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PharmTech.com The Real Message Behind Commercial mRNA Products April eBook 2023 Pharmaceutical Technology ® 13 mRNA TReNds "Checkpoint pathways evolved to regulate the T-cell response to cancer cells. Some tumors suppress T-cell response, so checkpoint inhibitors can overcome this suppression. While this allows normal T-cell anti-tumor activity to develop, this activity appears more effective in cells with a higher mutational burden," says Lewis. Another reason for failure is that current immune therapies often have safety issues or lack efficacy, or a combination of both, points out Gerrit Dispersyn, CEO, Phio Pharmaceuticals. Regardless of background, he explains, there is a need for more refined therapies to reprogram immune cells and tumor cells. Therefore, there is a need to target the internal cell machinery that can be achieved with oligonucleotide (i.e., nucleic acid)-based therapeutics. Currently available commercial IO products mainly fall into two categories: immune checkpoint anti- bodies and chimeric antigen receptor T cell (CAR-T) therapy, Dispersyn notes. He explains that immune checkpoint antibodies "remove the brakes" of all T cells, including the auto-reactive ones, which leads to dose-limiting toxicity. Meanwhile, CAR-T thera- pies have limited access to solid tumors. Thus, the use of oligonucleotides has the potential to improve efficacy against solid tumors. "Of the different platform technologies, it is becom- ing more and more clear that the shortcomings of the currently used platforms—whether it's antibodies, cell- based therapeutics, or gene therapy—are being realized. Therefore, new approaches to fine tuning or helping overcome these challenges is partially explaining the turn to RNA-based therapeutics," says Dispersyn. "Triggering immune responses to fight disease is incredibly challenging, and we do not fully under- stand the complexities behind it," adds Matthew Scholz, CEO of Oisin Biotechnologies, a US-based late preclinical stage company specializing in ther- apeutics for age-related diseases, and OncoSenX, a US-based late-stage pre-clinica l cancer company. Scholz notes that there is significant variability in the population as well as heterogeneity within tu- mors. A therapeutic that targets a surface protein or requires functional T-cell infiltration can therefore be rendered ineffective in many patients. Targeting disease at the cellular level using RNA and DNA to "code" for a desired response is a more specific and nuanced approach, he asserts. "With nucleic acid-based technologies, only the code for proteins is delivered. With DNA as a pay- load, tissue-specific expression of the cargo can be achieved through rationa l promoter selection as well," says Scholz. "Think of it as a software approach to mobilizing the immune system: nucleic acids pro- vide the program and the immune system interprets the program and responds accordingly. The caveat of this approach is the nucleic acids must be delivered to the right cells in the body for the program to run effectively, in this case T cells for immune modula- tion and tumor cells themselves to eliminate tumors." For oncology indications, some immunotherapies are powerful at activating immune responses to attack and destroy tumor cells, specifies Jake Becraft, PhD, co- founder and CEO of Strand Therapeutics, an emerging biopharmaceutical company. However, one of the major shortcomings of these therapeutic agents is unexpected, off-target effects that can cause serious adverse reac- tions and life-threatening toxicities, he adds. The major advantage of nucleic acid-based therapeutics lies in the fact that they can be used to accurately target a tumor or tissue, then have a specific therapeutic protein, biologic, or immune engager expressed only at the site of inter- est. "This localization dramatically decreases the risks of off-target effects and improves safety and efficacy," Becraft states. While nucleic acid-based therapies may not over- come all their challenges, they enable more precise cel- lular targeting and extended activity than small-mole- cule or protein-based therapies, adds Lewis. According to Lewis, preclinical studies demonstrate that thera- peutic gene expression can be targeted to specific tis- sue types with tissue-specific promoters, which can potentially improve efficacy while reducing side ef- fects that result from off-target activity. Furthermore, cancer cells have high turnover rates, and DNA-based therapies provide a longer duration of activity than protein and small-molecule therapies, Lewis adds. Nucleic acid focus Much of the focus today is on RNA and RNA-related technology for developing "next-generation" biother- apeutics. The benefits of RNA technology, according to Dispersyn, is that it does not require modification of the genome. For instance, Phio is using an RNA in- terference (RNAi) approach to developing therapeu- tics because RNAi is transient and not permanent. In comparison, gene-editing approaches may result in permanent issues or toxicity. "In cases where permanent modif ication is not requ i red, we have t he opt ion to use R NA-ba sed therapeutics. This is because DNA is not directly linked to proteins. RNA is a required intermediary step between genetic material and the protein. It is the proteins that make a disease present or absent. Since every translation of the genome goes to RNA, theoretically, almost everything can be solved using RNA therapies. This may be a more helpful solution than editing DNA, which is permanent and the long- term effects of which are largely unknown at this time," Dispersyn says. With much of the focus on RNA-based approaches for developing nucleic acid-based therapeutics, where does DNA fit in?