July 24, 2024

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What will be the next frontier for mRNA technology?

What will be the next frontier for mRNA technology?



 

After COVID-19 and Nobel Prizes, What will be the next frontier for mRNA technology?

On October 2nd, the Nobel Assembly at the Karolinska Institute in Sweden announced the awarding of the Nobel Prize to Katalin Karikó of the German biotechnology company BioNTech and Dr. Drew Weissman, a professor at the University of Pennsylvania.

They were honored for their groundbreaking work on base modifications in RNA, which played a pivotal role in the development of effective mRNA vaccines against COVID-19.

 

This success story represents the triumph of decades of foundational scientific research.

In 2005, Karikó and Weissman discovered that replacing uridine with pseudouridine in mRNA could effectively suppress the inflammatory response caused by the injection of exogenous mRNA into mammals, addressing issues related to high immunogenicity and increasing the expression of relevant proteins.

This breakthrough paved the way for companies like BioNTech and Moderna to develop their COVID-19 vaccines, BNT163 and mRNA-1273.

 

Fifteen years later, as the COVID-19 pandemic struck, these mRNA vaccines were rapidly developed and widely used, proving the therapeutic potential of mRNA and the safety of lipid nanoparticle (LNP) delivery systems at lower doses. mRNA drugs transitioned from concept to reality, opening a pathway from research and development to commercialization.

But this is far from the beginning of mRNA research. Prior to COVID-19, scientists had been exploring the use of mRNA as a therapeutic tool for several decades, with a focus on areas like oncology and viral infectious diseases. Nobel laureate Weissman, for instance, had dedicated efforts to developing an mRNA vaccine for HIV.

Moreover, mRNA is not the endpoint; it’s just the beginning. Moderna’s CEO, Stéphane Bancel, stated in May that the company would become a great rare disease company in the future.

Among its 48 ongoing projects, six are targeted at rare diseases, including propionic acidemia, methylmalonic acidemia, Von Gierke disease, ornithine transcarbamylase deficiency, phenylketonuria, and Crigler-Najjar syndrome type 1 (CN-1). BioNTech’s pipeline includes a substantial focus on solid tumors.

 

With the global spotlight on the Nobel Prize and the unexpected battle against COVID-19, mRNA technology has now embarked on its original journey, with multiple potential destinations.

 


Next Stop: Cancer

Several companies, including Moderna, BioNTech, CureVac, and Chinese companies like Shuwen Biotech and New Horizon Health, have entered clinical trials or applied for clinical trials for mRNA cancer vaccines.

These vaccines target indications such as melanoma, head and neck squamous cell carcinoma, colorectal cancer, pancreatic cancer, non-small cell lung cancer, liver cancer, and gastric cancer.

mRNA cancer vaccines can be broadly categorized into two types: those targeting tumor-associated antigens (TAA) and those targeting tumor neoantigens. The latter, driven by recent discoveries in neoantigens, has witnessed faster development, with some products entering Phase 3 clinical trials in the United States and Europe.

In February, Moderna’s personalized cancer vaccine mRNA-4157, used in combination with Merck’s PD-1 inhibitor Keytruda, received FDA breakthrough therapy designation for adjuvant treatment in high-risk melanoma patients after complete resection. In July, this combination entered Phase 3 clinical trials, becoming the world’s first Phase 3 clinical trial for an mRNA cancer vaccine. Interim data from the Phase 2b study showed a 44% reduction in the risk of recurrence or death compared to Keytruda monotherapy, with 83.4% of patients experiencing 12 months of recurrence-free survival.

Moderna’s mRNA-4157 has already received FDA breakthrough therapy designation, and its approval could have a similar impact as the COVID-19 vaccines. The Nobel Prize recognition may further boost the approval of personalized cancer vaccines. It’s believed that the first cancer vaccine product is likely to be approved and on the market within one to two years.

BioNTech, another leading player in the mRNA field and the recipient of this year’s Nobel Prize, has four mRNA cancer vaccines in Phase 2 clinical trials. Among these, BNT 122, a personalized cancer vaccine, is being studied in combination with Keytruda for melanoma and as a monotherapy for colorectal cancer.

The other three are universal cancer vaccines, with BNT116 being studied in combination with Regeneron’s PD-1 inhibitor cemiplimab for non-small cell lung cancer, BNT111 in combination with cemiplimab for advanced melanoma, and BNT113 in combination with Keytruda for HPV16+ head and neck cancer.

 

What will be the next frontier for mRNA technology?

 

Looking at the pipeline, the combination of mRNA cancer vaccines with PD-1/L1 inhibitors appears to be a significant trend and direction. This intersection of two hot fields in combination therapy seems promising.

