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The success of mRNA-based vaccines paves the way for mRNA in oncology and beyond.
With the success of messenger RNA (mRNA) in the COVID-19 vaccines, the biopharma industry is responding with enthusiasm and intense focus on the development of mRNA-based therapeutics for other disease states. A primary area of focus is oncology, where developers see much promise in their use for treating cancers.
mRNA has a number of properties that can be exploited in oncology therapeutics, says Tim Van Assche, PhD, director, Business Development, Etherna, a Belgium-based mRNA/lipid nanoparticle (LNP) technologies company. Van Assche lists the following mRNA properties:
mRNA-based therapeutics offer a personalized cancer therapy and have the potential to revolutionize cancer treatment with a highly tailored approach, emphasizes Andreas Dreps, PhD, senior vice-president, Drug Development Services, ICON. “Cancer antigens, or the molecules that immune cells target, can vary greatly from person to person. This means that no one treatment is going to be effective for all patients, even within the same cancer type. However, mRNA cancer vaccines can be tailored for specific antigens based on the unique expression of an individual’s tumor,” Dreps states.
Dreps further explains that the ability to specifically tailor mRNA cancer vaccines allows these vaccines to harness the patient’s own immune system to specifically target and eliminate tumor cells. This results in a highly personalized approach to oncology that primes the immune system to target an individual patient’s specific cancer.
There are currently several methods in play to treat cancer, notes Yasser Kehail, senior product manager—mRNA CDMO, Aldevron. These methods include chemotherapy, stem cell treatment, monoclonal antibodies (e.g., human epidermal growth factor receptor positive, anti-programmed cell death protein 1), and now chimeric antigen T cell (CAR-T) therapy, he lists. “However, treating a solid tumor remains a challenge, and is not being addressed with CAR-T,” Kehail says.
The biggest advantage of using mRNA for oncology therapeutics, therefore, is targeted delivery. “We have seen success recently with hepatocarcinoma, where the mRNA–LNP [lipid nanoparticle] complex is delivered directly to the liver and inhibits the cancer from spreading. In addition, we have also seen success with mRNA neoantigens for pancreatic cancer, as seen in a study published by Memorial Sloan Kettering (1),” Kehail states.
An mRNA-based cancer vaccine functions similarly to mRNA vaccines for pathogens, such as COVID-19, by indirectly provoking an immune response, explains Martin Lachs, PhD, vice-president, Project Management, Oncology, ICON. “The mRNA contained in the vaccine encodes the instructions for healthy cells to temporarily produce cancer-specific antigens. Immune cells will recognize these antigens as foreign and become trained in targeting and destroying cells that express them. This provides the immune system with an improved capacity to recognize and fight cancer cells,” Lachs says.
The treatment resemblesnatural processes because cellular immunity within a body works the same way, says Kaido Kurrikoff, CEO, Vectiopep. “The dendritic cells ‘become aware’ of a new pathogen and forward the molecular signature of the pathogen to the killer T cells. These, in turn, eliminate (kill) the unwanted cells. In the case of mRNA therapeutics, we just have to insert the molecular signature of the cancer in mRNA, making the dendritic cells ‘aware’ of cancer cells, which results in the killer T cells eliminating malignant cells,” he explains.
“The beauty of this approach is that our immune system is able to continuously survey and detect potential recurrence or metastases, whereas the traditional therapies last only as long as the drug is present in the circulation,” Kurrikoff adds.
The core of an mRNA therapeutic for oncology treatment lays in its ability to induce a tumor-antigen specific cytotoxic T cell response and induce intratumoral expression of mRNA-encoded immune-modulatory factors. “The induction of a systemic anti-tumor immune response has the potential to eradicate all present tumors and prevent tumor recurrence,” says Van Assche.
In addition to their therapeutic advantages, mRNA products have an easier manufacturing process, according to Van Assche. Manufacturing of mRNA is also faster and cheaper compared to other biologicals, he emphasizes. Furthermore, in-vivo drug delivery is facilitated via lipid nanoparticles (LNPs), and significant efforts are being made to develop LNPs targeted to specific organs and cell types. “In time, LNPs will be developed that can be targeted to specific cell types in the tumor,” Van Assche predicts.
From Kehail’s perspective, however, new challenges arise even as the industry explores the advantages of mRNA therapy in cancer. For example, he explains that, for neoantigens and personalized medicine, manufacturing challenges arise because of the cost of producing good manufacturing practice (GMP)-grade material.
“Essentially, a batch is manufactured for only one patient at a time. This one batch needs the same amount of analytics, development, and quality control oversight as the batch process for thousands of patients. In addition, the output volume required for a patient-specific manufacturing process is extremely small,” Kehail explains.
Kehail points out that current GMP manufacturing processes are designed for larger batches, which will require contract development and manufacturing organizations to either retrofit systems or create purpose-built systems for personalized medicine. “Industry innovations are needed to overcome the limitations for GMP-grade, small-scale manufacturing,” he adds.
