Category: mRNA

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mRNA Pharmaceuticals Precision Medicine

Targeting Pancreatic Cancer: The Race for a Vaccine

Madhura Kadam—McMaster Biology & BND 2023

We are very close to a pancreatic cancer vaccine. Indeed, there are currently many clinical trials being conducted that are testing the efficacy of various pancreatic cancer vaccines candidates—some with promising preliminary results.

To provide some background, pancreatic cancer is the fourth most common cause of cancer death in the U.S.3. Pancreatic cancers occur when cells in the pancreas are damaged, causing them to grow out of control3. Current treatments available to treat pancreatic cancer include surgery, chemotherapy, radiation therapy, immunotherapy and dietary changes2. Vaccines that treat cancers, also known as therapeutic vaccines, are a type of cancer treatment called immunotherapy1. These vaccines work to boost the immunity of the patient to fight cancers1.

Figure 1. Image depicting pancreatic cancer. Adapted from the National Cancer Institute9

There are currently many promising clinical trials underway testing vaccines for pancreatic cancer. One of the most successful trials was conducted by Dr. Balachandran in collaboration with the BioNTech company5. They created a mRNA vaccine that targeted neoantigen proteins5. Neoantigens are proteins present on the cancer that alert the immune system of the presence of abnormal development in the body to stop the cancer from spreading5. In 8 of the 16 patients, the vaccine activated T cells of the immune system that recognize the patient’s own pancreatic cancer cells, triggering the immune system to attack the cancer6. There were also delays in the recurrence of pancreatic cancers in these patients5. These findings suggest that T-cell activation of the immune system through the vaccine may have the desired effect of keeping pancreatic cancer in check.

Figure 2. Targeting neoantigen proteins. Adapted from Pearlman et al8

Figure 3. Mechanism for the functioning of cancer vaccines. Adapted from Roy7

mRNA vaccines are created by genetically sequencing the neoantigens proteins in the pancreatic tumors of patients5. The genetic sequences of neoantigens act as a template for making mRNA vaccines. When the vaccine is injected into the person’s bloodstream, it causes the immune cells known as dendritic cells to make the neoantigen proteins5. The dendritic cells train the rest of the immune system to recognize and attack tumor cells expressing the same neoantigen proteins5. Since the immune system is aware of neoantigens as a “harmful protein” to the body, the cancer may have less chance of returning as it is most likely to be destroyed by the immune system5.

Another vaccine developed by Elizabeth Jaffee, M.D., and Daniel Laheru, M.D., is also currently in the clinical trial phase1. This vaccine uses pancreatic cancer cells that are treated with radiation to inhibit their ability to grow1. These cancer cells are also altered genetically to secrete a molecule called GM-CSF1. This molecule attracts immune system cells to the site of the tumor vaccine where they encounter antigen proteins of the radiated cells1. Once these antigens are recognized, this trains the immune system to attack any remaining pancreatic cancer cells in the body1. The mechanism for this vaccine is like that of the mRNA vaccine mentioned above, but the specific proteins and antigen targets that are used differ between the two treatments.

Many other clinical trials for pancreatic cancer vaccines are also currently under development4. These trials include vaccines that are cell based, DNA-based, peptide based and microorganism based4. In summary, many pancreatic cancer vaccines are currently under development at different stages of testing. More clinical testing and FDA approval is required for these vaccines to be commercially available, however the advancements in current vaccinations point to a hopeful future for vaccines to be an effective treatment for pancreatic cancers.

