The Future Of mRNA For Cancer Treatment

By Life Science Connect Editorial Staff

Growing evidence supporting the effectiveness and safety of clinically approved mRNA vaccines, coupled with burgeoning interest in mRNA-based therapeutics, has positioned mRNA technology to become one of the major pillars in cancer drug development. As additional mRNA-based cancer immunotherapies vaccines enter clinical development, operational and supply chain challenges must be addressed to reduce turnaround times and COGS.

In a recent Cell & Gene Live event, Cell & Gene chief editor Erin Harris sat down with J. Andrew Case, head of supply chain – Cell & Gene Therapies at Genentech, and Daniel Getts, CEO and cofounder of Myeloid Therapeutics, to explore the technologies and research approaches being leveraged in the mRNA space. The pair also discussed their own companies’ novel technologies, well as some of the key objectives, considerations, and strategies that accompany mRNA manufacturing.

mRNA’s Potential For The Biotherapeutic Pipeline

Therapies based in mRNA have significant potential to enable faster, more flexible, more cost-effective therapeutic production. The technologies available today have enabled the production of a wide range of functional proteins or peptides in the human body by way of mRNA-based vaccines or therapeutic agents. According to Getts, the suitability of mRNA for certain applications is what led Myeloid to use it for its therapies, which are focused on leveraging the myeloid compartment, the “orchestrator of all immunity,” to tackle high unmet medical needs such as solid tumors. “I believe we’re the first to deliver a [CAR-T] using mRNA into human beings,” he said.

Because myeloid cells encompass a number of cell types, including dendritic cells, macrophages, neutrophils, and others, traditional delivery mechanisms such as viral vectors can be ill-suited to these therapies, as they tend to drive cells to differentiate into macrophages alone – or to die off, Getts said.  Myeloid’s lead asset, MT-302, is a TROP2-targeting in vivo CAR-T therapy designed to express inside the myeloid compartment; it has also utilized mRNA to engineer myeloid cells ex vivo. “What I can tell you, from both the cell therapy and our in vivo delivery technology, is we are able to engineer these cells with significant efficiency using RNA,” Getts explained. “For our cell therapy it’s a one-day manufacturing process – we don’t have to activate the cells or culture them.” Myeloid has observed that, in non-human primates, up to 40 percent of the circulating myeloid compartment expresses the CAR following product administration. In one patient tumor, it showed that, 17 days after treatment, 25 new T cell receptors had been induced. “We have a very strong belief that this approach is taking a significant step forward, and that by using RNA, we can accelerate not only our technology but a number of other technologies as well.”

The broad landscape made possible by mRNA technologies has the potential to transform a number of arenas, Getts said, from vaccines to Aptima tests, self-amplifying and self-activating RNA, circular and micro-RNA, antisense oligonucleotides, CRISPR editing, CAR-Ts, and other modalities. Part of this is tied to a favorable COGS when compared to many other approaches, Getts said, as well as the rapidity with which different constructs can be tested. He compared a typical lentiviral approach, which often takes between one and three months to reach therapeutic production, to an mRNA application, where new constructs can be generated for testing in less than a week. “I really think the versatility of RNA and where it can be applied is limitless in the context of Myeloid Therapeutics,” he said.

For Case – and Genentech – one of the most interesting applications for mRNA is leveraging vaccine technology to develop customized cancer vaccines for individual patients. “In a sense it’s an autologous therapy, because it starts with a patient’s tumor cells that are sequenced to identify new antigen targets,” he explained. “These targets are then programmed into the RNA to create a vaccine with the belief this will create an immune response or train the immune system of a patient to attack a specific cancer.” Genentech is currently in clinical trials to demonstrate these technologies, he added.

