Current Breakthroughs in mRNA Cancer Vaccines

About 5 years ago, in 2020, the first COVID-19 vaccine was available for the public. Although controversial, the vaccines were undoubtedly produced quicker than precedented, though this sparked skepticism as well. This speed can be attributed to the previous rapid development of mRNA vaccines.

mRNA is a messenger RNA (extremely similar to DNA) that primarily works to teach cells how to build proteins. mRNA vaccines use this ability to teach cells to make proteins that are able to recognize foreign particles and trigger an immune response. mRNA vaccines are popular for more than one reason.

1. Easily degraded (reduces risk of toxicity)

2. Well-tolerated by the body

3. Ease of production (fast and efficient)

4. Non-infectious (doesn't introduce viruses, dead or alive, into the body)

5. Doesn't integrate into the host genome: eliminates risk of insertional mutagenesis (a process when foreign DNA may disrupt genes and lead to cancer)

6. Humor and cell-mediated immunity: necessary for activating or sustaining anti-tumor responses (in short, anti-cancer responses)

When a was paper published in 2022 in The Lancet Oncology Journal, three years ago, clinical trials were enrolling patients with various cancers in order to test the effects of mRNA vaccines. Trials reported positive responses to the vaccines without unmanageable side effects. However, in 2022, there had been no Trial 3 clinical trials performed.

Clinical Trials

Clinical trials are research studies that test medical, surgical, or behavioral interventions to determine if a new treatment of prevention method is safe for large-scale production. These trials are crucial for developing new, better therapies and ensuring their safety for possible public consumption.

Stage 1 trials are focused on evaluating a treatment's safety and appropriate dosage range. About 20 -100 participants (volunteers) are treated with a range of different doses and observed for any harmful side effects. These trials may involve risks even after passing an investigational drug check, so volunteers are often compensated for their participation.

Stage 2 trials are focused on evaluating the effectiveness of a new treatment. In about 100 - 300 volunteers, researchers observe the difference between the new treatment and the old treatment. This process ensures that the new proposed treatment is of benefit.

The final trials, stage 3 trials, are conducted on thousands to several thousands of participants. This mass testing provides further data proving the treatment's safety. This phase may last several years but once it is completed, the pharmaceutical company can request the FDA for approval to sell the drug.

mRNA Cancer Vaccines

mRNA vaccines are an attractive candidate for cancer vaccines. The aim of these vaccines is to induce or boost anti-tumor immune responses by utilizing tumor associated antigens (particles that trigger immune responses) and injecting them into the body.

In order to send these antigens into the body, researchers created autologous dendritic cells engineered with mRNA. These autologous dendritic cells are cells taken directly from the patient's body and modified with the necessary antigens. Vaccines were also either formulated (enclosed in a delivery system) or unformulated (not enclosed).

Figure 1. mRNA-based vaccine mode of action

The vaccines work like this:

1. mRNA enters the cytoplasm (the cell)

2. Ribosomes (structures that make proteins) read the mRNA and build an antigen

3. Antigens are broken down in the cell into small fragments (peptides)

4. Peptides enter either the MHC Class 1 or MHC Class 2 pathways

   
   

If entering the MHC Class 1 (Endogenous) Pathway:

• Peptides transported to endoplasmic reticulum (structure where protein synthesis occurs) by transporters

• Loaded onto MHC class 1 molecules

• MHC 1 and peptide is sent to the cell surface (displayed on the surface like flags)

• Cytotoxic T-cells (CD8+) then recognize the "flags"

If entering the MHC Class 2 (Exogenous) Pathway:

• Similar process to class 1

• Helper T-cells (CD4+) recognize these and work to activate B-cells (a white blood cell) to make antibodies

This process can be effective when battling cancer. Oftentimes, cancer cells are able to avoid being detected by the immune response by expressing molecules to resemble normal cells, suppressing the immune response, and creating a hostile environment for the immune system. However, mRNA vaccines work to overcome immune suppression by stimulating the immune system. Once T-cells recognize the tumor-specific antigens of cancer cells, they can be activated. The specific target provided helps the immune system overcome suppression.