References

  1. Hopkins Medicine. Pancreatic cancer vaccine [Internet]. Pancreatic Cancer Vaccine | Johns Hopkins Medicine. 2022 [cited 2022Nov27]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/pancreatic-cancer/pancreatic-cancer-vaccine
  2. Hopkins Medicine. Pancreatic cancer treatment [Internet]. Pancreatic Cancer Treatment | Johns Hopkins Medicine. 2022 [cited 2022Nov28]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/pancreatic-cancer/pancreatic-cancer-treatment
  3. Hopkins Medicine. Pancreatic cancer [Internet]. Pancreatic Cancer | Johns Hopkins Medicine. 2022 [cited 2022Nov28]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/pancreatic-cancer
  4. Huang X, Zhang G, Tang T-Y, Gao X, Liang T-B. Personalized pancreatic cancer therapy: From the perspective of mrna vaccine – military medical research [Internet]. BioMed Central. BioMed Central; 2022 [cited 2022Nov28]. Available from: https://mmrjournal.biomedcentral.com/articles/10.1186/s40779-022-00416-w/tables/2
  5. MSKCC. MSK mrna pancreatic cancer vaccine trial shows promising results [Internet]. Memorial Sloan Kettering Cancer Center. 2022 [cited 2022Nov28]. Available from: https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out
  6. Page ML. Pancreatic cancer vaccine: What to know about early promising results [Internet]. New Scientist. New Scientist; 2022 [cited 2022Nov28]. Available from: https://www.newscientist.com/article/2323437-pancreatic-cancer-vaccine-what-to-know-about-early-promising-results/
  7. Roy S. Cancer vaccines: Are we there yet? [Internet]. Cancer Vaccines: Are We There Yet? | Vanderbilt Institute for Infection, Immunology and Inflammation. 2020 [cited 2023Jan4]. Available from: https://www.vumc.org/viiii/immuknow/cancer-vaccines-are-we-there-yet
  8. Pearlman AH, Hwang MS, Konig MF, Hsiue EH-C, Douglass J, DiNapoli SR, et al. Targeting public neoantigens for cancer immunotherapy [Internet]. Nature News. Nature Publishing Group; 2021 [cited 2023Jan4]. Available from: https://www.nature.com/articles/s43018-021-00210-y
  9. National Cancer Institute. Pancreatic cancer treatment (adult) (PDQ®)–patient version [Internet]. National Cancer Institute. 2020 [cited 2023Jan4]. Available from: https://www.cancer.gov/types/pancreatic/patient/pancreatic-treatment-pdq
Categories
COVID-19 mRNA

mRNA Vaccines and the Future of Vaccination

Rodrigo Hontoria — McMaster University Honours Life Sciences 2023

Over the past 3 decades, scientists have been working with messenger RNA (mRNA) as a potential new method of producing simpler and more effective vaccines1 2. mRNA is a promising topic to assess because of its ability to produce a vast number of proteins, all depending on the coding of each mRNA. In a cell, mRNA is transcribed from DNA and undergoes a series of modifications that provide protection from the cellular environment, before finally being released into the cytoplasm for translation. Incorporating mRNA into modern vaccinations would provide three very beneficial outcomes:

  1. Safety – unlike other vaccines that require a weakened/damaged strain of the virus, mRNA vaccines provide a non-infectious route to immunity1 2. Also, after translation has occurred, mRNA is quickly degraded by the cell avoiding any long-lasting effects1.
  1. Efficacy – mRNA vaccines provide a highly detailed method for producing an immune response by inducing the production of whichever desired viral protein. In other words, mRNA strands can be made to encode the exact viral protein, without any of the deleterious and self-replicating genes of the virus. The lifespan/stability of mRNA can also be adjusted through changes in its 5’ cap and poly-A tail, or carrier molecule to change the time span of its desired effects2.
  1. Cost of production – Synthetic viral mRNAs are significantly less costly to produce compared to the manufacturing of proteins and viral antigens1.
A diagram of an mRNA vaccine in action. It shows a synthetic mRNA being translated by a ribosome into individual proteins from SARS-CoV-2, which induce an immune response.
Source: The Conversation

Setbacks and Advancements

In 1990, a group of scientists performed the first successful mRNA injection using reporter genes to induce the production of the corresponding proteins in mice1. In follow up experiments, physiological effects were observed in mice after the uptake of synthetic mRNA that stimulates the release of different hormones1 2. Although these early successes were very exciting and provided a potentially prosperous technology, many advancements in research were still necessary to achieve safety and efficiency. mRNA vaccine setbacks have been outlined thoroughly in past research projects, some of the most notable being: 

  1. Passage of mRNA from the bloodstream into the cell – through vaccination, mRNA will directly enter the bloodstream but how will cells be encouraged to uptake the mRNA?
  1. Stability/protection of mRNA when inside the cell – how will the mRNA be protected to avoid mutagenesis or breakdown?

