The Journey to a Personalized Vaccine: Dr. David Braun on Neoantigen mRNA Therapy in RCC

In this three-part series, Katy Beckermann, MD, PhD, of Tennessee Oncology, speaks with David Braun, MD, PhD, of Yale Cancer Center, on his Nature publication on a neoantigen vaccine that has demonstrated the ability to generate antitumor immunity in RCC.

In this segment, they highlight the logistical and biological considerations that influenced the trial design, the complexities of manufacturing and regulatory approval, the critical role of a multidisciplinary team in antigen selection and peptide synthesis, and the remarkable commitment of patients who underwent extensive procedures to advance the science, all while emphasizing the potential of such vaccines in the minimal residual disease setting.

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Dr. Beckermann: Congratulations on your Nature paper and this tremendous undertaking. It involved so many co-authors, so much incredible science, and so much and correlative research. I wanted to take some time today to learn more about what it took to make a trial like this happen, the key insights you gained, and where you see this work heading next.

Dr. Braun: This has been a project that took many years. We even have the vaccine anniversary marked on our calendar—it falls just a day away from our wedding anniversary—so it is something that has truly stayed with us for a long time. It has been incredible working with such an amazing team to see this project through.

Dr. Beckermann: To start, when you were developing the trial, you created a personalized cancer vaccine for patients at high risk of recurrence. Why did you feel that was the best place to start? Was it primarily logistical, or was there a strong biological rationale?

Dr. Braun: In reality, it was mostly logistically driven, but in hindsight, there is biological reasoning that supports it. At the time, this was a homegrown operation. We were not working with a company; it was just us shuttling tumor tissue back and forth, getting it sequenced. We had a team conducting mutation calling, and we would gather in a room for what we called the epitope selection board. Initially, we met in person, but during COVID, we transitioned to Zoom. We would spend hours reviewing every mutation, every antigen prediction, and debating how to prioritize them. Then, of course, we had to arrange for manufacturing, sterilization, and all the necessary regulatory steps.

That entire process took about 12 weeks on average. We had to consider the right clinical setting for this approach. When we began, adjuvant pembrolizumab had not yet been approved, so there was an unmet clinical need. At the same time, this was not a scenario with rapidly progressing metastatic disease, so we could afford to take 12 weeks to create and administer the vaccine.

In hindsight, we may have been fortunate with our timing. Vaccine studies have been conducted for years, including neoantigen vaccine trials in metastatic settings. While not a formal comparison, the studies that have shown success, particularly in melanoma with the V940 Moderna-based mRNA vaccine and the work from Memorial Sloan Kettering with Dr. Vinod Balachandran’s collaboration with BioNTech, have focused on the minimal residual disease setting, after surgical resection when only microscopic metastatic disease remains. That appears to be where vaccines have shown the most activity. Treating bulky macroscopic metastatic disease has been more challenging.

Looking ahead, while vaccines may still have potential in the metastatic space, I believe the optimal place to start remains the adjuvant setting.

Dr. Beckermann: You mentioned that the process took 12 weeks and required extensive teamwork. Did you face challenges in recruiting and enrolling patients for the trial? Additionally, with 40 co-authors, I know a great deal of effort went into the science, but what did it take to launch and coordinate everything?

Dr. Braun: There were significant challenges at every stage. The regulatory component was immense: getting the Investigational New Drug (IND) applications filed and approved, arranging contracts to manufacture peptides in a GMP-compliant facility, coordinating with the pharmacy for sterilization and organization. Once the tumor was resected, we had to determine who would handle it at each step: who would conduct pathology reviews, second looks, mutation calling, and antigen prediction. Then, when we met for the epitope selection, the team included not only clinicians and biologists but also peptide chemists, each contributing expertise I had never considered before. For example, a promising peptide target might be impossible to synthesize due to technical reasons or might precipitate in solution, rendering it unusable. These were all crucial factors that made working with this team so rewarding.

From the patient perspective, I was continually amazed by their dedication. We sought to learn as much as possible, which meant a significant commitment on their part. The study required frequent and large-volume blood draws, including leukapheresis before and during vaccination, to collect enough immune cells for analysis. In addition to using their tumor tissue, we performed skin biopsies at the vaccine site to assess local immune responses and conducted delayed-type hypersensitivity analyses to isolate vaccine-reactive T cells. Despite the intensive protocol—numerous injections and blood draws—patients participated with enthusiasm. Their willingness to contribute was inspiring. Of course, our primary focus is always their individual well-being, but many were genuinely excited to be part of something larger, helping to advance the field. That level of engagement was unexpected but deeply meaningful.

Dr. Beckermann: That is truly remarkable. I am constantly reminded that, while we strive to push the science forward and make meaningful discoveries, it is always about the people we serve. None of this would be possible without these incredible patients who are willing to help us make progress.