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PharmTech.com The Real Message Behind Commercial mRNA Products April eBook 2023 Pharmaceutical Technology ® 17 mRNA TReNds need to focus on delivering optimized DNA/ RNA 'software' sequences for more complex diseases," says Scholz. "Next-generation sequencing and analysis for new unique targets, along with software-based synthetic promoter design, will help us explore dif- ferent programming techniques for specific disease burdensin the future." Position in immuno-oncology Of the nucleic acid-based approaches to biotherapeu- tic development, RNAi has been especially pegged for its potential role in IO therapies. For instance, RNAi can be introduced into T cells. Fundamentally, T cells are like any other cell in that they can be pro- grammed by nucleic acid therapies, points out Scholz. Often in cancer, T cells are overwhelmed by tumor cells, and because of a built-in fail-safe mechanism, T cells can shut down when over whelmed, that is, they can go into T cell exhaustion. T cell exhaustion can be counteracted with the help of RNAi, however. "In essence, with careful selection of the nucleic acid payload, delivery of RNAi to T cells could be used to combat T cell exhaustion by breaking the inhibitory circuit from the inside, releasing T cells to seek out and fight both the primar y tumor and metastases alike," Scholz emphasizes. Scholz cautions, however, that RNAi technology has been limited in its ability to target and kill tumor cells directly simply because RNAi technology can- not distinguish a healthy cell from a tumor cell. "Our preclinical studies clearly demonstrate that a plasmid DNA-based suicide gene approach can distinguish tumor cells and effectively eliminate them. Using RNA and DNA in tumors has enormous potential. If you can deliver a precise payload to these tumors that target only that tumor's microenvironment you could, in theory, come up with many different ways to attack cancer at the cellular level. This, in essence, could get to the root cause of cancer. Being able to target spe- cific cancer traits systemically may also help to tackle metastatic cancers," Scholz explains. Conventional RNAi technolog y has limitations that prevent effective application in immuno-oncol- ogy, including challenges with delivery and stability, however, notes Dispersyn. Phio's platform allows RNAi to be used for increasing the tumor cell killing activity of immune cells, as well as for increasing the vulnerability of tumor cells toward such cell killing. For example, Phio's focus in adoptive cell therapy in- cludes using its technology to reduce the therapeutic immune cell's expression of immunosuppressive pro- teins, which can allow these immune cells to over- come tumor resistance mechanisms and improve their ability to destroy tumor cells. "Similarly, we can reprogram cells used in adoptive cell therapy, such as CAR T-cells, to increase their act- vity towards solid tumors. After expanding these im- mune cells ex vivo, and enhancing them with our RNAi compounds, the cells are returned to the patient for treatment," Dispersyn says. "RNAi could improve the efficacy and safety of cur- rent T-cell directed IO therapies by inhibiting the ex- pression of cancer-related proteins rather than inhibit- ing active proteins contributing to disease pathology," adds Lewis. Moreover, tissue-specific promoters may provide more precise control of this inhibitory activity to target cells and reduce off-target side effects. "As an example, some checkpoint inhibitors block CTLA-4 [checkpoints T-lymphocyte-associated protein 4] ac- tivity on T cells to overcome T-cell suppression and stimulate a T-cell response against the tumor. RNAi designed to inhibit CTLA-4 expression can achieve the same objective but be more effective because it pre- vents the CTLA-4 signaling pathway from turning on rather than inhibiting signaling once the pathway is active," Lewis explains. The value of mRNA therapeutics in immuno-oncol- ogy, meanwhile, lays in mRNA's ability to express thera- peutic proteins directly from inside the tumor, initiating the immune response that destroys cancer cells, adds Becraft. This approach enables the encoding of any spe- cific protein sequence that can then be delivered to the tumor itself. In this case, the tumor begins to directly secrete its own anti-tumor IO therapy, and it is this lo- calized expression that ensures the immune system can recognize and attack the tumor cells. What's more, this immune response can commence without the off-target effects that plague current immunotherapies that must circulate in the blood stream before reaching the tumor microenvironment, notes Becraft. "This same philosophy can also be adapted to CAR T-cell therapy, where synthetic protein receptors are expressed and embedded on the surface of a patient's T cells that then can recognize and kill off certain types of cancer cells. However, to accomplish this, current CAR-T therapies use a production method where the cells are extracted from the patient's body, genetically engi- neered, then transplanted back into the patient. This approach is difficult to scale and control due to infra- structure and reproducibility challenges," Becraft states. "At Strand, we believe we can bypass this issue using our self-amplifying mRNA therapeutics to deliver the instructions directly into the patient so that the T cells can make these protein receptors and become armed with the tools to recognize and kill the cancer cells." Though the use of nucleic acids in biotherapeutic de- velopment has long been studied in research, the prac- tical use of such therapeutics is still in its infancy at the industry level. However, progress toward commercial- ization is expected to move forward in light of grow- ing interest, investment, and success thus far of early entrants, such as mRNA vaccines. ■