However, the overall attitude is optimistic toward further development of mRNA therapeutics for cancer indications. “The first-generation immunotherapies (immune checkpoint inhibitors) have already demonstrated unprecedented therapeutic effects, never observed before with traditional therapies such as chemotherapy. The hope is that, with the addition of an mRNA approach, such effects can be extended to even higher numbers of patients and tumor types,” says Kurrikoff.
Also, mRNA-based drug delivery typically utilizes nanoparticles—often LNPs—to transport the therapeutic to the desired location; this delivery has been found to be more stable and biocompatible than traditional drugs, notes Dreps. LNPs are known for efficient intracellular delivery, and they provide a mechanism for targeted delivery, he adds.
Meanwhile, Lachs points out that, because of their targeted nature, mRNA vaccines direct immune response solely to cancer cells, rather than damaging healthy cells and tissue the way many chemotherapies do. “Additionally, when used in combination with other cancer treatments, mRNA cancer vaccines enable the treatment of a broader range of patients than other types of cell and gene therapies (CGTs). For example, early clinical trials of one combination therapy that utilized mRNA vaccines showed efficacy in treating patients with solid tumors, whereas the vast majority of successful CGTs have only been able to treat liquid tumors,” Lachs states.
As the mRNA therapeutic field is relatively new in terms of having marketed products, there are still hurdles to overcome in getting to market. In the field of oncology, for instance, precisely targeted mRNA vaccines may not be effective on their own. “Cancer is highly adaptable and adept at developing mechanisms to continue proliferation and survival,” says Dreps. “This includes evading the immune system, such as by using immune checkpoints to prevent attacks from T cells. As a result, some cancers may develop ways to resist the targeted immune response resulting from an mRNA vaccine.”
“To increase effectiveness,” Lachs adds, “mRNA cancer vaccines currently in development are primarily administered in combination with other cancer therapies, including immune checkpoint inhibitors or chemotherapies. This introduces challenges related to the complexity of therapeutic development and cost inflation for therapeutic development.”
Yet, the greatest hurdle is still the delivery, states Kurrikoff. “Current lipid-based technologies are very efficient in targeting cells in the liver, but not so good at any other tissues,” he explains. However, he believes that certain peptides may offer an efficient alternative, as these peptides have shown exceptional selectivity towards target cells, in this case, dendritic cells.
Van Assche points out that the current furthest advanced mRNA-based cancer therapies are cancer vaccines. “The development of mRNA-based cancer vaccines suffer from previous failures in the field with suboptimal cancer vaccine platforms, such as peptide-based vaccines. Due to these failures, there is a general cautiousness to invest in cancer vaccines from both the investment world and pharma. This restraint hampers the fast and thorough development of mRNA-based cancer vaccines,” he states.
“This is unfortunate,” Van Assche continues, “as they have the potential to bring significant and sorely needed added value to the treatment of numerous patients as evidenced by the recent success with mRNA-based cancer vaccines.”
Looking ahead, “With the success of mRNA as a vaccine modality, we are now seeing mRNA being developed for enzyme replacement therapies such as ornithine transcarbamylase (OTC) deficiency and phenylketonuria,” says Kehail. “In addition, we are also seeing increased development activities in gene editing for hematological diseases, as well as protein replacement. Of course, the main challenges compared to vaccine development is high dose requirements, targeted delivery, and expression levels.”
Van Assche further elucidates by pointing out that the potential of mRNA-based therapies is only limited by the delivery methods for the mRNA. “Once a solution is found to deliver mRNA to any cell type and tissue, mRNA-based therapies can be used for any pathology,” he asserts.
Van Assche lists the following therapeutic applications that are within reach of mRNA-based therapies with the delivery solutions currently at play. These include:
Kurrikoff echoes the sentiments, also noting that protein replacement is a potential therapy area, provided that mRNA delivery is efficient. “We could, in theory, introduce any desired protein to our cells. This way, we could replace any dysfunctional protein with a new one and cure basically any disease. Obviously, we are far from such efficacy, and some tissues pose a considerable barrier, such as the brain,” he states.
“While the field of mRNA vaccine research is still in its early stages, the technology’s versatility, scalability, and speed of development make it especially promising for numerous disease applications,” Dreps foresees. He explains that the production process for mRNA vaccines is especially advantageous for developing vaccines against emerging infectious diseases.
“Successful mRNA vaccines for COVID-19 have paved the way for the treatment of numerous infectious diseases, such as HIV, tuberculosis and Zika. Recent research with mRNA technology shows promise for developing a universal influenza vaccine that could immunize against all major influenza subtypes,” Lachs adds.
1. Rojas, L. A.; Sethna, Z.; Soares, K. C.; et al. Personalized RNA Neoantigen Vaccines Stimulate T Cells in Pancreatic Cancer. Nature 2023, 618, 144–150. DOI: 10.1038/s41586-023-06063-y
Feliza Mirasol is the science editor for BioPharm International.
Volume 37, No. 1
When referring to this article, please cite it as Mirasol, F. From Vaccines to Oncology and Beyond: Tracking mRNA’s Progress. BioPharm International 2024, 37 (1), 14–17.