Personalized mRNA Cancer Immunotherapies: Closing The Biological Knowledge Gap

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

We’ve been saying for years that personalized cancer vaccines are going to be the bridge carrying mRNA from the land of infectious diseases to the realm of therapeutics. Given Moderna’s latest news, it would seem we’re well on our way to making this a reality.

As such, it was a great honor to take Advancing RNA on the road to London to CPI’s/BIA’s/Imperial College London’s RNA Vaccines & Therapeutics Conference to moderate a discussion on personalized cancer immunotherapies with the Cancer Vaccine Launch Pad’s Dr. Lennard Lee; Wellcome Leap’s Parker Moss; MHRA’s Andreea Iftimia-Mander; and CPI’s Juliana Haggerty.

When deciding how I wanted to frame my takeaways from this panel discussion, I was drawn to a quote from Dr. Lee: “If you want to feed a family, give them a fish. But if you want to empower them — in this case, if you want to empower the entire cancer research system in the UK to advance across the world — you need to give them a boat and a fishing rod.”

In the following two-part article, I’ll share the advancements (the “boats” and “fishing rods”) needed in two areas — biological knowledge and manufacturing — to ensure we’re capable of meeting patients’ needs in the personalized sector. After all, as CPI’s Haggerty emphasized, there’s a lot at stake. “If we just do the same thing as cell therapies, then we’ve failed; if these products are only available to a handful of individuals, then we haven’t done enough.”

The Great Information Challenge: Unpacking Divergent Clinical Outcomes

It seems every conversation I embark upon is underwritten by the truth that biology is a vexing mistress — and this conversation at the RNA Vaccines & Therapeutics conference was no exception. Whether it be analytical or clinical, we have a long way to go before we fully understand which of our measurements tie back to a drug’s biological activity and why some of our mRNA medicines boast different outcomes.

“I think one of the biggest gaps that still remains is evidence integration and measurement confidence,” the MHRA’s Iftimia-Mander explained.” We still don’t understand why different medicines have different outcomes. We have more and more measurement methods — cool analytical tools that the industry is developing. However, we’re still not sure how to interpret the resulting data. For me, the million-dollar question is: Which of these critical quality attributes correlate directly to biological activity and how do they link to safety profiles?”

We don’t have to search too hard to see a great example of two mRNA products in the same class demonstrating strikingly different results. Over the past few weeks, we’ve been celebrating the news of Moderna’s success in melanoma while also scratching our heads over the failure of BioNTech’s candidate in colorectal cancer.

“When I talk to people in the industry and ask why Moderna’s candidate succeeded and BioNTech’s failed in colorectal cancer, no one has a clue,” Wellcome Leap’s Moss explained.

There are, of course, many potential hypotheses beyond why this was the case — some of which tie back to the nuances of tumor biology. Perhaps the most common reason circulating is about the differences in tumor type, with melanoma being a “hotter” tumor type — or one more easily recognized and accessible by the immune system — compared to “colder” colorectal tumors.

It’s also important to note that BioNTech’s product was given as a monotherapy without an immune checkpoint inhibitor, the addition of which keeps tumors from suppressing critical T-cell activity. In fact, as one expert once expressed to me in a previous panel discussion, we’re a long way from a stand-alone mRNA in oncology; combinations may be one of the most important tools we have at our disposal today to make mRNA a stronger player in oncology today.

As Moss went on to outline, other variables like differences in neoantigen prioritization, UTR optimization, LNP blebbing, LNP age, and manufacturing turnaround time could all be at play here, as well.

“There are so many variables that we have to factor in,” he said. “It’s a big information challenge to answer. I can’t see any one organization getting all that data in one place to solve this problem. There’s going to have to be an industry-wide effort to get the data together so that one day we can have a model where we plug in the ideal properties for each medicine (e.g., target cell type, immunogenicity profile, transfection levels, etc.) and it will tell you which formulation and adjuvant will be most successful. But we’re a long way from that.”

In the meantime, Moss emphasized that some of the work ahead of us in the cancer immunotherapy space is to improve our neoantigen prioritization. We ultimately want to arrive at a better understanding of which neoantigens are eliciting the most powerful T-cell responses, and why some of them consistently escape the immune system. Many vaccines today encode 30-40 neoantigens at a time. Though this may seem like a lot, it is a tiny number compared to ~10^8 search space of potential cancer antigens. As such, we need a much more rational design process that will help therapeutic vaccine designers make better and more rapid choices to improve turn-around-time before patients’ tumors evolve.

A design approach that would be particularly helpful in cancer vaccines is a design-make-test-learn loop. In this approach, a molecular design is tested on assays, and the success and failure results feed into algorithms that improve the next iteration of design. If we were to cater this specifically to a personalized medicine, Moss pointed particularly to Elispot analysis, in which a patient’s T-cell responses to vaccine peptides are measured, generating feedback that could improve algorithms selecting targets for future patients.

“In an ideal world, a neutral third party could host a platform like this to help patients and clinicians select the best neoantigen vaccine for their particular immune profile,” he explained.

If there is one thing to take away from where we are today, it’s that we’re clearly in the “foothills” of the cancer vaccine breakthrough. However, Moss remains optimistic.

“The challenge has been laid down, and there are great scientific teams all around the world that will be working on keeping patients in remission from this emperor of all maladies,” he concluded.

Stay tuned for part 2, in which CPI’s Haggerty outlines some of the biggest gaps we’re facing in the manufacturing sector.