RNA: Opportunities And Challenges

The COVID pandemic was core to demonstrating the merits of mRNA-based vaccines, particularly around the timeframes needed to produce drug substance when compared to traditional approaches. This accelerated development, coupled with the comparative cost-effectiveness of mRNA-based therapies, is likely to mean far more investment in their development, as organizations work to prove out their utility for indications like cancer. “This really could be the technology we’ve been waiting for to help facilitate cost-effective therapeutics,” Getts said. “As we move forward, maybe we don’t have to spend $200,000 to make a CAR T cell; maybe we can get the cost of goods into a realm that makes sense.”

In the cancer world, there are a number of important considerations linked to foundational science that an ideal therapeutic must address. One is a suppressed antitumor response from cancer patients – something that mRNA cancer vaccines in trials like Genentech’s have shown promise in correcting. “This shows, from a scientific and medical perspective, that there is an immune system that we can go into and we can really drive it,” Getts said. Genentech and others are leveraging what was learned in making Covid vaccines for certain cancers such as melanoma and, in Genentech’s case, pancreatic cancer. “These are big populations globally if this therapy proves out,” Case said. He noted that Genentech has reached a point where it can, from the point at which it receives a patient’s tumor sample, turn around and deliver a first dose within 30 days.

Because RNA tends to be very stable, its transition between batch sizes is straightforward, with an incremental difference in cost between a 1-liter and a 5-liter run, for example. As such, Myeloid’s approach is to generate larger batches of RNA and separate them into lots to use in multiple lipid nanoparticle (LNP) manufacturing runs, offsetting some downstream risk, according to Getts. “You don’t have to put all of your eggs in one basket,” he said. “And from a clinical and FDA perspective, you get the opportunity – at least for LNP and fill/finish – to get more experience, complete more runs, and get a better handle on your CMC.”

While much progress has been made in the RNA space, there still exists opportunity to optimize these modalities around things like stability and dosing. Myeloid uses artificial intelligence (AI) and machine learning (ML) to evaluate the structure of RNA; it will typically generate more than 10,000 constructs for evaluation using codon optimization technologies to introduce different hairpin loops and tweak their stability and free energy. “We’re also looking at things that impact translation, ribosomal interactions with the RNA strand, and so on,” Getts said. “This is on the linear RNA side. For the circular RNA side, even with UTR on circular RNA, what we've found using the technology that I mentioned and the approaches I've mentioned, if we look at translation of RNA and protein expression, we can get it out to 12 days in certain instances using a linear RNA.”

The Future Of mRNA Vaccines For Cancer

Another big hurdle for mRNA-based cancer vaccines is addressing heterogeneity – even within the same patient, the heterogeneity of a tumor and its associated metastases has attracted a wealth of research. What scientists have found is that, ultimately, it’s about more than activating T cells: “Within these patients, myeloid cells can take up, in this case, an RNA vaccine, and they can process antigen and activate T cells,” Getts said. “I think this is step one for us. Steps two, three, and four are,  in patients that aren't adjuvant or haven't had these tumors surgically removed, how do we make the tumor marker environment more amenable to being attacked by the immune system?”

As Genentech has demonstrated, its cancer vaccines can activate relevant T cells, and personalized cancer vaccines have the potential to address the problem of heterogeneity. According to Getts, the next step is to take advantage of the myeloid cells penetrating these tumors. “People often find it amazing when I cite some of these statistics – glioblastoma can be 75 percent blood-derived myeloid cells, ovarian cancer up to 50 percent, triple-negative breast cancer roughly 50 percent,” he said. “These are the cells that often cause pathology like in a Covid-inflamed lung, for example; they're exactly the same progenitor cells, it’s just that the cancer shuts them down. So, our ability to activate these cells within tumors is the orchestrator of the immune response.”

If leveraged effectively in the tumor microenvironment, these myeloid cells, as the cells the vaccines use to activate T cells, could both kill tumor cells and liberate the neoantigens. “To me, the way to approach tumor heterogeneity is really to take that next step and do what is being done in vivo directly inside the tumor and it will kill two birds with one stone,” Getts explained. “One, it will liberate the neoantigen and then second, it's going to soften up that tumor microenvironment to make it amenable to T cell penetration and killing of the tumor cells.”