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28 May, 2024
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Op-ed: The far-reaching benefits of mRNA technology

The rapid advance of mRNA vaccines has led to a tremendous acceleration of cancer vaccines

by Dimitrios P. Kontoyiannis

The mRNA platform is a tantalizingly simple and transformative technology, scaling the scope of targeting diseases in ways that were previously unimaginable.

Although the time this takes will shrink with the implementation of this technology in modern medicine, it is still too early to fully evaluate its safety and effectiveness in humans.

First, with the rapid, nimble and flexible manufacturing process, cutting costs and time for vaccine production, this technology, which is essentially a biological software, has revolutionized the field of vaccine development. Not surprisingly, as the real-world experience with Covid-19 has shown, mRNA vaccine-on-demand-approaches have become a very attractive alternative to conventional vaccine approaches that are being tested for a variety of infections such as rabies, tuberculosis, influenza and many other viruses, for both human infections and veterinary purposes. The possibilities of even further advancing vaccinology are enormous as it is now possible to target diverse antigens to stimulate different arms of immunity or even several pathogens with a single dose.

Beyond vaccinology, mRNA technology can cross-fertilize the work on off-the-shelf treatments for cancer, many other chronic conditions or regenerative medicine. Importantly, the use of mRNA as a therapeutic tool or vaccines in cancer has been rapidly expanding. Scientists may never devise a single vaccine for cancer because cancer is a constellation of many maladies. But what if we could train our bodies to attack our own specific tumor? The rapid advance of mRNA vaccines led to a tremendous acceleration of cancer vaccines. It works something like this: For each cancer patient, a genetic analysis of the tumor is performed and an individually tailored mRNA vaccine is designed. The custom mRNA is then either directly injected or following ex vivo loading of the custom mRNA to transfected immune cells. There are several ongoing clinical trials for personalized vaccines in basically every solid cancer. We have entered an era where it is possible that our own immune system can be primed to go after the residual tumor cells and provide a cure.

In addition, the targeted delivery of mRNA therapeutics to diseased organs has the potential to minimize systemic toxicity and reduce the amount of drugs needed to reach the relevant sites. For example, stem cell generation or enhancement for cardiovascular, liver or brain regeneration, either via mRNA-based stimulation, cell-operated secretion of growth factors or direct tissue restoration, could also be assisted with mRNA manipulation of stem cells.

Finally, recombinantly produced monoclonal antibodies, despite their promise for a myriad of indications, are hindered by manufacturing and purification challenges that result in high costs and long lead times. Through the natural role of mRNA as a transient carrier of genetic information for translation into proteins, in vivo expression of mRNA-encoded antibodies offer many advantages.

However, several challenges exist for the successful implementation of such technology beyond vaccines.

First, the wider application of mRNA-based therapeutics is still limited by the need for improved vectors or drug delivery systems and their short-lived expression in target tissues. It is currently quite difficult to rationally design nanoparticles that selectively target specific tissues and to overcome the poor stability, cell targeting, and translational efficiency of naked mRNA.

Furthermore, the observed suboptimal efficacy of mRNA Covid-19 vaccines in immunosuppressed patients points to an unresolved challenge that has historically plagued vaccinology. How to elicit robust immune responses in patients with a defective immune system is a major unmet need and work has been going on in developing adjuvants (e.g. modifying the lipid nanoparticle carriers or in cases of tumor vaccines co-delivery with other immunotherapeutic agents such as checkpoint inhibitors).

The safety and tolerability profile of these emerging technologies needs to be fully elucidated, including the relative roles of the RNA and the lipid nanovesicle carriers in stimulating proinflammatory innate immune responses. For example, the tissue production of the therapeutic protein can give rise to inter-patient variability, depending on the particular characteristics of the target tissue, and lead to toxicities. In addition, we also need a further understanding of fundamental immunology to better optimize mRNA therapeutics.

Here is an example of the importance of fundamental basic research: The very rapid protein structure-based design of coronavirus mRNA vaccines was accomplished only because basic science made it easy, with the decoding in 2017 of the key vulnerability of coronaviruses, that of the spike. In contrast, developing mRNA vaccines against HIV remains a promise and challenge, in view of the high degree of complexity of HIV immunopathogenesis. However, the attributes of mRNA vaccines, the durability of responses, ease in production, ability to encode complex protein designs and safety as immunogens make them a prime platform for HIV vaccine development.

Finally, mRNA vaccine access and cost remain an issue for poor countries. Perhaps the development of self-amplifying mRNA vaccines, which require the injection of one-hundredth of the material to have the same effect, would be advantageous compared to the current expensive conventional mRNA vaccines.

The Covid-19 pandemy catalyzed one of the most rapid medical developments in history. The mRNA story will not end with Covid-19. With human-edited mRNA, we could theoretically commandeer our cellular machinery to mass-produce proteins that either promote repair or request our cells to cook up the menu protein with which our immune system can react to an invader. Although the time this takes will shrink with the implementation of this technology in modern medicine, it is still too early to fully evaluate its safety and effectiveness in humans.

A futuristic view of mRNA technology is that we will have a toolbox to tackle different applications, such as prophylactic versus therapeutic vaccines for both a variety of acute/chronic infections and other non-ID entities. Their future in vaccinology is currently the “low-hanging fruit” as mRNA vaccines have already far-reaching health, social and economic benefits.

However, more work is needed in evaluating the true impact of this novel technology in non-infectious diseases applications. For example, in cancer, in contrast to infectious diseases which offer a portfolio of traditional vaccines to benchmark the lack of conventional vaccines makes it difficult to weigh the true effectiveness of the mRNA approach.

Dimitrios P. Kontoyiannis is the Robert C. Hickey Chair in Clinical Care, professor and deputy head of the Division of Internal Medicine at the MD Anderson Cancer Center in Houston, Texas.

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