To overcome these problems, companies such as Pfizer, BioNTech, and Moderna invested a lot of time, money, and effort into making mRNA vaccines effective. To facilitate transport of mRNA into the cell, common transfection reagents such as cationic lipids, calcium phosphate, and cationic polymer liposomes are used3 4. mRNA stability was achieved with the addition of untranslated regions (UTRs) added to the 5’ and 3’1 3. 

COVID-19 and Future Applications

On January 9, 2020, the Global Health Organization along with Chinese Health Authorities identified the novel coronavirus as 2019-nCoV (COVID-19)6. 2 days later, the Chinese government globally released the genomic sequence of the virus6. Pfizer, BioNTech, and Moderna were quick to start working on the vaccine. Only 11 months after COVID-19 was identified, the United States and United Kingdom established the latest mRNA vaccines as safe and effective1. 

Pfizer-BioNTech and Moderna mRNA vaccines code for a spike protein found on the membrane of the virus. Cellular uptake of the mRNA induces the production of a spike protein inside the host cell. The spike protein by itself is harmless and non-infectious but nonetheless, causes an immunological response that is remembered by the immune system. Pfizer-BioNTech and Moderna both require two doses of the vaccine, Pfizer-BioNTech requiring 21 days of separation, and Moderna requiring 28 days. Pfizer-BioNTech has a high effectiveness rate of 95% while Moderna is slightly lower at 94.1%.

Further applications for mRNA vaccines are contributing to the treatment of many more viral agents, among these are Ebola, Zika and Influenza. Cancer treatments, and genetic therapies are also looking at mRNA vaccines as a potential treatment to produce proteins that the body requires. 

Image result for covid 19 vaccines
Source: Aljazeera

References

  1. Pardy N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in vaccinology. Nat [Internet]. 2018 Jan 12 [cited 2021 Feb 12];17:261–279. Available from: https://www.nature.com/articles/nrd.2017.243
  2. Harvard Health Publishing: Why are mRNA vaccines so exciting? [Internet]. Komaroff A, editor. [cited 2021 Feb 12]. Available from: https://www.health.harvard.edu/blog/why-are-mrna-vaccines-so-exciting-2020121021599
  3. Kim TK, Eberwine JH. Mammalian cell transfection: the present and the future. Nat Lib Med [Internet]. 2010 Jun 13 [cited 2021 Feb 14];397:3173–3178. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911531/
  4. Pfizer.com [Internet]. THE FACTS ABOUT PFIZER AND BIONTECH’S COVID-19 VACCINE. c2002 [cited 2021 Feb 13]. Available from: https://www.pfizer.com/news/hot-topics/the_facts_about_pfizer_and_biontech_s_covid_19_vaccine
  5. Huang J, Yang C, Xu XF, Xu W, Liu S. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Nat [Internet]. 2020 Aug 3 [cited 2021 Feb 13];41:1141–1149. Available from: https://www.nature.com/articles/s41401-020-0485-4
  6. Whole genome of novel coronavirus, 2019-nCoV, sequenced. Sci Da [Internet]. 2020 Jan 31 [cited 2021 Feb 12]. Available from: https://www.sciencedaily.com/releases/2020/01/200131114748.htm
  7. Zhang C, Maruggi G, Shan H, Li J. Advances in mRNA Vaccines for Infectious Diseases. Front In Immu [Internet]. 2019 Mar 27 [cited 2021 Feb 12]. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2019.00594/full