterogeneity, which is the diversity of cancer cells in a tumor. The latter is due to the fact that solid tumors can vary a lot when it comes to the individual person and sometimes this applies to one patient’s body itself. The molecular diversity in the solid tumors makes it incredibly difficult to treat because the molecular diversity can contribute to the CAR-T cells being unable to function properly (National Cancer Institute, 2019).

The magic of CAR-T cell therapy in cHL shines through when the patient has relapsed or has experienced primary refractory diseases. A study shows that responses to Anti-CD30 CAR-T cell therapies are superior to bendamustine in patients who have previously been treated with bendamustine. In addition to this, when the CAR-T cell therapy was used following fludarabine-containing lymphodepletion regimens it resulted in 59% of complete responses out of 32 patients. The most prevalent toxicities were grade 3 or higher hematologic adverse events. The overall response rate of patients that received fludarabine-based lymphodepletion was 72% (Ramos et al., 2020).

The bottomline is that CAR-T cell therapy should be done when patients are relapsing or experiencing refractory diseases in relation to cHL, because the safety of use is incredible while also maintaining high response rates.

Daniel Godiksen, Youth Medical Journal 2022

References

Cleveland Clinic. (2022, April 7). Cytokine Release Syndrome: Symptoms, What It Is & Treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/22700-cytokine-release-syndrome

Mohty, R., Dulery, R., Bazarbachi, A. H., Savani, M., Hamed, R. A., Bazarbachi, A., & Mohty, M. (2021). Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies. Blood Cancer Journal, 11(7), 1–10. https://doi.org/10.1038/s41408-021-00518-z

National Cancer Institute. (2019, July 30). CAR T Cells: Engineering Immune Cells to Treat Cancer. National Cancer Institute; Cancer.gov. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

Ramos, C. A., Grover, N. S., Beaven, A. W., Lulla, P. D., Wu, M.-F., Ivanova, A., Wang, T., Shea, T. C., Rooney, C. M., Dittus, C., Park, S. I., Gee, A. P., Eldridge, P. W., McKay, K. L., Mehta, B., Cheng, C. J., Buchanan, F. B., Grilley, B. J., Morrison, K., & Brenner, M. K. (2020). Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. Journal of Clinical Oncology, 38(32), 3794–3804. https://doi.org/10.1200/jco.20.01342

Shanbhag, S., & Ambinder, R. F. (2017). Hodgkin lymphoma: A review and update on recent progress. CA: A Cancer Journal for Clinicians, 68(2), 116–132. https://doi.org/10.3322/caac.21438

Sterner, R. C., & Sterner, R. M. (2021). CAR-T Cell therapy: Current Limitations and Potential Strategies. Blood Cancer Journal, 11(4), 1–11. https://doi.org/10.1038/s41408-021-00459-7