Historically, one challenge faced by cancer vaccines was their limited efficacy. However, mRNA cancer vaccines hold promise due to their ability to induce a robust cellular immune response, which is crucial for therapeutic cancer vaccines. By designing mRNA sequences that encode multiple epitopes, the vaccine can trigger the simultaneous expression of multiple genes in the body, leading to increased expression of relevant immune factors, immune cell activation, overcoming immune tolerance, and extending the lifespan of T cells. These features make mRNA drugs more efficient in generating antibodies and small molecules.

 

One Swiss company achieved a twofold increase in overall efficacy by combining a peptide with PD-1.

Using mRNA to express CAR (chimeric antigen receptor) may reduce off-target effects caused by CAR-T cells recognizing healthy cells. In August, Kochi Pharmaceutical announced a collaboration with Moderna to study the combined therapeutic effect of Kochi’s Claudin18.2 CAR-T and Moderna’s experimental Claudin18.2 mRNA cancer vaccine.

There’s also potential for mRNA monotherapy. If we can effectively control 50 mutated genes associated with a particular cancer and enhance the function of the immune system, as well as regulate the expression of anti-cancer genes like P53, we may improve the tumor microenvironment. This is a direction that requires industry effort to achieve.

In the broader context of cancer vaccine development, personalized cancer vaccines have indeed made the fastest progress. Breakthroughs in this area can drive progress in the entire field of mRNA cancer vaccines. Besides personalized vaccines, universal mRNA cancer vaccines will continue to make progress in directions where antigens are well-defined and targets are clear, such as HPV and KRAS vaccines. Universal vaccines for other indications may take more time.

As an emerging technology, mRNA cancer vaccines still face challenges. The optimization of mRNA sequences and codons, delivery systems, formulations, production technology, and regulatory pathways all require continuous exploration and improvement. The development of personalized cancer vaccines involves not only mRNA but also upstream tumor antigen screening, prediction of MHC-I-restricted neoantigens, and other technologies. These challenges are opportunities for innovation and collaboration.

The global market for cancer immunotherapy has grown rapidly in recent years, with PD-1/PD-L1 inhibitors accounting for a significant share. Combination therapy has become a dominant trend. In the future, the combination of mRNA cancer vaccines and PD-1/PD-L1 inhibitors will likely represent a significant opportunity. The question now is, will these therapies replace existing therapies or become complementary options in the landscape of cancer treatment?

 

 

 

Expansion Beyond Infectious Diseases and Oncology

While infectious diseases and oncology have been the primary focus of mRNA research, the technology’s potential reaches far beyond these areas.

a. Rare Diseases:

mRNA technology offers promise for the treatment of rare genetic diseases. By delivering corrected mRNA to cells, it’s possible to address the root cause of these conditions. As mentioned earlier, companies like Moderna and BioNTech are actively working on mRNA therapies for rare diseases.

b. Autoimmune Disorders:

mRNA could be used to modulate the immune system’s response in autoimmune disorders like rheumatoid arthritis, lupus, and multiple sclerosis. By targeting specific immune cells or molecules, it may be possible to reduce the autoimmune response.

c. Cardiovascular Diseases:

Researchers are exploring mRNA-based therapies for conditions like heart disease and high cholesterol. These therapies could help regulate gene expression to reduce the risk of cardiovascular events.

d. Neurological Disorders:

mRNA technology may hold potential for treating neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. By delivering specific mRNA sequences, researchers aim to promote the production of protective proteins or enzymes in the brain.

e. Genetic Editing: CRISPR-Cas9 technology has gained attention for gene editing, but mRNA could also play a role. By delivering modified mRNA with the desired genetic changes, it may be possible to correct genetic mutations responsible for various inherited diseases.

 

 

Global Expansion and Equity

The Nobel Prize recognition further underscores the importance of mRNA technology in healthcare.

This recognition could lead to increased investment and collaboration in research and development, further accelerating progress in the field.

Additionally, as more mRNA therapies are developed and approved, there’s an opportunity to improve global healthcare equity by making these treatments accessible to underserved populations.

 

 

Manufacturing and Cost Challenges

One of the challenges in the widespread adoption of mRNA therapies is the complexity of manufacturing and cost. Current mRNA production processes are intricate and require specialized facilities. Efforts are underway to simplify and scale up production, which could help reduce costs and make these therapies more accessible.

 

 

 

In conclusion, the Nobel Prize in Chemistry for the development of mRNA technology is a testament to the incredible potential of this field. While COVID-19 vaccines brought mRNA into the spotlight, the technology’s applications extend far beyond infectious diseases.

We can expect to see continued innovation and exploration in areas like oncology, rare diseases, autoimmune disorders, and more.

As mRNA technology matures and becomes more accessible, it has the potential to revolutionize how we approach and treat a wide range of diseases and medical conditions.

 

 

 

What will bethe next frontier for mRNA technology?

(source:internet, reference only)


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