Beyond the Hype: Industry Experts on the Reality of mRNA in Cancer Care
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
When I asked a panel of experts at RNA Leaders why mRNA was best positioned to shine in oncology, I was met with a few expected talking points and — better yet — a few I wasn’t expecting.
We may be able to easily answer “why” mRNA is well equipped to treat cancer, thanks to speed of development and economics alone. As Daniel Getts, CEO of Create Medicines (formerly Myeloid Therapeutics), argued, being able to move from “whiteboard sketch to clinic” in as little as four months is incredibly beneficial in this world where we can get carried away by the deceptive promises of animal models. Similarly, as Getts pointed out, the cash-happy economic environment of a few years ago enabled the ATMP space to embrace the platitude: “Build it and they will come.” But as we also know, “building it” has led to therapies that cost millions — and those willing to come and embrace such price tags have been fewer than we anticipated.
“It costs $600 for a dose of an in vivo CAR product. It costs $200k to make an autologous CAR product,” Getts said. “We talk about the potential of these technologies, and RNA actually brings the cost proposition back to reality.”
But the promised economic profile was not the only reality check of this discussion. Throughout this panel discussion, the speakers did not mince words about the uphill battles we face in making mRNA a shining star in oncology. Though we may be more easily able to answer “why mRNA” for oncology, it’s much more challenging to address “how” we’ll make mRNA an established standard of care.
Fortunately, this panel had a few ideas of where we could start.
Course Correcting Political & Regulatory Misconceptions
It should come as no surprise that each speaker circled around the industry’s need to “rebrand.” Of course, given the news today in the U.S., we can — first and foremost — take the term “rebrand” at face value. The current misunderstanding we face around the mRNA vaccines is a formidable barrier to the progression of mRNA into the therapeutics space — particularly given the policy implications such misconceptions can pose. As I’ve written in a handful of other recent articles (here and here), the Alliance for mRNA Medicines is hard at work course-correcting/doing crisis communications at the government level.
Likewise, on the regulatory front, the MHRA released guidance earlier this year clearly “rebranding” these products as personalized cancer immunotherapies, as opposed to cancer “vaccines.” Though it may seem like a small detail, the panel emphasized how meaningful this terminology shift is. It moves our therapies out of the same world as government vaccine mandates (and the baggage that came with these mandates) and reestablishes mRNA as what it ultimately needs to be: A dialogue between a patient and their physician about a therapeutic.
Combination Is Key: Positioning mRNA for Early Success
Of course, as we move beyond mRNA as a singular agent in infectious disease to the world of therapeutics, rebranding also takes on a second layer of meaning. Several years ago, I posed the question, Would mRNA be a “leading lady” or a “best supporting actor?” During this panel discussion at RNA Leaders, we arrived at a much more definitive answer.
“We can certainly have discussions about how we’re going to make an mRNA drug that’s going to potentially make a difference in cancer,” CureVac CBO Thaminda Ramanayake said. “But that isn’t going to happen for at least 10 years from what we know about the science today. So, I think we need to look at mRNA, not as an adjacent therapeutic, but as a novel modality that could potentially coexist among other modalities. We need to apply a more cooperative, collaborative, and combinatorial look at next-level regimens when we think about treating oncology patients in the future.”
Naturally, this will also mean working closely with regulators to ensure we’re asking the right scientific questions that create opportunities for mRNA to play the role of a “best supporting actor” within a broader treatment regimen. As Ramanayake went on to explain, “Because of regulatory requirements, you must show efficacy as a single agent. But there are instances in which you could show that mRNA can certainly make a difference in a combination setting. We need to be very creative in these early days working with regulators and avoid getting caught in dogma.”
Beyond the Vaccine Blueprint: Challenging the Scientific Dogma of mRNA
Speaking of dogma, I was struck by Getts’ impassioned answer of what it will take to keep the science of mRNA moving forward: Don’t assume that what is established is necessarily the be-all-end-all approach.
For example, in the early days of mRNA development — and certainly in the early stages of pandemic development — there were debates about modified vs. unmodified mRNA. As we already know, modified mRNA was the winner in the COVID vaccine field, and the pseudo-uridine discovery went on to win the Nobel Prize. But as Getts also shared, the company’s retrotransposon technology has been less successful when using pseudouridine-modified RNA. After dosing 45 pancreatic and liver cancer patients with in vivo CARs using pseudo-uridine-modified mRNA, the company has seen translation initiation issues and limited CAR expression.
“We need to stop accepting dogma,” he said. “Don’t just assume that because someone won a Nobel Prize for it that it must work for you. A lot of RNA knowledge is driven from giving vaccines.” And, as all the speakers emphasized throughout the discussion, using mRNA prophylactically in the infectious disease space as opposed to therapeutically in the cancer and autoimmune space is quite different in terms of expectations.
Level-Setting Expectations for a Long Game in Solid Tumors
We can be die-hard believers in mRNA’s therapeutic potential. But this doesn’t mean that we should ignore the reality of where we are today, either. Though this panel comprised experts who are dedicated to helping mRNA succeed in oncology and other therapeutic areas, they still emphasized the importance of being realistic.
“We are in the first inning,” Getts clarified. “We can’t say mRNA has been successful in cancer yet. There are no approved, personalized cancer immunotherapies.” As he went on to explain, though we have seen positive data for mRNA in the adjuvant setting, this is “not knocking the ball out of the park” therapeutically, nor does it make the best economic sense — especially when we consider the number of treatments already available to treat melanoma (one of the leading indications in which we’ve seen progress).
We’re finding ourselves at a difficult juncture. As a novel modality working alongside advanced therapies — namely cell therapies — therapeutic expectations have shifted. Though I’ve often emphasized the importance of learning from the ATMPs that have come before us in the personalized space, the panel emphasized the importance of distinguishing RNA’s therapeutic abilities from the other modalities.
“The minute you start to brand similarly, you set similar expectations to very different modalities,” Ramanayake said, which doesn’t do our industry any favors — especially as we try to work with investors and educate patients.
Getts reaffirmed this point, emphasizing that the success of CAR-T products has led to expectations that all other therapeutic agents will elicit a complete response each time. And for an immunomodulatory product, this may not be realistic given the progress of a patient’s disease by the time they receive treatment. In turn, it’s exceptionally important to educate and make sure that investors are ready to go down the long road we’re facing.
“We have to help level set investor expectations,” Getts concluded. “Solving solid tumors with a new technology takes a long time. Even when you tell people that the very first ex-vivo CAR-T cell therapy was dosed in 1988, people are shocked. It wasn’t until 2013 that we had the success that Carl June did. We’ve been working with RNA for a long time, but we haven’t been in the therapeutics world for long. So, we have to buckle up. We’re going to have to climb the hill.”