From Promise To Precision: Defining The Therapeutic Niche for mRNA
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
In the past eleven years of my career, I’ve been lucky to cover several specific subsects of the biologics industry — starting with biosimilars, moving into cell and gene therapies, and now (encoding) RNA therapies. Though these products are all part of the broader biologics sector, each modality naturally brings its own unique “flavor” to a company’s scientific, regulatory, and commercial strategies.
In the nascent encoding RNA space, we’re still in the thick of figuring out what makes our mRNA/RNA products “unique” performers — both preclinically and clinically. This in and of itself makes the mRNA/RNA space a challenging sector in which to strategize as a company leader today. But strategize, we are, and my conversations with executives at the end of 2024 explored how these RNA leaders are striving to identify RNA’s unique therapeutic selling points and where/how an RNA therapeutic can best meet patients’ needs in the years ahead. Though we may dream of mRNA as a “silver bullet” against every disease, the more realistic goal is to identify the indications in which mRNA will shine more brightly than other treatment options.
My previous article with CureVac CEO Alexander Zehnder laid out a few of the strategies and investments he and CureVac are leveraging to identify their products’ unique value propositions. However, as we also know, many of our earliest products simply give us a small (albeit still delightful) taste of what a therapeutic product can achieve. We also need longer term visions for how to improve our products and make them even more valuable for patients and, in turn, more competitive products overall.
Fortunately for us all, Zehnder went on to share more of his thoughts/visions on how mRNA neoantigen vaccines could become even more revolutionary for patient populations in the future. Though it may be early days, this conversation is a great case study for how RNA companies are striving to keep both scientific and commercial market opportunities top of mind from the earliest days of development.
mRNA Neoantigen Vaccines: A Great Case Study For “Why mRNA?”
The title of my previous article with Zehnder included the term “marriage,” and for good reason. There is a lot of incredible science being explored in the world. But as Zehnder beautifully explained, scientific opportunity/unmet need is only one half of the equation; it’s also important we understand “why” mRNA is the most complementary “partner” to that scientific opportunity.
Over the past year or so, we’ve started to learn that our mRNA products make excellent partners. As I explained in the first part of my Top 5 mRNA Developments of 2024 article, we saw some promising preclinical and clinical data released in the past year for mRNA in combinations with gene therapies and antibodies. However, the most high-profile mRNA-antibody “partnerships” of 2024 were undoubtedly mRNA neoantigen vaccines in combination with the PD-L1 immunotherapy Keytruda. While combination approaches are quite standard in the oncology world, Zehnder explained that the mRNA neoantigen vaccine – PD-L1 combination approach is a prime example of a strong marriage between scientific opportunity and mRNA technology.
“Checkpoint inhibitors are super complimentary to mRNA neoantigen vaccines,” Zehnder explained. “A checkpoint inhibitor essentially takes the brakes off the immune system, which enables the mRNA vaccine to come in and guide the immune system to the right target(s) on the tumor.”
In fact, as he went on to explain, though PD-L1 immunotherapies have been transformative in oncology, they are not the most precise therapies given how variable the expression of PD-L1 is on the surface of each patient’s tumor. Because mRNA can be programmed to encode multiple antigens, Zehnder considers mRNA neoantigen vaccines “Immunotherapy 2.0” because of their ability to more precisely lure the immune system to a diverse and personalized set of unique tumor antigens.
Personalized Vs. Off-The-Shelf: Future Opportunities For mRNA Cancer Vaccines
However, as we also know, the process of producing personalized mRNA cancer vaccines today is not exactly simple. Though we aren’t working with cell culture like our brave brethren in the autologous cell therapy space, we are not magically free of the same logistical, quality-, and turn-around-time-related challenges autologous cell and gene therapies face today. As one expert explained in this “Hot Take” on personalized mRNA medicines, the number of patients in some of the oncological indications we’re pursuing with personalized mRNA vaccines could cause immense growing pains for our analytical development colleagues in particular. And, as we’ve begun to learn in the cell therapy space, game-changing efficacy profiles have not always been enough to encourage the healthcare system to turn a blind eye to the challenges of manufacturing and reimbursing personalized therapies.
Obviously, every cell therapy and personalized RNA therapy company is dedicated to overcoming these manufacturing/logistics challenges in the long-term — CureVac included. However, though personalized approaches have proven to be therapeutically revolutionary thus far for certain patient populations, Zehnder also acknowledges another important truth: The personalized approach may not always be therapeutically necessary for each oncological indication.
“Personalized mRNA vaccines are the holy grail,” he acknowledged. “But at CureVac we’re exploring a dual strategy because for some oncology patients, speed is of the essence. You cannot wait six to eight weeks to produce a personalized cancer vaccine. So, we’ve spent a lot of time identifying which oncology indications would be best suited for a personalized approach, and which might be best for an off-the-shelf shared antigen approach.” For example, while tumors for certain cancers like adenocarcinoma can be quite heterogenous, there are also cancers — such as glioblastoma or squamous non-small cell lung cancer — in which different patients’ tumors share many of the same antigens.
“We don’t believe adenocarcinoma would be a good target for a shared antigen vaccine because there isn’t enough overlap in antigens across the patient population,” Zehnder clarified. “Adenocarcinoma would likely be a better target for a personalized cancer vaccine because these tumors are quite heterogenous.”
It goes without saying we’re still facing a steep scientific learning curve in the mRNA therapeutics space. Translation and delivery challenges necessitate our increased understanding of how each cell makes its decisions. Likewise, there’s a lot we still need to understand about each tumor we’re targeting with a neoantigen vaccine. As one expert shared at a conference last year, neoantigen prediction/selection is one of the most challenging steps for companies working on mRNA neoantigen vaccines. Aligning with the regulatory agencies over which antigens should be targeted or excluded is also no mean feat.
Zehnder elaborated more on this complexity, pointing to the fact that many of the neoantigen vaccines being explored today are encoding between 10-20 antigens. However, there’s still much to be learned about how our mRNA products “work”. Over time, we may be able to whittle down the number of antigens we’re encoding in our mRNA neoantigen vaccines as our knowledge about how they engage the immune system becomes more sophisticated.
As Zehnder concluded: “A long-term question we must answer as a space is: How many antigens do you truly need to encode to provoke a meaningful clinical response? Maybe it doesn’t need to be 10 or 15 antigens; maybe two to four will be enough for a neoantigen vaccine to be clinically meaningful. But before we can answer that question, we need to spend more time figuring out how to choose the right antigens.”